NIHRDataInsights/HRCSData huggingface dataset:
Title: Impacts of long-term elderly health care funding system reforms on behavioural and health outcomes.
Funder: Medical Research Council

Abstract: In order to carry out the project, a natural experimental approach will be employed by exploiting the exogenous variation in the price of long-term formal elderly care induced by the introduction of policies in Scotland and Germany. The identification strategy involves comparing a group of affected individuals (i.e. treatment group) to another group of otherwise very similar individuals who are not under the influence of the policy (i.e. control group). The econometric specifications that are likely to be used during the project include OLS, probit/logit models as well as single-spell and multiple-spell duration analysis framework. The two policies that will be used for the analysis are the 2002 Community Care and Health Act in Scotland and the 1995 German policy that introduced a universal long-term health insurance system. The Scottish policy enforced that the cost for personal care, which was previously paid by the elderly themselves, be abolished completely regardless of the care settings. This implies that cost incurred for personal care provided in residential care homes as well as individual houses are all covered. Available datasets include Home care, which is collected by Scottish Executive, as well as Scottish Health Survey and Scottish Household Survey commissioned by Scottish government. The German policy introduced mandatory public or private LTC insurances for the entire population of 82 million. 90% of the population belong to the public system and their employers each pay contributions equal to 0.85% of each employee's gross wages or salary. Introduction of long-term care insurance protects individuals from having to face large sum of cost at the end of their lives. Such a system may ensure individuals to accumulate needed care cost throughout their working lives, reducing the potential cost for the government. Datasets for the analysis is German Socio Economic Panel Study is provided by the German Institute for Economic Research.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: New non-paralytic botulinum molecules for the control of pain
Funder: Medical Research Council

Abstract: We have utilized the power of botulinum-mediated neuronal silencing and retargeted the botulinum molecule away from neuromuscular junction but retaining its actions on specific peripheral and central neuronal populations. We recently developed a new protein-linking approach that allows design of re-targeted versions of botulinum neurotoxins thereby opening a way towards meeting the need for acute reversible neuronal silencing. Specifically, the botulinum molecule was split into two halves that were expressed in E.coli as innocuous recombinant parts. Following purification, the two halves were linked together within 30 min. The re-assembled botulinum molecule exhibited the same efficacy on central neurons and brain slices as the native botulinum neurotoxin but had significantly reduced paralytic activity. Our results suggest that the new botulinum versions can provide a unique tool in probing CNS functions and blocking excessive neuronal activity in chronic pain conditions. We propose to fully evaluate the non-paralytic botulinum molecules in various pain models and develop new neuropeptide receptor-directed versions for dissecting neuronal circuits responsible for generation and maintenance of chronic pain. We will use synthetic chemistry to derive new molecules, in vitro tissue culture screens for selective uptake of conjugates coupled with immunohistochemical identification of different types of neurons and assays to measure release of neuropeptides. We will then translate this information to inflammatory and neuropathic pain models and record efficacy after peripheral or central application of botulinum constructs using behavioural analysis of mechanical and thermal sensitivity.


Research activity codes: 1.3 CHEMICAL AND PHYSICAL SCIENCES
Health categories: GENERIC HEALTH RELEVANCE
Title: Machine Learning - Early Warning System (ML-EWS)
Funder: Medical Research Council

Abstract: Serious adverse events (SAEs, such as cardiac arrest, unexpected intensive care unit admission, the need for emergency surgery, or death) are commonplace in hospitalised patients. A key factor in reducing the burden of unexpected in-hospital morbidity and mortality is the identification of those at risk of deterioration. Previous attempts to do this have focused only on limited variables (often at one timepoint), have had poor sensitivity/specificity, and/or have necessitated the introduction of expensive new technical systems and management processes. As a result, no effective system has yet been implemented. I therefore propose to develop a simple and widely- applicable multivariate decision tool for continuous tracking of SAE risk in all patients admitted to hospital. This will use high- dimension multivariate analysis of routinely collected blood tests will be married to existing patient data relating to co-morbidities, interventions and demographics. Little additional resource would be required to collate the data, interpret and act upon it, as all of these data are already stored electronically. If successful, this research will permit automatic and continuous individual risk stratification to guide clinical decision making and resource allocation, ultimately helping prevent serious adverse events.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: GENERIC HEALTH RELEVANCE
Title: Meta-analysis, complexity and heterogeneity (MACH): methodological review and development of guidance
Funder: Medical Research Council

