NIHRDataInsights/HRCSData huggingface dataset:
Title: Cellular interactions underpinning the anti-inflammatory action of Mesenchymal Stromal Cells in Donation after Cardiac Death liver injury
Funder: Medical Research Council

Abstract: Liver organ shortage has resulted in Donation after Cardiac Death (DCD) transplants with worse outcomes and an acute inflammatory insult causing liver and renal dysfunction with prolonged organ support and intensive care stay. Mesenchymal stromal cells (MSC) suppress immune cells responsible for inflammatory damage and could have a therapeutic role in DCD liver transplant. The optimum route of MSC administration is unclear with subcutaneous injection of alginate encapsulated MSC delivering superior anti-inflammatory action in certain models. I hypothesise that localised subcutaneous injections of encapsulated MSC can provide superior anti-inflammatory action in liver injury, which is mediated through licensing of anti-inflammatory myeloid-derived suppressive (MDSC). Aims: (1) To determine impact of route of administration of MSCs in models of immune-mediated liver injury as seen after DCD liver transplantation, (2) determine the functional bio-distribution of infused MSC and (3) determine if MSC exert their action by licensing myeloid derived suppressor cells. Methods: I will test the protective action of purified mouse MSC in models of liver injury that replicate the features seen after DCD liver transplant (models of partial hepatic ischaemia:reperfusion & the Mdr2-/- model of biliary injury/fibrosis). I will determine whether thermo-reactive encapsulation of MSC provides superior efficacy than conventional routes of administration. To ascertain where MSC are functioning in vivo I will lentivirally transfect MSC with a promoter driven fluorescent protein reporter that reflects indoleamine 2 3- dioxygenase expression. I will determine their bio-distribution using both IVIS & the state of the art CryoVizTM which provides quantitative 3D bio-distribution data in whole mice. Finally, using in vitro then RNA knock-down studies in vivo I will determine whether purified MSC exert their biological effects by induction of myeloid derived suppressor cells.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: ORAL AND GASTROINTESTINAL
Title: Metabonomic and genetic profiling in severe alcoholic hepatitis
Funder: Medical Research Council

Abstract: This study aims to elucidate the metabolic and genetic factors that contribute to the pathogenesis of alcoholic hepatitis. It will utilise the clinical data, DNA and serum samples collected as part of the STeroids Or Pentoxifylline for Alcoholic Hepatitis (STOPAH) study. Serum samples drawn from patients with severe alcoholic hepatitis (modified discriminant function >32) will undergo metabonomic analysis using 1H-NMR and mass spectrometry profiling techniques. A control population of patients with chronic liver disease (compensated and decompensated) will be used. Spectral profiles will be analysed using multivariate statistical analysis to identify changes in metabolites able to discriminate between the study populations. Sub-group analysis will be undertaken to identify metabolic markers predictive of outcome or response to treatment. DNA samples from the same group of patients with alcoholic hepatitis have undergone exome-wide single nucleotide polymorphism (SNP) genotyping at the Sanger Institute, Cambridge. Samples from a group of alcohol dependent individuals without evidence of liver disease have also been genotyped. The genetic data will be used to perform a genetic association study to identify SNPs associated with the development of progressive liver disease. For the alcoholic hepatitis cohort datasets will be combined to generate insights into the relationship between genotype, clinical and metabolic phenotype. The STOPAH clinical data set will be used to test the ability of currently employed scoring systems to predict mortality and treatment response and compare their performance to a novel scoring system that incorporates metabonomic data.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Urban drinking Water and Health Outcomes - Early Phase Study for a Randomized Controlled Trial in Accra, Ghana
Funder: Medical Research Council

