NIHRDataInsights/HRCSData huggingface dataset:
Title: Improving the diagnosis of meningitis in adults in the UK
Funder: Department of Health (England)

Abstract: Meningitis is a medical emergency. Rapidly determining the microbiological cause is essential to guide treatment. Newer diagnostic tests that look for multiple pathogens are becoming available but their role is unclear. Through a prospective observational study I will: a) determine if these newer tests perform better than current tests; b) use the latest molecular techniques to look for novel pathogens; c) explore barriers to the implementation of new tests into routine practice, which often prevent patients benefiting from such developments. Anticipated benefits of the research include better management, shorter hospital admissions, and fewer complications of treatment


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL;INFECTION
Title: EndoDecon: Cold gas plasma decontamination of flexible endoscopes
Funder: Department of Health and Social Care

Abstract: Endoscopy is a common procedure and there have been concerns regarding the risk of contamination with prions from infected tissue and other disease causing agent and the effective cleaning and sterilisation of the instrument to prevent cross infections between patients. Flexible endoscopes cannot be autoclaved and have to rely on manual cleaning. This project aims to develop a novel decontamination device that is capable of electrically producing transient reactive gas species (e.g. superoxide) within an endoscopic lumen of a few metres long. Unlike stable and toxic gases (e.g. ozone and hydrogen peroxide), these transient agents are produced at the point of need and recombine into harmless gases. They have been shown to remove proteins and prion from exposed flat surfaces without apparent damage to substrate material. The project will focus on technology innovation with active engagement of patient representatives. It is likely to lead to a new endoscope decontamination technology with enhanced safe use of flexible endoscopes, improved patient care, and additional saving to the NHS.

Lay abstract: Endoscopy is a common procedure and there have been concerns regarding the risk of contamination with prions from infected tissue and other disease causing agent and the effective cleaning and sterilisation of the instrument to prevent cross infections between patients. Flexible endoscopes cannot be autoclaved and have to rely on manual cleaning. This project aims to develop a novel decontamination device that is capable of electrically producing transient reactive gas species (e.g. superoxide) within an endoscopic lumen of a few metres long. Unlike stable and toxic gases (e.g. ozone and hydrogen peroxide), these transient agents are produced at the point of need and recombine into harmless gases. They have been shown to remove proteins and prion from exposed flat surfaces without apparent damage to substrate material. The project will focus on technology innovation with active engagement of patient representatives. It is likely to lead to a new endoscope decontamination technology with enhanced safe use of flexible endoscopes, improved patient care, and additional saving to the NHS.

Research activity codes: 5.3 MEDICAL DEVICES
Health categories: NEUROLOGICAL;INFECTION
Title: Understanding Infection in People with Dementia: Incidence, Impact and Prevention.
Funder: Department of Health and Social Care

Abstract: Summary As populations worldwide are ageing, the prevalence of dementia is increasing rapidly. Patients with dementia are at higher risk of infection. Infection may be a modifiable determinant of dementia outcomes. I aim to quantify the incidence of infection among people with dementia in the community and to determine the association of dementia with important outcomes in this population. The study encompasses four phases: 1. A systematic review of studies determining the association between infection and outcomes in dementia. 2. Analysis of primary care data from the Clinical Practice Research Datalink (CPRD) to measure the incidence of infections and subgroups at increased risk of infection, among people with dementia. 3. Analysis of patients accessing secondary mental health care within the South London and Maudsley NHS Foundation Trust from the Case Register Interactive Search (CRIS) system to quantify the association of infection with mortality, cognitive (Mini-Mental State Examination) and functional outcomes (Health of the Nation Outcomes Scale) among people with dementia. 4. Findings will be used to develop a public health intervention aimed at prevention and early management of infection among people with dementia. Research Question To what extent do common infections contribute to disease progression in older people with dementia and can this contribution be prevented? Research Aims To quantify the incidence of significant infection among people with dementia and to determine the association of infection with important outcomes in dementia. Objectives 1. To quantify the incidence of infection in people with dementia and the most common infections present. 2. To identify subgroups of older people with dementia who are at increased risk of infection. 3. To quantify the impact and physical, cognitive and functional outcomes associated with infection in people with dementia. 4. To assess whether an intervention aimed at prevention and early management of infection among people with dementia can be designed for evaluation as part of a complex intervention trial.

