NIHRDataInsights/HRCSData huggingface dataset:
Title: Charting the molecular logic of embryonic blood formation at single cell resolution
Funder: Wellcome Trust

Abstract: During development, the cells of an embryo divide and gradually specify towards mature cell-types. This process of cell-type specification is incredibly complex and is regulated via a multitude of underlying layers. Ultimately, the identity of a cell is determined by which genes are actively expressed in that cell. Some genes, termed transcription factors (TFs), are important regulators of the expression of other genes. Understanding the precise role of TFs and how networks of TFs change during cell-type specification is important to understand how similar cells can give rise to vastly different mature cell-types. In this project, I will investigate the role of important TFs on the format of embryonic blood, one of the first cell-types to be specified. To do this, I will knock-out (KO) specific TFs using genetic perturbations, and measure the effect on blood formation in the developing embryo at a single-cell resolution. Additionally, I will aim to determine where on the DNA these TFs bind when there is no KO, as this is another important indicator of their function. Together, this will give insight into the role of important TFs and how changes to TF networks underlie cell-type specification during early embryonic blood formation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Investigating genetic architecture of extreme and unexpected phenotypes using phenotype prediction in the UK Biobank
Funder: Wellcome Trust

Abstract: Genetics underpins variability in observed traits. While many people study the genetic effects driving phenotypic variation for the general population, I am interested in using data from the UK Biobank1 to study the genetic effects responsible for the rare individuals with outlier phenotype measurements. I will consider two types of phenotypic outliers: 1. An individual whose measured trait is at an extreme end of the cohort-wide distribution. 2. An individual whose measured trait differs significantly from the trait expected based on their genetic predisposition. To identify this type of outlier we start by predicting the expected phenotypes. We will use both existing methods for phenotype prediction using genetics or family history of disease, and develop a novel method trained on data from the ALSPAC dataset7. Using these definitions, we will determine outliers for all heritable and commonly measured phenotypes across ancestry groups. We will seek to discover associations between outlier status and genetic variation, outlier status for other phenotypes, sex, age, and ancestry. I expect this work to improve our understanding of the genetic basis for outliers, lead to an understanding of ancestry-dependent diagnosis patterns, explain why some existing phenotype prediction methods perform poorly, and inform future phenotype prediction methods.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Focussing on biomedical discovery in the north-East of England: A high-throughput/high-content live imaging system for cells, tissues and small model organisms
Funder: Wellcome Trust

Abstract: The Flow Cytometry & Imaging Facility, Leeds Institute of Medical Research, needs to expand capability and capacity for live cell and high content imaging (HCI) to serve the local and wider scientific community. We request part-funding of a LIPSI high content/multichannel live-cell imager with environmental control (Nikon Instruments UK Ltd). The acquisition of a state-of-the-art LIPSI will replace our obsolete Operetta and Incucyte instruments and will transform our Facility by allowing fully integrated, automated, high-throughput, and high-content/live-cell imaging. The system allows very rapid epifluorescence (six simultaneous fluorescence channels), chromogenic and DIC acquisitions whilst running multiple time-lapse assays with sampling rates up to 60fps. This allows imaging of long-term live-cell 2D/3D cell cultures, tissue sections, small model organisms or rapid HCI of fixed cells. For increased throughput, the LIPSI includes motorised stage, robotic handler and environmentally-controlled plate-holder. This enables streamlined automated processing of multiplexed long-term live cell functional assays, with complex imaging schedules in both hypoxic and normoxic environments for up to 20 plates. Standard acquisitions comprise multichannel, time-lapse, multiple-positions, z-stacks, large images and multidimensional imaging using standard plastic or glass SBS plate, dish and slide formats used within the Facility.

Lay abstract: imaging (HCI) at the University of Leeds. HCI of cells is used in biological research and drug discovery to assess specific characteristics or behaviours (“phenotypes”) of cultured cells. Microscopical imaging measures visual features such as cell shape, cellular organization, the location of specific proteins within the cells, or the changes in these features over time. This equipment will hugely automate the analysis of these visual features in components of cells, whole cells, complex tissues (“spheroids” and “organoids”), patient-derived clinical specimens and even small animal models of human disease. The research enables rapid and opportunistic discovery science in an exciting range of basic biomedical research, as well as translational research for patient benefit, using a system that is affordable, exceptionally versatile and easy-to-use. The popularity of HCI means that the equipment will be used at full capacity.

Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Understanding the social determinants of outcomes important to older people at the end of life: reducing social inequality in palliative care
Funder: Dunhill Medical Trust

Abstract: Aim To understand the relationship between old age, social disadvantage and health outcomes at the end of life, in order to inform effective health policies targeted at reducing social inequality in palliative and end of life care. Objectives a) To identify and review existing evidence on the effect of socio-economic factors on place of death and other end of life outcomes important to older people. b) To investigate the interrelationships between old age, socio-economic factors and place of death using secondary analysis of nationally representative longitudinal cohort data. c) To explore the relationship between social deprivation and patient centred outcome measures in older adults receiving specialist palliative care, using prospectively collected clinical data.


Research activity codes: 7.2 END OF LIFE CARE;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Exploring Everyday Ethics in Palliative Care in China: A Qualitative Empirical Bioethics Study
Funder: Wellcome Trust

Abstract: Existing research and training in palliative care ethics appear not to focus on, or be tailored to, practice in China. This research aims to fill these gaps by: first, identifying and exploring the ethical challenges Chinese healthcare professionals have confronted during their provision of palliative care; second, identifying the ethical training they have received and the extent to which they feel prepared to address relevant challenges; and, third, proposing changes, for example, to existing training in order to better equip these professionals. The significance of this research includes offering up-to-date knowledge of palliative care provision and relevant ethical training in China, assessing the utility of these training schemes and eventually making insightful suggestions. This is an "empirical bioethics" project, which has three phases (mapping-framing-shaping). The mapping phase involves literature reviews. The framing phase involves qualitative research. The researcher plans to retrieve and thematically analyse empirical data via one-to-one semi-structured interviews. Considering the unique cultural and social background, the data collection will be undertaken in Mandarin in selected hospitals in China. The shaping phase then combines the previous theoretical and empirical findings, using an "empirical bioethics" methodology - reflexive balancing - with a view to making recommendations for future practice.

Lay abstract: How to make an ethical, or morally right, decisions has always been controversial, since everyone has their own moral standards. The provision of palliative care is no exception. In practice, healthcare professionals may encounter conflicts between patients', families' and their moral beliefs of what is best for patients. While this is not uncommon, this experience has not been thoroughly researched yet. In addition, different cultural backgrounds can also result in different conflicts. Currently, most studies focus on the West, and Asian cultures are rather underexplored. Therefore, I plan to investigate how Chinese healthcare professionals experience these conflicts during their practices of palliative care via one-to-one interviews. I will gain empirical knowledge about what these challenges are, if they have been trained to deal with it, and how effective these trainings are. Based on these results, I also expect to make insightful suggestions on its improvement.

Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: GENERIC HEALTH RELEVANCE
Title: Best interests and sufficient benefit: The ethics of hard decisions in healthcare
Funder: Wellcome Trust

Abstract: Patients’ 'best interests' are important in healthcare, but their use faces challenges: 1. Resource allocation: As well as aggregate measurements like population health, healthcare resource allocation should be sensitive to individual patients' claims. The idea of best interests provides limited guidance here, since resource constraints mean we cannot promote everyone's best interests. 2. Value disagreement: Caring for patients who cannot communicate preferences – including infants – often generates fundamental value disagreement between carers and medical professionals over their best interests. My proposal explores whether a principle of sufficiency - the idea that it is particularly important to prevent people from being very badly off - can help. Sufficiency has received renewed attention in political philosophy; my research will build on recent theoretical advances, developing a theory that is responsive and applicable to practical challenges. Goals 3. Systematically outline challenges to best interests and existing work on sufficiency; 4. Generate a novel sufficiency-based approach that can be used in healthcare decisions; 5. Consider challenges and develop recommendations for two related practical issues: resource allocation and the care of critically ill infants; 6. Publish 12 peer-reviewed journal articles; 7. Disseminate research findings via websites and public-engagement activity at Oxford; 8. Host a workshop on the role of sufficiency in healthcare.

Lay abstract: Healthcare decisions often focus on patients' "best interests". This has limits. Many think we should distribute health resources in ways that promote population health, but also respect individual claims. Yet resource constraints mean we cannot promote everyone's best interests. The idea of best interests is also of limited help in cases where people disagree on what is best for critically ill infants, e.g. seeking novel treatments or providing palliative care. My project explores whether the idea of "sufficiency" can help with these challenging decisions by offering a principle of justice that is less demanding than best interests. Sufficiency-based approaches emphasise the moral importance of keeping people above particular thresholds (e.g., the level of autonomy that allows people to make important decisions about their lives). I will build on recent work in political philosophy, developing a novel principle of sufficiency theory that is responsive to the practical needs of healthcare decision-making.

Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: The Animal Research Nexus: Changing Constitutions of Science, Health and Welfare
Funder: Wellcome Trust

Abstract: Animal research remains a controversial public issue. Engagement is too often orientated toward the resolution of a polarized for/against debate taking the form of linear provision of information from specialist to non-specialist. Our programme, which draws on humanities and social sciences approaches to understanding animal research, challenges polarization to create new dynamic cultures of communication. Alongside our academic research, we bring together the diverse stakeholder community, patient groups and publics, to work in partnership with arts and engagement professionals to co-create evolving activities and events which share the complexities and consequences of animal research. Our work is structured around two complementary pathways: 1. Everyday Interventions. Short, mobile, and material activities transported into existing spaces like festivals, museums, and classrooms, provide accessible engagement with animal research. Playful reflection and discussion is engendered through commonplace practices (e.g. games and crafting) to disrupt preconceptions about animal research, prompt conversations, and engage ethical issues. Familiar tactile activities allow animal research to be encountered as relatable ‘everyday’ work without high levels of knowledge (see https://vimeo.com/346172368). 2. Immersive experiences: Bespoke immersive theatre allows participants to enter the world of animal research as the decision makers in an unfolding narrative, guided by actors, to experience the challenges and choices that shape the practice of animal research. The interactive structure allows participant to explore, through group interaction and learning, how scientific and social concerns inform governance and practice of animal research without requiring the need for high level specialist knowledge or necessitating a universal for/against choice (see https://vimeo.com/346172464).


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: GENERIC HEALTH RELEVANCE
Title: Hazardous Hospitals: Cultures of Safety in NHS General Hospitals, c.1960–2012
Funder: Wellcome Trust

Abstract: In recent decades, the 'safety' of patients and staff has become a pressing concern in the British National Health Service (NHS). However, little is understood about how and why these ideas and practices evolved historically, and were spread throughout the NHS. My project, Hazardous Hospitals, addresses this lacuna by exploring ideas and practices around 'safety' in NHS general hospitals from 1960-2012. It analyses the development, promotion and institutionalisation of 'safety cultures': ideas, values and behaviours around safety, as well as the systems and processes which support and sustain them. My outputs will be a major monograph exploring the history and meaning of 'safety' in the NHS, an article in History & Policy, as well as 2-3 journal articles exploring sub-topics, such as occupational health. I ask: 1. What defines the ‘safety culture’ of NHS hospitals? How can these ‘safety cultures’ vary? 2. How was safety in hospitals assessed, and in what ways did it come to the attention of NHS managers and policymakers after 1960? 3. How did NHS managers promote safety among their staff? 4. What role did groups such as patient organisations, safety campaigners and the press play in depicting, challenging and promoting reform of hospital ‘safety cultures’?

Lay abstract: The publication of the Francis Report (2013) into healthcare failures at the Mid Staffordshire NHS Foundation Trust dramatically refocused public and political attention on issues of 'safety' in the British NHS. ‘Safety’ has increasingly occupied the attention of policymakers in recent decades, with hospital managers establishing various systems and processes to protect patients and staff from harm. These include alert systems, policies around patient consultation, and campaigns for preventing harms such as falls and healthcare-associated infections. However, little is understood about how and why these ideas and practices around ‘safety’ in the NHS evolved. My project explores the history of safety in the NHS, highlighting how hospitals have promoted ‘safety cultures’: ideas, values and behaviours which support safety. Drawing upon a rich seam of archival material, and a distinctive methodology which visualises hospitals in a systematic way, my project makes a timely contribution to historical understandings of the NHS.

Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: GENERIC HEALTH RELEVANCE
Title: Wellcome Centre for Mitochondrial Research Enrichment Application
Funder: Wellcome Trust

Abstract: The Wellcome Centre for Mitochondrial Research is committed to effectively engaging with our patients and the wider audiences, putting our patients at the heart of everything we do. Engagement enrichment funding will allow us to carry out strategically aligned and important activities that are additional to those specified within our current strategy. These activities will benefit our research, enhance and enrich our current programme of activities as well as engage and empower a wider cross section of our patient population. More specifically additional funding will help us to further: &bull; ENGAGE patients across the entirety of mitochondrial research that we conduct at the Centre &bull; ENHANCE capacity to enable a culture of effective, focussed and impactful public engagement amongst our researchers and patients &bull; ENRICH and improve diversity and inclusion within our patient community &bull; EMPOWER ourselves and key stakeholders to work smarter by extending and strengthening key partnerships and collaborations to achieve shared strategic aims The result of these enrichment activities will be to enhance trust and empowerment within the mitochondrial disease patient community to engage with the work of the Centre. This in turn will benefit our audiences, our research and provide a lasting impact.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: A modern cryo-EM facility at Imperial College London
Funder: Wellcome Trust

Abstract: Cryo-electron microscopy (cryoEM) is becoming the major tool in elucidating the inner workings of cellular machines. In 1997, Imperial College London, with help from the Wellcome Trust, established the first cryoEM facility dedicated to single particle work in the UK and, through the continuing support of WT, has been an international leading player and centre of excellence in cryoEM. Our current user community has benefited tremendously from this excellent facility. However, equipment in the facility, especially for grid preparation and handling, is in urgent need of upgrading or refurbishment, and is insufficient in capacity. With the successful award of a Titan Krios from the WT (LonCEM) and access to national resources (eBIC), the focus of our facility is shifting from data collection to sample preparation, screening and preliminary data generation. We therefore request funds to upgrade our facilities in terms of grid preparation and screening to maintain competitiveness and embrace new technology development. The proposed upgrades will transform the throughput and quality of our sample preparation providing a state of the art capability allowing us to make optimal use of the LonCEM Krios facility when that comes online (late 2018) as well as other national (eBIC) and international resources.

Lay abstract: In recent years, cryo-electron microscopy has made substantial progress and it is now possible to visualise protein complexes in atomic details. The technical equipment and demand for achieving such exciting results is extremely high and expensive. The Centre for Structural Biology (CSB) of Imperial College London harbours an electron microscopy facility, which was established approximately 20 years ago. Currently, there are four electron microscopes available in the facility and, due to recent developments in high resolution cryoEM, the number of users has started to exponentially rise in recent years. The increased demand, combined with the fact that some equipment requires upgrades or replacement due to its age, requires an upgrade of our sample preparation and screening within the cryo-EM facility. For more information about our projects for which this cryo-EM facility was essential, some recent highlights of our research can be seen here: http://www.imperial.ac.uk/centre-for-structural-biology/research/

Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Cellular and sub-cellular sampling using laser capture microdissection to understand disease mechanisms
Funder: Wellcome Trust

Abstract: We propose a laser microdissection microscope (LMD) system that due to its high precision and contact-free laser technology allows the quickest and safest method of microdissection to extract precisely defined samples comprising intact biomolecules. The sample preparation method allows users to define exactly where to extract tissue from within a tissue section, cultured live cells or embryonic fish larvae. After selection, the specimen is separated from the tissue or cell culture by the laser and subsequently transported into the collection device with a targeted laser pulse. The ability of LMD to select specific cells or sub-cellular structures is enhanced by using infrared laser-based optical trap and tweezers. These tools permit manipulation of cells or particles for extraction, in addition to moving cells, beads or particles in live tissues, without damage, for measuring of tissue stiffness or flow. Extracted samples are processed for downstream quantification using genomics, transcriptomics, microarrays, next generation sequencing, biochips, or proteomics. This will allow users to precisely correlate ‘upstream’ measurements such as imaging of cells or physiological readouts with molecular characterisation, something that is not available to the research community at King’s and presents a key barrier to our research goals.

Lay abstract: Tissues are composed of many different cell types arranged in specific patterns, why it is often necessary to obtain pure samples of the cells of interest for meaningful measurements. Laser microdissection (LMD) is a precise method that uses a laser to cut out specific cells or structures of interest from microscopic regions of tissues/cells/organisms. The ‘cut-out’ material is contamination-free and can then be used for molecular analyses. We are thus able to isolate cells or structures from within whilst recording their position in space and time. Our analyses thus reflect the characteristics of the cells within their natural environment, which other methods cannot. We can also move cells or particles within live tissue or cell cultures without causing damage, and by doing this we can also measure force or stiffness. This technology will enhance our understanding of how cells behave and their characteristics in normal and disease states.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE