NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Epidemiology and outbreak prediction of yellow fever virus
Funder: Wellcome Trust

Abstract: Yellow fever virus (YFV) outbreaks are escalating worldwide despite the existence of a vaccine. Global travel raises the chance that YFV will become established in Asia, where populations are not vaccinated and an outbreak would be catastrophic. Our ability to predict and control YFV outbreaks is reduced by our lack of knowledge about (i) transmission of YFV in its sylvatic reservoir (non-human primates) and (ii) how YFV escapes from this reservoir to spread amongst people in urban areas. Severe under-reporting in both humans and non-human primates hampers our ability to directly study YFV transmission behaviour. Recent advances in portable genome sequencing and virus genomic epidemiology (including phylodynamics) offer new opportunities to use virus genomic data to reconstruct unobserved outbreak dynamics, even when sampling is sparse. I will combine these techniques to improve our understanding of YFV epidemiology, by: (i) integrating viral genomic data into newly-refined YFV mathematical models for improved outbreak prediction; (ii) implementing phylodynamic approaches to identify drivers of sylvatic transmission, and; (iii) exploiting new strategies to generate virus sequences from traditionally neglected times and locations. My Fellowship research findings will improve YFV outbreak prediction and contribute to the development of refined vaccination strategies.

Lay Abstract: Mosquito-borne virus outbreaks are intensifying worldwide. Escalation of yellow fever virus (YFV) is particularly concerning because - despite widespread vaccination - it kills more than other mosquito-borne viruses. Severe under-reporting has prevented deeper understanding of how YFV spreads. We know strikingly little about YFV transmission in its animal reservoir, or how YFV escapes this reservoir to cause large outbreaks of human disease. Recent breakthroughs in virus genome sequencing and analysis offer new opportunities to generate data and reconstruct YFV transmission behaviour from sparsely sampled cases. My goal is to combine and exploit these new approaches to improve our understanding of YFV. I will implement innovative sequencing strategies to more effectively obtain YFV genomes from undersampled populations, and use these data to improve computational models of transmission. My research will identify what drives virus spread and improve our ability to predict and control outbreaks of YFV and other zoonotic diseases.

Research Activity Codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health Categories: INFECTION
Award Title: Epigenetic pathways in healthy aging and neurodegeneration
Funder: Medical Research Council

Abstract: Cognitive decline and dementia are among the most frightening and challenging aspects of aging. Age is the number one risk factor for mental decline although the underlying mechanisms remain unclear. Age and environmental risk factors interplay with genetic risks to impact the predisposition to cognitive impairment. Although most research has focused on the accumulation of protein aggregates that characterize diseases like Alzheimer’s, to date, therapeutics directed to the aggregates have been unsuccessful in clinical trials, highlighting the need to identify pathways that are upstream of plaques and tangles formation, or even new independent mechanisms. The chromatin state, composed of genomic DNA and post-translationally modified histones, is the molecular substrate for the integration of environmental stimuli and genetic instructions into the epigenetic landscape. Epigenetic regulation has emerged as a critical player in aging of lower organisms and, because of its role in integrating environmental stressors into the genome, represents a probable—and therapeutically tractable—player in age-related diseases. My studies on epigenetics of aging brain and Alzheimer’s disease (AD) have revealed that epigenetic plasticity is central to AD, and that healthy aging and AD are distinct epigenetic states. Genome-wide epigenetic analyses in human brain have revealed that different histone marks are differently associated with healthy aging and disease, and that they drive different downstream functional pathways, such as pro-disease (through H3K27ac and H3K9ac changes) and disease protective pathways (through H4K16ac changes) (Nativio et al, Nature Neuroscience 2018; Nativio et al, Nature Genetics; 2020). My overarching hypothesis is that among the molecular changes associated with aging, some are adaptive responses that counteract unavoidable stressful factors—in contrast to changes that favour disease onset. The identification of epigenetic protective mechanisms activated upon stress will be valuable to the design of strategies aiming to prevent, and perhaps treat, age-related neurodegeneration. For the future, I plan to mechanistically interrogate the epigenome to discover chromatin pathways that confer resistance to age-related neurodegeneration and that promote healthy aging. Because of the interplay between environment and genetic risk, I will also investigate the functional relevance of genetic risk variants in the context of epigenetic regulation.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: NEUROLOGICAL
Award Title: Essential ionic triggers for enveloped virus entry
Funder: Medical Research Council