Lay abstract: People with dementia are more likely to be admitted to hospital with infections, after which they often deteriorate. Infection may be an important target for public health interventions as infections are potentially preventable. I will analyse two large datasets that collect records from GPs, mental health services, and hospital admissions. This will allow me to establish what the added risk of infection is, which infections and which patients are at highest risk, and whether infections are associated with worse health outcomes, in people with dementia. Using these outputs, I will develop an intervention to reduce infection among people with dementia.

Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: NEUROLOGICAL;INFECTION
Title: Optimisation, harmonisation and standardisation of real-time QuIC analysis of CSF in the diagnosis of sporadic Creutzfeldt-Jakob disease
Funder: Medical Research Council

Abstract: This proposal focuses on the optimisation of a recently developed analytical procedure called real-time quaking-induced conversion (RT-QuIC) which detects disease-associated prion protein in cerebrospinal fluid (CSF) of patients with sporadic Creutzfeldt-Jakob disease (sCJD). Two independent studies have shown recently that analysing CSF samples from patients with suspected sCJD using this technique has enabled those patients with disease to be identified with a high degree of sensitivity and specificity. This is a major advance in the development of a disease-specific pre-mortem diagnostic test for sCJD and there is considerable interest in establishing this test as a routine diagnostic test in Europe. It is important that RT-QuIC is optimised in terms of analytical performance and that there is a common approach to the clinical application of this technique, prior to its widespread use. It is crucial that this happens in a co-ordinated manner to ensure consistency between laboratories and that the factors affecting the test performance are thoroughly investigated. This is a focussed and well-defined project with clear objectives and is achievable within the time-frame allocated. The consortium consists of well respected scientists and clinicians who have a wealth of experience in harmonising and standardising diagnostic tests for sCJD. They are well known to each other and have collaborated closely in the past. In addition we have as advisory experts the scientists who have developed this technique to ensure that the consortium has the best possible scientific support. Once this test is harmonised and standardised across Europe it has the potential to lead to more accurate pre-mortem diagnosis of sCJD.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL;INFECTION
Title: Responsive Operational Research Support for Health Protection Policy
Funder: Department of Health (England)

Abstract: Operational Research is the use of mathematical analysis and computer modelling to provide information to decision makers. This may involve estimating the potential consequences of a particular course of action during a pandemic, estimating future levels of a particular disease or, say, determining how best to deliver a particular service. The proposed grant will fund a team of Operational Researchers to work in close collaboration with staff at the Department of Health to inform policy decisions on matters of health protection. We intend to provide a flexible, responsive research facility to meet the needs of the Department of Health and so the programme of work is not set in stone. However, we are likely to tackle questions about how the national immunisation programme should evolve in response to the emergence of new vaccines. Because we will be conducting the work in close collaboration with staff at the Department of Health, there is a good chance that our research will directly inform policy decisions.


Research activity codes: 8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES);8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: NEUROLOGICAL;INFECTION
Title: The impact of systemic bacterial and viral infections on innate immune responses in the brain.
Funder: Wellcome Trust

Abstract: When we have an infection such as a cold or 'flu', we feel ill and our mood and memory are affected, but this is reversible and we recover. Animal studies have shown, however, that this effect is no longer harmless if a degenerative process has begun in the brain. We have also shown that people with Alzheimer's disease who suffer from a systemic bacterial or viral infection decline more rapidly. Surprisingly, we know remarkably little about how peripheral infections affect the immune cells in t he brain: for how long an infection affects the brain immune cells, and whether different infections have different effects. We propose that infections 'prime' the immune cells in the brain so that a second insult, injury or disease induces these cells to make molecules with the potential to cause permanent damage to nerve cells. We also propose that immune cells in the aged brain are more reactive than in the young brain; they are more easily primed by systemic infections and give exaggerated responses to a second insult. We believe that understanding how infections affect the young and aged brain will lead to interventions to improve the quality of life of the elderly with brain disease.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: NEUROLOGICAL;INFECTION
Title: MICA: Towards using historical data for research prioritisation in children
Funder: Medical Research Council