Abstract: Background: Use of sachet water (small quantities of water sold in plastic bags) is growing rapidly in West Africa, yet its health impact and the proper policy response remain unclear. Reviewers of our 2013 Joint Global Health Trials application for a full-scale trial of subsidised sachet water (reference: MR/L004313/1) requested preliminary data on the topics discussed below. Objectives: To quantify the effect of greater sachet water use on childhood diarrhoea (the primary outcome) and thus evaluate the cost-effectiveness of free or subsidised sachet water provision as a health intervention. Subjects: Ghanaian children aged 6-36 months living in neighbourhoods lacking access to reliably treated piped water in Accra. Early Phase Study Design: A feasibility study using the main study protocol among 80 households in 4 districts to assess contamination between intervention and control groups and unintended harm to sachet vendors. We shall also undertake a cross-sectional, city-wide sachet water quality survey to assess intervention safety. Proposed analysis: For the early phase study, we shall assess retention, household behaviour and vendor sales in response to sachet provision and estimate sachet water microbial compliance. Main Study Design: A three-arm randomised controlled trial of 3,600 households. Carers in the control group will receive education on diarrhoea prevention and treatment; the second arm will receive vouchers for 2 litres of free drinking-water sachets per day (value: $0.20) plus education, and the third arm will receive vouchers for 2 litres/day of subsidised sachets plus education. Child health outcome measures will include diarrhoeal disease, growth, and related proximate measures. Engagement and Dissemination: We shall hold regular stakeholder meetings throughout the early phase project and a final dissemination event in Accra. Subject to early phase findings, we aim to submit a revised trial proposal to the Global Health Trials scheme.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: ORAL AND GASTROINTESTINAL
Title: In vitro and in silico models of gut bacterial diversity and its impacts on human health
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Gut bacteria play a vital role in human digestion and protection from disease, yet understanding of how these communities influence host function has been limited, and reliant on experiments on rodents. This project will devise new in vitro and in silico models to replace the use of rodents and to increase understanding of interactions between gut bacterial diversity and human cell function, focusing on the fermentation of fibre and its effects on human cells.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: ORAL AND GASTROINTESTINAL
Title: Combinatorial mathematical modelling & novel toxicological profiling of drug-induced hepatotoxicity
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Adverse drug reactions are a serious concern for both public health but also during drug development. drug induced hepatotoxicity is a primary reason for the failure of new medicines. There is considerable research into mechanistic evaluations of why compounds fail in development. There is currently no systematic framework which is able to direct research into areas of data deficiency. This application seeks to combine innovative mathematical modelling with state-of-the-art technologies in toxicological research, in order to establish a theoretical/experimental protocol that produces the most informative data with reduced animal testing.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: ORAL AND GASTROINTESTINAL
Title: Applying the 3Rs to Liver Fibrosis Research
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Liver disease is a major killer and one of the few major diseases predicted to rise in the future because of obesity and viral infections. Finding treatments requires the use of animals because several different cell types and several tissues combine to produce the main disease outcome – fibrosis or tissue scarring. This project will develop an animal model to test treatments that is less severe than the currently used surgical model. The project will also develop a way to image fibrosis using a novel antibody system developed by the applicants, so that fibrosis severity can be determined in live animals. By developing these refinements, the project will replace more severe procedures and reduce the numbers of animals required in liver disease research.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: ORAL AND GASTROINTESTINAL
Title: Refining the study of fatigue in mouse models of chronic liver disease
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Fatigue is a common and frequently debilitating symptom that occurs in a wide of chronic liver diseases such as Primary Biliary Cirrhosis. Unfortunately it also is very difficult to treat. There is therefore a critical clinical need to elucidate disease mechanisms and develop therapies that alleviate the symptom of fatigue. Rodent models are invaluable in this process but unfortunately in vivo fatigue studies typically have a considerable impact on the animals involved. The main objective of this project is to refine the study of fatigue in mouse models of chronic liver disease by developing more sensitive, less invasive methods of assessing fatigue. As an alternative to methods such as the forced swim test that have been used to assess fatigue, in this project mice will be assessed using a transponder-based automated homecage. This approach has both welfare and scientific benefits as the multi-faceted components of fatigue will be continuously, non-invasively assessed in animals that are socially housed in an enriched environment. Because of the similarities in many symptoms of fatigue regardless of aetiology, the assessment techniques developed in this project will be applicable to in vivo research on the fatigue of other origins. Early markers of ill health or poor welfare applicable to other murine disease models will also be identified in this project. A further objective of this project, through collaboration with the Newcastle liver research group, will be to identify refined animal models. The bile duct ligated (BDL) rodent model has most frequently been used to study fatigue in chronic liver disease however the BDL procedure has a substantial impact on the animals examined. Many of the mouse models already being studied for other purposes in our animal unit are less invasive than the BDL model, likely to be more appropriate models of chronic fatigue and will not need to be used specifically for this project. Ageing nuclear factor κΒ knockout mice for example, show particular promise as an alternative, non-invasive model of Primary Biliary Cirrhosis.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: ORAL AND GASTROINTESTINAL
Title: Mechanisms of intestinal epithelial responses to inflammatory modulators
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Inflammatory bowel diseases (IBD) are on the rise in the western world, and colon cancer is a leading cause of cancer-related deaths worldwide. Both these diseases involve the intestinal epithelium, the single layer of epithelial cells that is responsible for nutrient absorption and also for protection from the external environment. Associated with the gut epithelium is a complex network of immune cells that help to protect the epithelium against environmental insults. The continuous exposure to food-derived particles, innocuous microbial products from commensal bacteria, as well as pathogenic bacteria, viruses and fungi, require the gut immune system to maintain a fine balance between non-responsiveness and full activation and inflammation. Understanding how the epithelium responds to inflammation is of paramount importance to understand how the epithelium contributes to resolution of inflammation. Furthermore, knowing the mechanisms that contribute to defects in this balance as occurs in IBD is key to detect and treat these common diseases. Using intestinal epithelial organoids our work aims to determine the molecular detail that underpin responses of the epithelium to different inflammatory mediators, specifically how they affect proliferation, differentiation, gene expression, and barrier function. Furthermore, we will identify signalling pathways involved and measure the contributions of novel immune response modulators including the aryl hydrocarbon receptor (AHR) and Hypoxia-inducible factor 1 (HIF1alpha). This will establish how inflammatory responses in the gut are coordinated. Finally, we aim to create a pilot repository of intestinal organoids derived from genetically modified mice that will serve as an experimental resource for animal replacement within the scientific community.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Surgical Performance - from Concept to Measurement to Implementation
Funder: Department of Health (England)

Abstract: Objectives: To enhance performance of the surgeon within the elective surgical pathway in terms of knowledge, skills and attitudes, leading to improved surgeon-specific, team-based and patient derived outcomes. Design: A surgical elective care pathway has been defined. Consensus will be sought for this pathway, together with definition of outcome measures. Five individual clinical and pseudo-clinical trials shall be performed, recruiting 140 subjects and 100 patient cases. The final part shall be a pre- and post-intervention prospective clinical study, bringing together the individual aspects of the five prior studies. Techniques/approaches: This will encompass the following: 1. cognitive knowledge (delivered through an online system); 2. mental practice (the use of mental imagery to rehearse a task symbolically prior to performance); 3. deliberate practice (engagement in activities “deliberately” chosen for their ability to improve performance and maintain it at the highest level); 4. handover of the post-operative surgical plan; 5. standardised process for post-operative surgical ward round Measurements/outcomes: These will be based upon scores for the knowledge test, technical skills measures (structured post-hoc blinded video analysis), observational checklist for teams in the operating room, structured report forms from nursing and junior surgical staff, and patient outcomes – these are divided into validated self-report questionnaires and clinical outcomes, i.e. in-hospital complication rates, including death, up to 30 days, unplanned admission to high dependency or intensive care environment, and return to operating theatre.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;6.4 SURGERY
Health categories: ORAL AND GASTROINTESTINAL
Title: The efficacy, cost-effectiveness and feasibility of screening for common dental diseases by Dental Care Professionals
Funder: Department of Health (England)

Abstract: Over the last 10 years access has been a problem in NHS dentistry. In doctors’ surgeries many of the tasks performed by doctors are now undertaken by nurses. In contrast, the role of Dental Care Professionals (DCPs) e.g. dental therapists, in dental practice is underdeveloped. A substantial proportion of the funding for NHS dentistry involves paying the most expensive person, the dentist, to undertake routine "check-ups" on patients who often don’t need any treatment. In contrast, almost half of the population can’t access a dentist, or use services infrequently. These tend to be patients who have greater treatment needs, which do require dentist’s skills. This research programme will examine whether DCPs can detect the common dental diseases and will compare the costs of dentists and DCPs to do this. We will also ask dentists and patients how acceptable it would be to use DCPs in this way. Finally, the approach will be piloted in four dental practices to provide initial information on the feasibility of using DCPs like this in day to day practice. If effective, this use of DCPs could substantially reduce the costs of dental services to the NHS or alternatively free up dentists' time to increase access.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;8.2 HEALTH AND WELFARE ECONOMICS
Health categories: ORAL AND GASTROINTESTINAL
Title: Hypnotherapy for irritable bowel syndrome: streamlining provision
Funder: Department of Health (England)

