NIHRDataInsights/HRCSData huggingface dataset:
Title: Improving the Quality of Dentistry (IQuaD): A randomised controlled trial comparing oral hygiene advice and periodontal instrumentation for the prevention and management of periodontal disease in dentate adults attending dental primary care
Funder: Chief Scientist Office (Scotland)

Abstract: Periodontal disease is the most common oral disease affecting adults. Effective self-care (tooth brushing and interdental aids) for plaque control and removal of risk factors such as calculus by periodontal instrumentation (PI) commonly known as a “scale and polish” are considered necessary to prevent and treat periodontal disease. A Cochrane review found evidence that psychological interventions resulted in improvements in oral hygiene behaviours but there is a lack of reliable evidence to inform clinicians of the relative effectiveness of different types of Oral Hygiene Advice (OHA) on the prevention of periodontal disease in adults. Similarly there is mixed evidence on the effectiveness and optimal frequency of PI. The majority of trials that have been carried out to date have been of poor to moderate quality with few conducted in primary care and a lack of patient centred outcomes and economic analyses reported. The IQuaD trial will investigate the effectiveness and cost effectiveness of the following dental management strategies in general dental practices across the UK: 1.Personalised OHA versus routine OHA 2.12 monthly PI versus 6 monthly PI 3.No PI versus 6 monthly PI Participating dentists (60) will be cluster randomised to provide routine (current practice) or theory-based personalised (to the needs of the patient) OHA. A total of 1860 individual eligible patients will be randomised to no PI 6 monthly PI or 12 monthly PI (310 to each group within each cluster of routine or personalised OHA randomised dentists). Clinical outcomes assessed by gingival inflammation/bleeding measured according to the Gingival Index of Loe will be measured at baseline and at 3 years follow-up by trained outcome assessors who are blinded to allocation participants will be followed-up by postal questionnaires sent annually.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: ORAL AND GASTROINTESTINAL
Title: Double blind randomised controlled trial of percutaneous tibial nerve stimulation vs sham electrical stimulation in the treatment of faecal incontinence: CONtrol of Faecal Incontinence using Distal NeuromodulaTion (The CONFIDeNT Trial)
Funder: Department of Health (England)

Abstract: DESIGN: Pragmatic multi-centre double-blinded placebo-controlled trial of 212 patients randomized to receive the intervention (PTNS) or sham (needle insertion and electrical stimulation). All patients follow an assessment period recruitment allocation standard 3 month treatment protocol (one 30 min session per week) with trial outcomes determined at 14 weeks.SETTING: 14 UK centres providing specialist nurse-led treatment for pelvic floor disorders. The fully registered Pragmatic Clinical Trials Unit at Barts and the London School of Medicine and Dentistry will be the coordinating CTU.TARGET POPULATION: Patients aged > 18 years with FI who have failed conservative treatments and whose symptoms are sufficiently severe to merit further intervention.HEALTH TECHNOLOGIES BEING ASSESSED: PTNS (Urgent PC) is produced by a single manufacturer (Uroplasty ®). The equipment includes a hand held pulse generator unit and single use leads and fine needle electrodes. Needle insertion is performed in a sitting position in an outpatient setting on either leg adhering to the manufacturers protocol (and specialist training). Treatment is for 30 mins weekly for a duration of 12 weeks. Validated sham stimulation - insertion of the urgent PC needle subcutaneously at the same site with electrical stimulation delivered to the distal foot using TENS.MEASUREMENT OF COSTS AND OUTCOMES: Primary outcome variable: change in weekly FI episodes [calculated from bowel diaries] expressed as proportion of patients achieving = 50% reduction in FI episodes per week. Secondary outcomes: (1) percentage change FI episodes per week (2) numeric decrease in FI episodes per week (3) validated patient-rated quantitative outcomes including symptom severity score (Cleveland Clinic Score) disease-specific: FI-QOL and generic: EQ-5D QOL measures (4) FI-specific patient-centered outcomes (5 validated key issues) (5) Likert scales of patients global impression of success (0-10) (6) Short urinary symptom assessment. Adverse events and anti-diarrhoeal drug usage will also be recorded. Economic analysis will measure direct NHS costs with utilities derived from the EQ-5D.


Research activity codes: 6.3 MEDICAL DEVICES
Health categories: ORAL AND GASTROINTESTINAL
Title: Pivotal role of the Keap1-Nrf2 pathway in the pathogenesis and prevention of non-alcoholic steatohepatitis induced cirrhosis
Funder: Medical Research Council

Abstract: Part 1. We will perform a longditudinal study of C57BL/6 Nrf2+/+ mice in which the development of disease will be monitored by measuring plasma markers of steatosis, insulin sensitivity, inflammation, oxidative stress and fibrosis. Upon sacrifice of the animals, we will perform various histological examinations (H&E, Van Glieson, reticulin, Oil Red O and TUNEL staining), and measure changes in expression of key hepatic genes associated with lipid metabolism, inflammation, redox status and fibrosis. Furthermore, in the first part of the project we will also test whether administration of a 'Western' high fat/high fructose (HFF) diet increases the rate at which NASH, fibrosis and cirrhosis develop in C57BL/6 Nrf2+/+ mice, and examine whether both the HF and HFF diets provide appropriate models for human liver disease. The rate at which NASH developes and progresses in wild-type mice fed the HFF diet will be evaluated using the same measurements employed for mice on the HF diet, and compared with the latter. Part 2. We will use the same criteria set out above to test the prediction that loss of Nrf2 results in a rapid acceleration in the rate at which NASH, fibrosis and cirrhosis develop in C57BL/6 Nrf2-/- mice placed on the HF and HFF diets. Part 3. We will test the hypothesis that either genetic or pharmacological upregulation of Nrf2 provides protection against NASH, fibrosis and cirrhosis in mice placed on the HF or HFF diets: genetic upregulation of Nrf2 will be studied in C57BL/6 Keap1-floxed (i.e., Keap1loxP/loxP) mice in which Keap1, an E3 ubiquitin ligase substrate adaptor protein that represses Nrf2, is substantially downregulated; pharmacological upregulation of Nrf2 will be achieved using the potent chemopreventive agent TBE31, which is a strong inhibitor of Keap1. As one control, we will generate Keap1-floxed::Nrf2-/- and place them on the HF and HFF diets. As a second control, we will treat Nrf2-/- mice placed on the HF and HFF diets with TBE31.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Calcium signalling, organelle dysfunction and pancreatitis
Funder: Medical Research Council