Abstract: The proposed research will be structured into two workpackages (WPs). Methodological developments will be embedded in three indications, namely, epilepsy, human immunodeficiency virus (HIV) and asthma. WP1 will develop Bayesian multivariate random effects meta-analytic models for synthesizing individual patient data from historical pharmacokinetic-pharmacodynamic (PK-PD) studies in order to quantify the strength of prior evidence supporting an assumption of similar PK-PD relationships in adults and children for a novel medicine. Historical data may be related, but not perfectly relevant, to the assumption we wish to verify because, for example, historical trials concerned a different but similar medicine to the one of current interest. Therefore, the meta-analytic model will incorporate expert opinion on the effects of biases on key parameters that arise because historical data are not perfectly relevant to the target question. Strategies and software for eliciting expert opinion on the effects of biases will be developed. A Bayesian decision theoretic approach will be adopted to measure the expected utility of collecting PK-PD data in children for verifying assumed similarities with adults, given the strength of historical evidence supporting assumptions. Utilities will incorporate sampling costs and the costs of making erroneous assumptions. Work will also formulate Bayesian adaptive designs for paediatric PK-PD studies conducted to verify an extrapolation assumption. Properties of developed methodologies will be illustrated using simulation and through application to datasets provided by GlaxoSmithKline. WP2 will explore using frequentist and Bayesian finite regression mixture modelling as a data driven approach for determining the number and definition of paediatric subgroups with different PK-PD relationships. Open source software implementing proposed methodologies will be developed.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: NEUROLOGICAL;INFECTION;RESPIRATORY
Title: Over one year for defining the role of autoantibodies in paediatric inflammatory demyelinating disease
Funder: Action Medical Research

Abstract: Background Prompt intervention is essential to suppress the development of long term cognitive and physical disabilities in children with multiple sclerosis (MS) and other inflammatory demyelinating diseases, but the only treatments currently available are those used in adults. This is a major problem because increasing evidence suggests damage to the nervous system in children and adults with MS does not necessarily involve the same disease mechanisms Recent results reveal many children, but not adult patients, have antibodies in their blood with properties indicating they can attack the brain and spinal cord. If this is the case, these young patients could benefit from antibody-depleting treatments known to block antibody-mediated effects in other diseases. However, before these treatments can be introduced routinely to treat these children, proof is required that these antibodies contribute to the development of disease. The research project The primary aim of this project is to use a newly developed test to determine whether children with MS and a related disease, acute disseminated encephalomyelitis (ADEM) have autoantibodies in their blood that can directly attack nerves in the brain and spinal cord. The team will then test whether high levels of these autoantibodies predict a poor outcome for the patient. This project should determine if a rational basis exists for the introduction of antibody-depleting treatments to prevent irreversible damage to the nervous system of children with MS or ADEM. This is important as there are currently no specific treatments for preventing chronic irreversible disability in these devastating diseases.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Investigating the microglial role of ALS/FTD risk gene TBK1
Funder: Wellcome Trust

Abstract: Neuronal dysfunction and degeneration are central to amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and co-existent ALS/FTD. However, it is increasingly being recognised that non-neuronal cells actively contribute to disease pathogenesis. Recent genetic studies have identified several ALS/FTD risk genes with immune roles, highlighting immune dysfunction as a key early pathogenic mechanism. We aim to investigate the role of one of these genes, TANK-binding kinase 1 (TBK1), in microglia, the resident immune cells of the brain. We will use stable microglial cell lines and human induced pluripotent stem cell-derived microglia, along with pharmacological inhibition and genetic manipulation of TBK1, to investigate the role of TBK1 in key microglial functions. In particular we aim to determine the role of TBK1 in microglial immune signalling, phagocytic activity, autophagy and mitochondrial homeostasis using cutting-edge high content imaging techniques and cellular assays. By doing so, we hope to define the role of TBK1 in microglia and further understand how deficits in TBK1 function may drive neuronal loss in ALS/FTD, with the ultimate aim of identifying novel therapeutic targets.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Mechanisms of human sickness.
Funder: Wellcome Trust

Abstract: Anyone who has ever experienced a viral or bacterial infection knows what it means to feel sick. Infection anywhere in the body triggers an inflammatory response, and by actions on the brain, a carefully coordinated group of cognitive, emotional and motivation changes known as 'sickness behaviour'. Fortunately, sickness symptoms such as fatigue, lowering of mood, poor concentration and memory are usually self-limiting. However, when the immune system is chronically activated they can become high ly debilitating or even life-threatening. Immune influences on the brain have also recently been implicated in the cause of common mood and memory disorders such as depression and Alzheimer's disease. Strikingly however, the mechanism of these actions are currently poorly understood. The present proposal seeks to address this issue. To achieve this, I shall adopt an innovative approach combining fMRI and acute inflammatory challenge with a series of carefully developed experimental tasks tes ting emotional, motivational and memory processes. Empirical data will be used to develop a mechanistic model of how the immune system modulates brain function to cause individual sickness symptoms Identification of the neural mechanisms of sickness as proposed here will motivate the design of future therapies targeting these common and disabling symptoms