Abstract: Background ‘Gut focused’ hypnotherapy relieves the symptoms of irritable bowel syndrome (IBS) in 70% of patients with improvement being maintained for at least five years. Demand and interest in hypnotherapy for IBS is very high but provision remains patchy. This is probably because it is time consuming, costly to provide and there are no set protocols on exactly how it should be delivered. A better defined, streamlined approach to treatment could result in greater numbers of patients being treated as well as making the package far more attractive to NHS providers and less expensive. Hypnotherapy improves some of the physiological abnormalities of IBS and it would be useful to establish if it also rectifies abnormal cortisol and cytokine levels recently described in this condition. Aims The principle aim of this project is to establish whether an intensive, highly structured and streamlined approach to gut focused hypnosis, involving only six sessions of treatment is as effective as the current practise of offering twelve sessions of therapy. This could potentially double the output of an individual therapist or unit, drastically reduce waiting times and encourage others to adopt this approach to treatment. The opportunity will also be taken to assess whether symptom improvement is accompanied by any changes in cortisol or peripheral blood cytokines which can be assessed at no additional cost. Plan of Investigation 1. Irritable bowel syndrome outpatients suitable for the study will be randomly allocated to receive either the current regime of twelve sessions or the streamlined test treatment of six sessions. Outcomes will be assessed by recording and comparing symptom severity, anxiety, depression, quality of life and economic factors in the two treatment groups. 2. Hypothalamopituitary status will be assessed by measuring blood cortisol levels. 3. Peripheral blood cytokines (IL-6, IL-8 and sIL-6R) will also be measured to see if hypnotherapy results in a reduction in their concentration. Potential Impact Hypnotherapy could be viewed as one of the most effective treatments for IBS but at present is only available to a tiny proportion of patients. If the protocol to be tested here proves effective it could lead to hypnotherapy being made available to much larger numbers of patients. In addition, the provision of a standardised, cost effective package should ensure uniformity of treatment as well as encouraging other NHS providers to adopt this approach. By following the pituitary and cytokine response to treatment it may be possible to further understand the mechanism by which hypnosis mediates its benefit.


Research activity codes: 6.8 COMPLEMENTARY
Health categories: ORAL AND GASTROINTESTINAL
Title: Biodegradable stent in benign oesophageal stricture compared to standard balloon dilatation treatment
Funder: Department of Health (England)

Abstract: Background Current management of benign oesophageal strictures involves endoscopic dilatation using balloons or polyvinyl bougies. The procedure often needs to be repeated and is associated with significant morbidity, unpredictable outcomes, costs to NHS and risks oesophageal perforation and bleeding in about 5% of patients. The alternative option of surgery is less acceptable to patients. The use of removable stents for benign biliary strictures, without the need for repeated endoscopy or surgery, has been reported in literature,. Removable and biodegradable stents are now available for the management of benign oesophageal strictures, but there is little efficacy data for these stents in long term management. Biodegradable stents have the advantage that no removal procedure is required. Aims This pilot study will assess the potential effectiveness and cost-effectiveness of biodegradable stent placement in patients with benign oesophageal stricture. The primary endpoint is the average dysphagia (swallowing) score response over 12 months. Secondary end points will include acceptibility of procedures to patients, the number of repeat endoscopic procedures, frequency of refractory disease, adverse events, quality of life assessed physically using surrogate markers such as weight and serum albumin and by generic quality of life assessment (EuroQol EQ-5D). Finally patient level, NHS perspective, cost and cost-effectiveness analysis will be conducted. Plan of Investigation This multicentre study will utilise a type of randomised controlled trial called a Prospective Randomised Open Blinded Evaluation (PROBE). Fifty symptomatic adult patients diagnosed with a new or existing stricture will be consented from 6 NHS hospital sites and randomised to biodegradable oesophageal stent or standard balloon dilatation. Patients will be assessed by a blinded observer at baseline, 3, 6 and 12 months according to study aims Potential Impact Oesophageal stricture is a distressing and disabling condition, requiring endoscopic dilatation, often repeatedly for treatment, with associated risks. Although theoretically attractive there are no comparative studies using biodegradable stents in this condition. This trial will inform the appropriate design of a definitive national study if the findings of the pilot study are favourable. The potential benefits of biodegradable stenting include improved swallowing and quality of life as well as decreased exposure to procedural risks in patients, procedure costs and adverse event management for the NHS. The proposed study is a necessary step to provide the evidence-base to improve patient care.


Research activity codes: 6.3 MEDICAL DEVICES
Health categories: ORAL AND GASTROINTESTINAL