Abstract: To cause disease, viruses must first enter cells and many viruses do this by hijacking the endocytic network by mimicking cellular cargos. Once inside an endosome, a virus is effectively trapped, and must escape to continue its lifecycle. Here, we propose experiments that will provide new understanding of the endosome escape mechanism, based on our exciting new research findings. Viruses escape from endosomes using protein spikes that cover their exterior and mediate the merging of the viral and endosomal membranes (fusion). The spikes respond to chemical signals within endosomes causing structural changes, switching spikes from a pre-fusion to a fusion-active conformation. This allows spikes to interact with the endosomal membrane from the inside, and soon after, fusion occurs allowing the viral genome to enter the cell. How spikes respond to chemical signals is poorly understood, and highlighting this, we recently showed that an important class of viruses known as bunyaviruses require potassium ions (K+) to escape from endosomes. We showed K+ is required to switch spikes from pre-fusion to fusion-active states, which represents a paradigm shift in the understanding of virus entry. In this project, we will examine whether the K+ requirement is a characteristic of the wider bunyavirus group and whether other ions within endosomes mediate similar spike changes. Next, we will use cryo-EM and X-ray crystallography to reveal high-resolution structures of spikes in their pre-fusion and fusion-active conformations. Finally, we will use genetic techniques to identify spike residues that mediate these structural changes. Together these experiments will characterise endosomal fusion triggers and reveal the molecular details of how spikes become fusogenic, which is critical for virus entry. Improved understanding of endosome escape is required to aid the rational design of strategies to block spike fusogenesis; drugs that can do this would prevent infection and disease.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFECTION
Award Title: Establishing a network to catalyse collaboration for reducing immune ageing (CARINA: CAtalyst Reducing ImmuNe Ageing)
Funder: Medical Research Council

Abstract: The CARINA network will actively engage with researchers from different disciplines, and at different career stages, to facilitate re-focussing of their research towards immune ageing and intervention. An initial meeting of the listed individuals will showcase a short summary of their activities (2 slides, 5 mins each). Breakout sessions of different groups will be set tasks to discuss how to deliver each of our aims, which are:  A gap analysis of key research questions  Establish new interdisciplinary partnerships  Assimilate new technology and experimental systems  Explore disciplinary cross-over with immunity Investigate routes for intervention  Widen stakeholder engagement  Each group will summarize their discussions and we will identify key observations that will be collated and sent to the whole network. This identifies initial key areas of potential for integrated expertise and would potentially deliver research impact.   Subsequently there will be a series of online meetings where we will expand our discussions to further pinpoint areas that coalesce research activity towards a new direction for impact on ageing immunity. For these online meetings, we will encourage our early career academics to lead the discussions. A second face to face meeting, within the first 12 months, will use intermixing of discussion groups and structure the discussions around the promising areas for research - gaps that can ideally be met through interdisciplinary studies. Months 12-24 will follow a similar pattern of meetings, the difference being that we will be able to identify areas for interdisciplinary grants by the partners of the network. Subcontracted support from the British Society for Immunology (BSI) is crucial for effective communication and conference delivery and is more cost effective than recruiting a single Project Manager, as many different experienced individuals from the BSI will deliver support for different aspects of the network.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health Categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Award Title: Establishing the role of Staphylococcus aureus RNA-binding proteins in regulating host adaptive responses and antibiotic resistance.
Funder: Wellcome Trust

Abstract: Staphylococcus aureus is a major human pathogen associated with thousands of deaths each year. S. aureus can adapt to survive and thrive inside human immune cells (macrophages) and has developed resistance to multiple antibiotic classes making it a dangerous pathogen.  We hypothesise that S. aureus uses the interactions between proteins and RNA to control the adaptation to surviving inside human macrophages and to avoid being killed by antibiotics.
 
 
 

We will assess how the pathogen changes which proteins are bound to RNA when exposed to environmental challenges including those seen in human infection and antibiotic treatment. We will assess how these changes occur in the whole organism and in specific key proteins. We aim to engineer bacteria which have proteins which can’t properly bind RNA and to see if they are less fit to survive in simulated infection, when infecting human immune cells, in an insect model of infection and when exposed to antibiotic therapy.
 