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: NEUROLOGICAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Role of IL-4 in immune regulation
Funder: Wellcome Trust

Abstract: In autoimmune diseases such as multiple sclerosis (MS), there is a deregulation of the immune system leading to an immune response being mounted against self-antigens. In Tg4 mice, experimental autoimmune encephalomyelitis (EAE), the mouse model of MS, is induced in by administration of an acetylatednine residue peptide of myelin basic protein (Ac1-9) in combination with adjuvant. Repeated administration of soluble MBP Ac1-9 induces tolerance with no EAE development. These tolerised mice have an increased production of IL-10from TH1 cells with reduced IL-2 and IFN-y production. Previous work has shownthat culturing T H1 cells with IL-4 in vitro induces IL-1 0 and blocking IL-4 with a monoclonal antibody inhibits IL-10 secretion. This project will test the in vivo role of IL-4 in the induction ofIL-1 0 from T H1 cells in the context of peptide induced tolerance and how themolecular basis and signalling downstream of the IL-4 receptor is IL-10 regulated. Furthermore I will investigate the relative role of the antigen presenting cell in this negative feedback loop. I will also look at the relative roles of IL-4 and IL-1 0 in the antagonism of T H1 responses by T H2 cells. Together these investigations will give us a further understanding intothe role of IL-4 in the context of induced tolerance to EAE.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Defining spatiotemporal patterns regulating T cell function in peripheral tolerance induction.
Funder: Wellcome Trust

Abstract: Multiple sclerosis (MS) is a disease in which peripheral tolerance breaks down , resulting in a broad spectrum of symptoms. Treatment of MS is primarily bys uppressing inflammation and treating symptoms that arise in the acute phaseso f the disease, but it has been shown that in a mouse model of MS, experimental autoimmune encephalomyelitis (EAE), tolerance can be induced by repeated trea tments with the antigen. In the Tg4 mouse, this antigen is myelin basic peptid e (MBP) and over the course of tolerance induction, T cells undergo a switchf rom an auto-reactive, pathogenic, interferon gamma (IFN-y)-producing T H1 phenotype to a more protective interleukin (IL)-1 0 producing phenotype (IL-1 O.T H1 ). Duringtolerisation, alterations to normal T cell signalling occur, the s pecifics of which are poorly understood. This project aims to expand the amoun t of information known about the altered signalling in tolerance, using the Tg 4 mouse model of EAE. These mice will be used to produce pathogenic andtolerised T cells,into which signalling sensors can be transfected. Live cell imaging can then be used to follow the spatiotemporal localisation of a number of key signalling proteins. Alterations to these patterns between cell types will gives indications as to key differences in signalling.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: 1st Milestone tranche 2
Funder: Wellcome Trust

Abstract: Pain comes in three distinct varieties. Acute pain is produced directly by an injury and has an essential protective function; inflammatory pain (IP) is associated with injury, infection or chronic conditions such as arthritis; and neuropathic pain (NP) is caused by nerve damage in conditions such as post-herpetic neuralgia and diabetic neuropathy. Acute pain is essential for protection from damage but IP and NP can impose major limitations on lifestyle and working patterns. Currently available treatments for IP and NP have major drawbacks: NSAIDs cause gastric and renal damage; opioids cause constipation and problems with tolerance and addiction; and treatments for NP have limited efficacy and major side effects. The applicant lab has discovered that both IP and NP are abolished in mice when an ion channel called HCN2 is genetically deleted, suggesting that drugs blocking HCN2 will have value as novel analgesics. HCN isoforms also play essential roles in the heart and brain, so it will be essential to develop HCN2-selective blockers which do not affect cardiac function and are excluded from the brain. We will test these blockers in animal models of IP and NP. In separate parallel studies we will use a known nonselective HCN blocker, ivabradine, to carry out proof-of-principle studies in human NP.


Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL;INFLAMMATORY AND IMMUNE SYSTEM