Abstract: OBJECTIVES AND APPROACH. The overarching aim is to develop guidance on making a decision as to whether to conduct a meta-analysis or not when reviewing quantitative evidence. The project involves five phases. In Phases 1 and 2, we will conduct a methodological review and three workshops and consultations with experts, to inform the development of new guidance on the appropriate conduct of meta-analysis. In Phase 3, we will use case studies of completed meta-analyses and systematic reviews to investigate the feasibility of conducting meta-analyses; to consider what different synthesis types add to a review; and to explore researchers' reasons for the adoption of certain synthesis types. We will conduct a small number of semi-structured interviews with review authors to explore the reasoning behind their decisions. In Phase 4, we will investigate the impact of meta-analysis on the perceived utility of reviews to users by conducting a randomised controlled trial, by comparing a wholly narrative evidence synthesis with one that includes a meta-analysis. In Phase 5, we will run two workshops to draw together the elements of the project and produce usable guidance for reviewers. APPLICATION OF THE RESEARCH RESULTS. The project will be informed throughout by an advisory group consisting of research methodologists and review users (e.g., policymakers, practitioners) to ensure the usefulness and appropriateness of the project outputs. The guidance will be disseminated widely. We anticipate that this work will aid better methodological decision making, leading to both fewer missed opportunities and inappropriate applications of meta-analysis. It will also provide guidance about the appropriate reporting of the decision process when writing up reviews. Finally, it will facilitate knowledge translation by gaining a better understanding of the perceived ease of use, credibility, and utility by decision-makers of different types of synthesis outputs.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Losing the losses: understanding the reasons for attrition in randomised trials and developing the evidence to prevent it
Funder: Medical Research Council

Abstract: Missing data is known to negatively impact research. It can increase costs to conduct research, reduce capacity to conduct research either due to financial restrictions or finite patient populations and can bias the conclusions of research. During the conduct of a clinical trial its performance is usually monitored by the Research Networks in terms of its progress in recruiting to target but there has been a less coordinated emphasis placed on monitoring retention of randomised participants. Recruiting and randomising people who are not subsequently retained for the primary outcome measure can actually be worse for the analysis of the trial than not randomising that patient at all. This means that an emphasis on strategies to monitor and boost recruitment alone could be badly misplaced, if the extra patients recruited are not retained. In a Delphi survey of UKCRC registered clinical trials units retention was highlighted as a priority for research. Approaches to maximise retention thereby minimising missing data should be informed by reasons for loss of participants to final analysis. Reasons may vary depending on characteristics of condition under study, participant types and settings. This project will: 1)Systematically review reasons for missing data in a cohort of published trials 2) Identify strategies to address missing outcome data by conducting an evaluation of NIHR trials and by collating knowledge and experience related to retention strategies within the network of CTU Directors. 3) Conduct qualitative interviews with clinical trial staff to further understanding of current practice regarding monitoring of missing outcome data in ongoing trials 4)Conduct a Delphi survey across the network of CTU Directors to assess priority interventions to pursue


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: SENIORS USP (Seniors - Understanding Sedentary Patterns)
Funder: Chief Scientist Office (Scotland)

