NIHRDataInsights/HRCSData huggingface dataset:
Title: Can a system intervention employing team-based case review help improve quality and safety of paediatric hospital care in Kenya?
Funder: Wellcome Trust

Abstract: In Kenya 6% of children admitted to hospital die, a figure many times higher than developed countries. Severe illness and co-morbidity underlie many deaths and require a coordinated response from health-worker teams to deliver multiple interventions safely across admission periods of several days. This can expose many team and system weaknesses that need to be addressed to improve outcomes. I will build on prior work in Kenya to: 1. Comprehensively describe quality and safety concerns, avoidable mortality, their relationship with case severity and case complexity and the changing epidemiology of care in multiple Kenyan county hospitals 2. Co-design the tools and procedures that enable multi-site, team-based case review (TCR) to diagnose and tackle inpatient quality and safety concerns locally and at scale 3. Test if intervention can reduce the frequency of modifiable factors that undermine quality and safety of hospital care and reduce potentially avoidable mortality 4. Undertake empirical work to refine a theory of change supporting a detailed process evaluation and critical exploration of mechanisms of intervention effect spanning individual providers, teams, organisations and institutions This work will be a major contribution to the field of quality and safety in Africa and help develop scalable improvement interventions.

Lay abstract: Many more children die in Kenyan hospitals than in richer countries, often from treatable illnesses. Preventing deaths in very sick children requires health-workers to act effectively as a team to initiate correct care rapidly and sustain good care over time. When teams do not or cannot act effectively mistakes can be made and children may not receive what they need. I aim to: 1. Develop an approach with Kenyans that helps healthcare teams reflect on events surrounding a child death in hospital and identify what and how work needs to be changed 2. Test the effect of the approach developed by comparing improvements in care in hospitals that use this approach and those that don’t and see how it is actually delivered 3. Develop a model that helps us think through how generating and sharing the insights from reviewing deaths might change how teams, local and national managers and experts in child health act to improve care 4. Use the findings to understand what the major problems in providing care to sick children are and how these might vary across patients, time and place Work aims to enable health systems to providing continuous, safe care in countries like Kenya.

Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: Molecular Dissection of Conjugative Transport in Gram-negative Bacteria
Funder: Wellcome Trust

Abstract: Type 4 secretion (T4S) systems mediate transfer of DNA from one bacterium to another in a process called "bacterial conjugation". As a result, T4S systems are crucial players in the spread of antibiotic resistance among bacterial populations. They also mediate secretion and injection of protein effectors into eukaryotic host cells, and therefore, are important virulence factors in bacterial pathogenesis. This proposal focuses on conjugative T4S systems in Gram-negative bacteria. Conjugation starts with the processing of the DNA at a defined site called the origin of transfer (OriT). This processing step is executed by a large complex called the relaxosome, containing a protein called the "relaxase", and several accessory proteins. During processing, the relaxase nicks and covalently attaches to the DNA and it is this ssDNA-protein conjugate that is transported through the T4S system. Prior to transport, donor and recipient cells come together to form a conjugative junction. Our research goals are the following: i-determine the structure of the relaxosome bound to OriT; ii-trap the ssDNA-protein conjugate within the T4S machinery and solve the structure of this substrate-trapped system in order to elucidate the secretion path; iii- investigate the structure and architecture of conjugative junctions between donor and recipient cells.

Lay abstract: The spread of antibiotic resistance genes among bacterial pathogens has become a key public health issue, causing thousands of untimely death in the UK. One important means by which these genes propagate from one bacterium to another is through bacterial conjugation, the process by which DNA is transferred from a donor cell to a recipient cell. This process is mediated by a large macromolecular pump (or secretion system) embedded in the membranes of donor cells and called a "type 4 secretion (T4S) system". Conjugation starts with the processing of the DNA by a large complex termed the relaxosome. It is followed by donor and recipient cells coming together to form tight conjugative junctions. This is followed by transfer through the T4S system. We aim to elucidate the mechanism of each of these steps in order to provide the basis of designing inhibitors of bacterial conjugation.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: Forensic epidemiology and impact of substandard and falsified antimicrobials on public health
Funder: Wellcome Trust

Abstract: Substandard and falsified (SF) antimicrobials are a massive but underappreciated global health challenge in great need of innovative research to inform interventions. We will build on our collective pioneering research, to construct an innovative, multidisciplinary research hub that will improve understanding and inform global policy and action. Leading specialists investigating illegal wildlife trade, forensic genomics and chemistry, social network analysis and modelling, will work together to answer two main aims: 1. How can innovative forensic tools be used to identify sources and trade routes? How can novel genomic (‘pharmabiome’), chemical and isotopic analysis with social network techniques be used to characterise the epidemiology of SF antimicrobials to inform policy and action to improve our global pharmaceutical supply quality? We will conduct high-throughput sequencing and novel chemical analysis of falsified and genuine antimicrobials to determine their comparative pharmabiome/chemical spectra, followed by social network analysis of origins and trade routes. 2. What are the public health impacts of SF antimicrobials? What are the modelled impacts of SF antimicrobials on patient outcome, global public health, especially engendering antimicrobial resistance and how can these be minimised? Using a One Health approach, which pathogen-antimicrobial pairs are at greatest risk of SF antimicrobials?

Lay abstract: Poor quality medicines (falsified, aka counterfeit, and substandard) for treating infections are a massive underappreciated global health challenge in great need of innovative research informing interventions. We will build on our collective pioneering research, constructing an innovative, multidisciplinary research collaboration, improving our understanding and informing global policy and action. Leading specialists investigating illegal wildlife trade, forensics, social network analysis and modelling, will work together to address two main aims: 1. How can innovative forensic techniques be used to identify falsified antimicrobial sources and trade routes? We will compare signatures of trace DNA found in tablets and chemistry of falsified, substandard and genuine antimicrobials to determine their characteristic signatures, combined with social network analysis to illuminate their origins and trade routes. 2. What are the public health impacts of poor quality antimicrobials? What are the impacts of poor quality antimicrobials on patient outcome, global public health, especially antimicrobial resistance?

Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: An advanced cryoEM instrument for the University of Cambridge
Funder: Wellcome Trust

Abstract: We seek support to consolidate an advanced electron cryo-microscopy (cryo-EM) facility dedicated to structural studies of biological macromolecular assemblies. The facility would provide a revolutionary new tool to the large structural biology community in the University that would enable acquisition of critical data in support of a wide and diverse range of projects tackling fundamental problems in molecular biology relevant to human health. Currently, the named applicants primarily use X-ray crystallography to study large assemblies, but many of these samples cannot be readily crystallised. The recent development of a new generation of direct electron detectors, together with sophisticated data-processing software, has dramatically improved cryo-EM analysis, which now achieves routinely sub-nanometer resolution. Until recently, researchers in the university did not have access to cryoEM, but this has changed with the recent Wellcome Trust award to purchase a cryo-EM instrument for sample screening and intermediate resolution structure determination. We are building on this support, to develop the second phase of our strategy and seek funding for an advanced microscope capable of high resolution structure determination to complement and extend our existing instrumentations.

Lay abstract: The development of new methods to examine the structure and assembly of biological molecules has underpinned major conceptual advances in our understanding of life, from the basis for genetic heredity to the origins of dysfunction in complex diseases. For more than half a century, X-ray crystallography and NMR spectroscopy have been the main tools for elucidating the detailed structure of biological molecules at the atomic level. The challenge in the future is to understand how the molecules interact to form larger macromolecular assemblies in the cell and how aberrant assembly processes can result in disease. Large, dynamic assemblies are very challenging to study by X-ray crystallography and NMR, but in the last few years advances in electron microscopy have made it a powerful method to elucidate the structure of complex assemblies at near atomic resolution. Numerous researchers in the University will use the new electron microscope facility, and new computational approaches to process EM data, to elucidate the structure of key biological complexes. The biological processes studied are very diverse, but each of the studies will help to advance fundamental science by understanding the structure of biologically important assemblies and thereby the molecular basis of many different diseases.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: A London consortium to establish a high resolution cryo-electron microscopy facility for research and training
Funder: Wellcome Trust