 
 

The identification of critical pathways involved in the adaptation of S. aureus to the host environment may reveal new therapeutic targets for the control of infection.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFECTION
Award Title: Ethnic inequalities in health care utilisation and care quality
Funder: The Health Foundation

Abstract: The number of people in the UK who are living with multiple long-term conditions (MLTCs) is rising, and those with MLTCs have reduced quality of life and a higher risk of mortality. There is evidence that people from some minority ethnic groups may be at a greater risk of having MLTCs when compared to people from the white majority population.

There is growing evidence of ethnic inequalities in health care, in particular in relation to access to services. However, to date, there has been little evidence uncovered on ethnic inequalities in the prevalence, health care utilisation and care quality for people with MLTCs.

About the project 
The project team will synthesise existing evidence and use nationally representative data to provide an up-to-date description of how MLTCs vary across ethnic groups in the UK.

They will describe ethnic differences in health care quality (including continuity of care) and outcomes (including quality of life and survival) for people with MLTCs, and will provide evidence on these inequalities for policy makers, practitioners and academia.

A combination of survey data and electronic health record data will be used to understand the level of health care need and the differences in each of these data sources.

The project team will describe and appraise the current evidence, make it accessible to interested parties, and identify the gaps.


Research Activity Codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Ethnic inequalities in mortality and service use in people with mental disorders and multi-morbidities during the COVID-19 pandemic
Funder: The Health Foundation

Abstract: There are stark inequalities in the UK mental health care system for people from minority ethnic groups, including poorer access to evidence-based treatments and higher rates of detention. Life expectancy in people with mental disorders is 15 to 20 years lower than the general population, mostly due to preventable long-term physical health conditions – and this is also seen in minority ethnic groups.

The COVID-19 pandemic has magnified these inequalities, with an alarming trend towards higher COVID-19 infections and mortality in minority ethnic groups. Research by King’s College London indicates higher rates of death during the UK lockdown in people with mental disorders.

The pandemic has led to some routine health care being suspended, people being discharged from secondary care and care being delivered remotely. This, alongside people staying away from hospital, may have contributed to higher numbers of deaths in people with mental disorders, possibly with disproportionate impacts on people from minority ethnic groups.

This research project will involve analysing more than 50,000 records from primary and secondary mental health care to assess whether changes to services as a result of COVID-19 magnified inequalities in care pathways, and whether it was associated with more deaths in people with mental disorders and long-term conditions.

With the support of Black Thrive, a partnership for Black wellbeing, 50 interviews will be held with mental health service users across London, Birmingham and Manchester to understand their perspectives.

All recommendations resulting from the research will be co-produced with people with lived experience, informing health care delivery and improving patient safety, as the pandemic continues.


Research Activity Codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health Categories: MENTAL HEALTH
Award Title: Europe PMC 2021-2026
Funder: Wellcome Trust

Abstract: In the next five years, the necessity for open science to solve global challenges will become increasingly apparent, and the need for Europe PMC as a critical piece of infrastructure will crystallise in the minds and usage patterns of researchers. The world of scientific publishing will undergo major changes, as routes for rapid and transparent publishing emerge, and efforts such as Plan S push towards universal open access. Europe PMC will support these goals by aggregating millions of articles and making them widely available. With a leading role in preprint aggregation and standards development, Europe PMC will be the go-to resource for searching life sciences literature from publication through review, revision, and citation. Publications at all stages need to be grounded in unambiguous links to supporting data, authors and reviewers, funding, and institutions, to build transparency and trust in the content; building these links will be a major direction for Europe PMC. Finally, transformative change in content search and retrieval will come from the development of AI methods that work on open access full text, encouraged by the Europe PMC platform for text and data mining, as well as the demonstration of machine learning benefits in user interfaces.