Abstract: Prolonged sitting (sedentary behaviour) is an adverse health behaviour which predicts health risk, independent of other activity behaviours. Interventions aiming to reduce sedentary behaviour require knowledge about the determinants and long- and short-term effects of being sedentary. We will collect objective measures of current patterns of activity and sedentary behaviour (using activPal monitors) in 750 older people (in their 60s, 70s and 80s) from two large cohorts: the West of Scotland Twenty-07 Study and the Lothian Birth Cohort 1936. We will characterise the most sensitive objective and subjective ways of reporting activity behaviour. Cohort members have participated in a wide range of prior investigations (e.g. cognitive tests; questionnaires, including self-reported activity/sitting time; medical examinations; blood tests; brain scans). We will use these longitudinal data to investigate individual, social and environmental determinants of current activity/sedentary behaviours and identify which factors are associated with high risk of sedentary behaviour as people age. We will explore the consistency of associations across the cohorts, and the effect that activity/sedentary behaviour has on subsequent health outcomes. Within a selected subsample (n=48) we will investigate the meaning/relevance/importance of, and attitudes towards, sedentary behaviour. Collectively we aim to produce definitive data on: the determinants of sedentary behaviour; the health/cognitive outcomes of long-term inactivity; the views of older people on becoming less sedentary; and the potential benefits to an older person of sitting less or breaking periods of sedentary behaviour more frequently. We will provide recommendations for tailoring future interventions to change and report on older people's activity behaviour.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: GENERIC HEALTH RELEVANCE
Title: Sedentary behaviour in older adults: investigating a new therapeutic paradigm
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Recent evidence has shown that many of deleterious factors associated with older age are ameliorated by higher levels of moderate-to-vigorous intensity physical activity (MVPA). In contrast, little is known about the role of sedentary behaviour (sitting) in older adults. Observational and intervention level data in the general population suggests that reducing sedentary time has significant impacts on metabolic health, cardiovascular disease and mortality, independent of MVPA. This suggests that potential improvements in health may be gained by simply helping individuals substitute time spent sitting with time spent standing or in light-intensity ambulation. However, little is known about whether reducing sedentary behaviour promotes health and well-being in older adults. This grant is therefore primarily focused on investigating the impact of sedentary behaviour in older adults. This will provide the foundations with which to inform larger efficacy trials and public health initiatives aimed at reducing sedentary behaviour in the future. We propose three distinct, but complementary, work packages that will enable a step change in knowledge around the impact of sedentary behaviour in older adults. 1) Utilising existing datasets, which have both objective and subjective measures of sedentary behaviour and MVPA, work package one will focus on establishing the prevalence and strength and nature of the association between sedentary behaviour, MVPA and health in older adults. 2) Work package two will refine the measurement of sedentary behaviour by combining accelerometry with radio frequency identification (RFID) technology to provide a more accurate and detailed assessment of sedentary behaviour. 3) Work package three, in a laboratory setting, investigates the acute effect of sedentary time, reduced sedentary time and increased light-intensity physical activity on metabolic and psychological health in a sample of 116 multi-ethnic older adults.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.7 PHYSICAL
Health categories: GENERIC HEALTH RELEVANCE
Title: Integrated mutagenesis, bio-informatic and fluorescence approaches to characterize the molecular basis of antagonist action at P2X7 receptors for ATP
Funder: Medical Research Council

Abstract: Activation of P2X7 receptors by ATP released from damaged cells plays a significant role in inflammatory conditions, and the receptor is an important therapeutic target. However we know little about the molecular basis of antagonist action at these receptors. Our pilot mutagenesis and bioinformatics studies have identified potential orthosteric and allosteric binding sites for four chemically distinct P2X7 receptor selective antagonists. We will use an iterative cycle of mutagenesis and in silico molecular docking to test and refine models for binding of each of the P2X7 receptor antagonists. We will initially generate chimeras replacing stretches of residues comprising the predicted antagonist binding site of the human P2X7 receptor with those from the P2X7 receptor antagonist insensitive P2X1 receptor. These will be expressed in Xenopus oocytes and their pharmacological properties characterized electrophysiologically to identify the regions of the receptor important for antagonist action. We will then generate individual cysteine point mutants of variant residues within these regions to identify which residues are important for antagonist action. These data will be used to further refine molecular models and enable us to make predictions about the nature of the interaction between the antagonist and the residues required for high affinity antagonist binding that can be tested with specific mutations. To further substantiate the binding site model(s) the accessibility of introduced cysteine residues will be probed using biochemical methods to determine whether the incorporation of cysteine reactive fluorescence compounds is sensitive to antagonists. In addition voltage clamp fluorometry of labelled P2X7 receptor cysteine mutants adjacent to the antagonist binding site will be used to directly measure the kinetics of drug action. These studies will increase our fundamental knowledge of drug action at this distinct family of ion channels.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.1 PHARMACEUTICALS
Health categories: GENERIC HEALTH RELEVANCE
Title: The Collaborative Computational Project for NMR (CCPN): Supporting biomolecular NMR and community driven NMR software development.
Funder: Medical Research Council

Abstract: The CCPN software is now well established and founded upon a stable UML-based data model. Custom Python scripts are used to generate software libraries (APIs) in Python, Java and C, using storage in XML for Python/C and SQL for Java. These APIs, with their built-in validity checking and backwards and forwards data compatibility, form the basis of the CcpNmr suite of software. The coming period will bring the development of CcpNmr version 3 (v3), including Analysis, Analysis Lite, FormatExchange and integration with 3rd party programs The new version aims to provide an improved user experience, greater ease of use, customizability and specialization for particular application areas, in part through the use of the faster, more modern Qt graphics library. The v3 software will also provide for user-specified task-oriented layouts that allow customization of the graphical interface, e.g. for solid-state NMR, small molecules or metabolomics. Together with a new high-level subroutine library, this will allow speedy and user-focused 3rd party development of CCPN- enabled software. We will work closely with our partners in developing software and tools for NMR and other biophysical techniques, to encourage further integration with CCPN software. The CCPN Data Model will be extended as required and we will train developers in the use of the CCPN software libraries. In collaborative scientific projects, we will participate in new avenues in the areas of data analysis, including structure calculations and the use of chemical shifts. We will further develop tools to facilitate access to remote services on the grid, both via web browsers and from inside Analysis. For interacting with our user base, we will continue to provide the usual fast user support as well as improve our bug tracking and handling. We will continue to run courses for users, including (new) events organised jointly with WeNMR and regularly interact with relevant stakeholders.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: The Role of Nanog in Establishment and Patterning of Embryonic Pluripotency
Funder: Medical Research Council

Abstract: Pluripotency defines a cell's potential to give rise to progenitors of any somatic lineage, or to primordial germ cells which establish the germ line. Cells with this potential are not found in conventional animal models, including Xenopus and zebrafish, which have a predetermined germ line. Therefore we develop axolotl embryos as a model system. Axolotls represent the amphibian ancestor to vertebrates, and retain ancestral vertebrate developmental mechanisms that are conserved in mammals, including pluripotency. We recently isolated an axolotl Nanog ortholog, and showed it has conserved functional activity in mouse embryonic stem cells (ESC). Nanog is not conserved in Xenopus, but here we show it is a master regulator of axolotl development, required to initiate development, and then for specification to the ectodermal and mesodermal lineages. We identify Nanog interaction with Nodal signalling as a critical step in establishing pluripotency, as a prelude to further development. We will establish transcriptomes from Nanog morphant embryos, identifying Nanog targets during the Nodal dependent priming that triggers somatic development. We will determine Nanog's role as a transcription factor in mesoderm development, using animal caps from wild-type and morphant embryos that are exposed to activin to identify Nanog targets. The mesoderm is subdivided into somatic (nodal dependent) and germ line (nodal independent) mesoderm. The loss of Nanog diverts both these tissue types to endoderm. Brachyury, itself not dependent on Nanog, is required for the induction of both mesoderm populations. We will use protein synthesis inhibition experiments to identify Nodal and Brachyury targets that are modulated by the presence of Nanog to establish the Nanog dependent regulatory networks for pluripotency and subsequent mesoderm specification. These studies will identify conserved mechanisms that govern development of differentiated tissues from pluripotent cells in mammals.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Structure/Function Implications of Phospholipid Recognition by Notch-Ligands
Funder: Medical Research Council

Abstract: This grant aims to investigate the structural and functional significance of a novel property of the N-terminus of Jagged-1, identified by structure determination. We wish to establish the role of this novel property in the molecular mechanisms underlying Notch binding, trans-activation and cis-inhibition. Using the well-established collaboration between the Lea (biophysics) and Handford (biochemical) laboratories, we will investigate i) the structural basis for this novel property in other Notch ligands belonging to the Jagged/Serrate and Delta-like families (Drosophila Serrate, human J-2, human Dll-1,-4) using X-ray crystallography , NMR and SPR methods ii) the functional importance of this novel property for Notch binding, trans-activation and cis-inhibition using molecular and cellular assays including ELISA, flow cytometry and luciferase complementation reporter assays. These data will give new mechanistic insights into the Notch signalling pathway which may be tested in in vivo models, provide a rational basis for the design of novel modulating antagonists and agonists, and facilitate the understanding of a number of diseases caused by mutations in genes encoding Notch ligands. Results will be disseminated at international conferences on Notch function which are held annually, and any commercial exploitation handled by ISIS Innovation, university of Oxford.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.3 CHEMICAL AND PHYSICAL SCIENCES
Health categories: GENERIC HEALTH RELEVANCE