Abstract: With the recent revolutionary advances in electron cryo-microscopy (cryo-EM), made possible largely by state-of-the-art microscopes (the Titan Krios), direct electron detectors and data processing, it is becoming realistic to determine atomic resolution structures of macromolecules using cryo-EM. Indeed, cryo-EM is the only method available for structural determinations of many large proteins and complexes that are difficult to produce or of transient, dynamic nature. Recent examples demonstrate that cryo-EM can be used to study proteins as small as 150 kDa and achieve resolution better than 2 Å, making cryo-EM potentially the leading methodology for most structural biology projects. London has the highest concentration of structural biologists in the UK, but to date the only Krios instruments are due to be installed at the Francis Crick institute for the sole usage of the large number of Crick-affiliated researchers. Consequently, the majority of London researchers have no rapid or local access to a Krios setup, significantly affecting our international competitiveness. The London consortium for cryo-EM (LonCEM) brings together researchers from Imperial College London, Institute of Cancer Research, Kings College London and Queen Mary University London and proposes to establish a high-resolution cryo-EM facility to enable excellent research, collaborations and training.

Lay abstract: With the recent revolutionary advances in electron cryo-microscopy (cryo-EM), made possible largely by state-of-the-art microscopes, direct electron detectors and advanced data processing, it is becoming realistic to resolve structures of macromolecules using cryo-EM. Indeed, cryo-EM is the only method available for structural determinations of many large proteins and complexes that are difficult to produce or of transient, dynamic nature, which form key players in many important biological processes. Structural information is crucial for our understanding of how these biological systems work and for rational drug discovery. London has the highest concentration of structural biologists in the UK, but to date the majority of London researchers have no rapid or local access to a Krios setup, significantly affecting our international competitiveness. The London consortium for cryo-EM (LonCEM) brings together researchers from Imperial College London, Institute of Cancer Research, Kings College London and Queen Mary’s University London and proposes to establish a high-resolution cryo-EM facility to enable excellent research, collaborations and training.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: Evolutionary basis of human diseases in western Eurasia: Insights from ancient genomics
Funder: Wellcome Trust

Abstract: Although large differences in disease susceptibility among present-day human populations have been widely reported, their evolutionary underpinnings remain poorly understood. This project aims to examine how, and to what extent, pathogens shaped disease susceptibility among present-day western Eurasians. We will use whole-genome sequence data from ancient humans and their pathogens to identify novel human genetic variants targeted by past selection, and catalogue novel pathogen variability, including that of now-extinct lineages. Next we will reconstruct the evolutionary history of these newly identified variants and lineages, along with those already known to be associated with disease susceptibility in present-day populations. Finally, we will uncover new associations between human genetic variants and infectious diseases. The focus will be on the last 10,000 years of human history, which encompass some of the greatest changes in our lifestyle, including the agricultural revolution, first known epidemics, and early urbanisation. The proposed study will provide fundamental insights into the evolutionary basis of disease susceptibility in present-day human populations, as well as the evolution of human pathogens. These findings will inform future experimental and clinical research, impact upon current and future healthcare strategies, including the design of diagnostic tests and drug development, and improve global pathogen outbreak monitoring.

Lay abstract: There is notable variation in health status and disease susceptibilities among worldwide human populations. However, the evolutionary underpinnings of this variation remain poorly understood despite their importance to assessing and, subsequently, addressing disease risk in an increasingly complex world. Our project aims to address this knowledge gap through the investigation of past demographic, selective, and epidemiological processes that shaped the present-day genetic profile of western Eurasians, using genomic data from ancient humans and their pathogens spanning the last 10,000 years. We aim to clarify the evolutionary histories of western Eurasians and their pathogens, and evaluate their impact on the health status and disease profiles of the present-day populations in the region. The proposed work has the potential to inform current and future healthcare strategies, including pathogen surveillance and vaccine, diagnostic, and drug development.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: A platform for drug target deconvolution and exploitation
Funder: Wellcome Trust

Abstract: The University of Dundee Mode of Action(MoA)group works on finding and confirming the molecular targets of compounds that have biological activity against a variety of different pathogens. The MoA group hasa toolbox of multipleorthogonaltechnologiesto undertake this work. They will be working with the Wellcome Trust HIT-NTD Flagship to determine the mode of action of compounds coming from the drug discovery programmes supported by Flagship, includingthose inleishmaniasis, Chagas’ disease, cryptosporidiosis and schistosomiasis. In addition,they will undertake some work on characterising novel molecular targets identified through this work. The project will be led by Dr Susan Wyllie and Prof Ian Gilbert and colleagues in Dundee. The Dundee MoA team will work in collaboration with Prof Karl Hoffmann at the University of Aberystwyth and Prof Rolf Muller at the Helmholtz Institute in Saarbruken.”

Lay abstract: The Mode of Action (MoA) group was established 4 years ago, funded by a Wellcome Strategic Award (2015-2020). The group now effectively underpins the kinetoplastid drug-discovery programmes within the Drug Discovery Unit (Wellcome Portfolio Award, 2017-2022) and also works with multiple academic groups and key stakeholders in NTD drug discovery. The group is focused on determining the MoA and/or molecular targets of compounds that are phenotypically-active against kinetoplastids. We have now developed an integrated drug target deconvolution strategy, employing a matrix of established and new methodologies encompassing high-throughput genetics, cell biology and chemical proteomics. This multi-disciplinary approach to target deconvolution has proven extremely effective, with the molecular targets of 20 compound series identified to date. Information emanating from these MoA studies has been invaluable in guiding anti-kinetoplastid drug discovery programmes. In our new programme of research, our overarching objective will be to support the drug discovery activities of the Wellcome HIT-NTD Flagship. To enable this principal objective our key aims will be to: • Source phenotypically-active molecules at various stages of development for target deconvolution studies • Identify novel and exploitable drug targets, by accessing new chemical space followed by target deconvolution • Develop new genetic, cell-based and chemical proteomics tools to expand MoA scope • Undertake detailed functional studies on selected, high-value drug targets • Expand our studies to include drug target deconvolution in other pathogens, initially Cryptosporidium and Schistosoma • Develop a suite of target-specific tools including: detailed protocols for protein expression, assay development and structural information to facilitate drug-discovery against new targets

Research activity codes: 5.1 PHARMACEUTICALS
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: The Imperial Immunity, Inflammation, Infection and Informatics (4i) Clinician Scientist Programme
Funder: Wellcome Trust

Abstract: Our aim is to develop the clinical academic leaders of the future. The clinician scientist, through education and training in both biomedical science and clinical medicine, is uniquely positioned to develop key insights and identify knowledge gaps between biomedical research and clinical practice. The Imperial Clinician Scientist programme focuses on the academic strengths of the College that are relevant to major health problems: Immunity, Inflammation, Infection and Informatics. The Imperial Immunity, Inflammation, Infection and Informatics (4i) programme will offer an unparalleled and comprehensive portfolio of high quality internationally competitive research fellowships. We have shaped our scheme to enable ‘early career success’ by placing talented individuals in a highly supportive environment and providing each individual with cutting-edge research projects under experienced supervision and mentorship. We propose to train a cohort of 6 clinician scientists per year across Imperial College and the embedded Medical Research Council Clinical Sciences Centre. Through eleven joint appointments and satellite laboratories with the Francis Crick Institute, our programme can offer training opportunities within this inter-disciplinary biomedical research institute. There is also the opportunity of training in the Lee Kong Chian School of Medicine, which is jointly managed by Imperial College and Nanyang Technological University, Singapore.

Lay abstract: No Data Entered

Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: Dundee Training Programme in Integrated Molecular, Cellular and Translational Biology
Funder: Wellcome Trust

Abstract: The proposed programme reflects the vision of University of Dundee to drive social change locally and transform lives globally through the creation, sharing and application of knowledge. A diverse cohort of students will flourish in a culture of excellence, developing research skills and attaining competencies in leadership, management and communication. They will experience world-leading life sciences research in a first-class training environment, with excellent core facilities and well-funded research groups, whilst enhancing research outputs with their energy and innovation. Students will participate in multidisciplinary research in Cellular Regulation, Protein Modification, Infection and Immunity and Drug Discovery and Translation. The flexible PhD programme will provide structured training in experimental design, data handling and processing, basic bio-computational skills and ethical standards in scientific research. By the end of year 1, students will have selected their research project and will have 3 years to consolidate their core bioscience skills, carrying out and documenting their research. There is the option for a career enhancement placement in year 3, while year 4 will support students in career choices and thesis submission. After thesis submission, flexible funding may be used to facilitate paper writing/completion or allow students to undertake a project in our Drug Discovery Unit.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE;INFECTION