Research Activity Codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: European Variation Archive
Funder: Wellcome Trust

Abstract: The European Variation Archive (EVA, https://www.ebi.ac.uk/eva/) is a primary open repository for archiving, accessioning and distributing genome variation, including single nucleotide variants, short insertions and deletions (indels), and larger structural variants (SVs) in any species. Services to researchers include long-term archiving of variants; calculation of standard variant annotation; and an intuitive browser to query and view variants from studies or across an entire species. The EVA peers with the NCBI-based dbSNP and dbVar databases to form a worldwide network for exchanging and brokering submissions, and to assign permanent study and locus identifiers. As described in this proposal, the EVA will become solely responsible for variant locus accessioning for all non-human species. We will provide access to all of the controlled access variation data in the European Genome-phenome Archive (EGA) in the EVA browser. The EVA will continue leading community standards bodies, including tasks for the Global Alliance for Genomics and Health (GA4GH), to develop data models for variant representation, data formats and APIs for data integration with other resources. EVA’s comprehensive API is extensively used by translational and species-specific resources.

Lay Abstract: The European Variation Archive (EVA, https://www.ebi.ac.uk/eva/) is an open and freely accessible repository for single nucleotide and structural genetic variants from any species. It currently provides access to 520M unique variants across 232 studies containing 322,587 samples from 27 species. The EVA facilitates data access through its browser which allows users to query by study, gene, variant identifier or chromosomal location. Both EVA’s technology and data are used by projects such as H3Africa and Open Targets where they are integrated with project-specific data to improve services for the community

Research Activity Codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Evaluating Health Impacts of Climate Adaptation Strategies
Funder: Wellcome Trust

Abstract: Focus Area 3: Adaptation to climate change   This research will develop a new evaluation tool for sustainable adaptation that will comprehensively incorporate direct and indirect health effects of adaptation interventions. It will explicitly focus on the wider effects of adaptation for the health and socio-economic wellbeing of the most vulnerable populations. The research will integrate insights from climate and hydrological sciences, social sciences, and health and economic sciences of disease burden and well-being.     The evaluation tool will be developed through cross-disciplinary interaction on concepts and methods, and then calibrated through empirical study of existing adaptations, focused on flooding. Flood risk is a prevalent climate impact globally and diverse adaptations currently being implemented globally. New empirical insights into flood adaptation will be generated focussing on three adaptation interventions for: flood infrastructure, planned relocation, and catchment-based planning across Ghana, Ireland, and UK. The project will undertake proof-of-concept evaluations for these interventions to develop the tool, generating specific lessons on flood adaptation and wider lessons on climate change adaptations more broadly.   The research will engage with UK stakeholders and other national and international agencies to ensure the tool, evidence and planned user interface will be policy-relevant for adaptation planning at the global scale.

Lay Abstract: Climate change will have widespread impacts: plans and investments are underway to adapt to those risks. Both climate impacts and adaptive responses have consequences for health and wider well-being.   Is adaptation sustainable? Our answer is that adaptation a) needs to include hidden impacts on health and wellbeing of those affected; and b) ensure that those investing in adaptation judge it in terms of effectiveness, fairness and robustness to future change.   We will develop a tool to help make decisions that meet these criteria. We will test the tool by evaluating different types of adaptations to flood risk that involve building hard defenses, moving people away, or preparing communities to cope and recover.   The project will lead to a) a tool that we will develop alongside agencies that will use it; b) a wider understanding of sustainable adaptation; and c) specific knowledge about the health impacts and sustainability of flood adaptations.

Research Activity Codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health Categories: GENERIC HEALTH RELEVANCE;INFECTION
Award Title: 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
Funder: Wellcome Trust

Abstract: 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.

Lay Abstract: Antibiotic-resistant bacterial infection (ARBI) is an infection caused by bacteria that can stop antibiotic from working against it. This causes people to be sick for longer and increases death risk. Researchers regularly analyze data of bacteria growth by blood culture test. However, in developing countries, those data are rarely analyzed and underuse of blood culture tests could bias the results.  I will evaluate ARBI situation in a tertiary-care hospital in 2015-2018 in Sulawesi, Indonesia. I will analyze large data sets and report parameters representing ARBI situation. Using antibiotic prescription data, I will also evaluate whether the blood culture test is used as often and within the timing as it is recommended and whether the underuse of blood culture test led to ARBI reports bias.   The study results will improve our standings on ARBI and could be used to inform healthcare workers and policymakers for actions against ARBI.

Research Activity Codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health Categories: INFECTION