Abstract: Acute pancreatitis is a sometimes fatal human disease in which the pro-enzymes synthesized in the pancreatic acinar cells are activated inside the cells (rather than after they have been secreted into the gut) and digest the pancreatic tissue (rather than the food in the gut). It is mostly caused by gallstones or excessive alcohol intake. Repeated attacks may lead to chronic pancreatitis, which increases markedly the risk of developing pancreatic cancer. There is currently no specific therapy for pancreatitis. We have recently identified molecules in the acinar cells responsible for the excessive intracellular Ca2+ release elicited by agents causing pancreatitis and been able to knock-out of these molecules and thereby prevent the fatal intracellular protease activation. Furthermore, we have discovered that a normally present intracellular molecule, calmodulin (CaM), exerts a protective action and found that application of a membrane-permeable Ca2+-like peptide can boost this protection. We now plan to test systematically the CaM-dependent mechanisms for inhibiting excessive intracellular Ca2+ release elicited by all the major known agents inducing pancreatitis. We shall specifically test the ability of Ca2+-like peptides to protect against intracellular protease activation using realistic mouse models of the disease. We also plan novel studies of a special cell type, namely the pancreatic stellate cell (PSC). Activated PSCs drive development of chronic pancreatitis and are responsible for production of the cancer-promoting stromal matrix. Intracellular Ca2+ is involved, but the mechanisms of Ca2+ transport and function in PSCs are obscure and essentially nothing is known about nervous control. Building on our experience with Ca2+- dependent control of the acinar cell function, we shall study nervous and chemical control of PSCs in mouse pancreatic lobules and test procedures to inhibit their excessive secretion of cancer-promoting materials.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Discovery of low-frequency ulcerative colitis risk variants using whole-genome sequencing
Funder: Medical Research Council

Abstract: Ulcerative colitis (UC) and Crohn's disease (CD) are the two most common forms of inflammatory bowel disease (IBD), which is characterised by chronic inflammation of the GI tract. In the UK, IBD affects around 400:100,000 people. Current therapies are expensive, don't always work, and can have severe side effects that necessitate regular clinical monitoring. Genome-wide association studies have identified 47 independent loci associated with UC but much of the disease heritability remains unexplained. In an effort to identify additional risk loci, gain further insights into the genetic and molecular architecture of IBD and move towards more personalised therapy, a whole-genome sequence based association study of 2000 UC cases and 4000 UK population controls will be carried out. The main objectives of the proposed research are: 1) Using whole-genome sequencing and genotype imputation, conduct highly-powered association tests to identify novel low-frequency variants of intermediate penetrance associated with UC. 2) Combine UC and CD whole-genome sequencing data to identify novel loci associated with IBD and better define the molecular architecture of the two diseases. 3) Utilise rich subphenotype data available across the UC samples to search for genetic markers of clinically relevant subphenotypes such as treatment response and disease severity. 4) Conduct fine-mapping of known loci to better identify causal variants. 5) Build and test predictive algorithms of disease status and severity using confirmed UC loci and clinical measures. 6) Address key issues concerning the design, analysis and interpretation of whole-genome sequence based association studies. All sequencing data and variant calls will be deposited in the European Genome-Phenome Archive to empower both methodological and applied research in other labs.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Investigating the role of SOX9 in liver fibrosis
Funder: Medical Research Council

Abstract: Fibrosis of the liver is characterised by progressive accumulation of ECM proteins and is a major cause of morbidity and mortality in the UK. End-stage liver fibrosis can be treated by liver transplantation, but this is limited by donor numbers. Anti-fibrotic therapies are desperately needed during earlier phases of the disease when the fibrosis is reversible. To achieve this, better mechanistic understanding of liver fibrosis is required. Despite progress in this area, there are still no approved anti fibrotic treatments. To tackle this problem, identifying core factors and their mechanism of action will be highly influential; SOX9 represents one of these factors. A series of data implicate ectopic expression of the Sry-box transcription factor, SOX9, as important in vitro in hepatic stellate cells and their deposition of extracellular matrix (ECM) characteristic of liver fibrosis. Two pressing challenges are now to test these data in vivo to determine if loss of Sox9 prevents or ameliorates liver fibrosis and if over-expression of Sox9 worsens or accelerates the disease; and to determine the genomic-wide binding of Sox9 to help identify direct genetic targets of Sox9 action and to elucidate the downstream pathways that may facilitate novel therapeutic intervention. Taken together, these experiments are anticipated to prove an important role for Sox9 in organ fibrosis and assist in identifying new pathways of value in the search for new therapies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: The Functional Significance of the Fn14/TWEAK Receptor-Ligand System in Ductular Reactive Cell Differentiation and Bile Ductule Neogenesis.
Funder: Medical Research Council

Abstract: The novel TNF receptor Fn14 is highly expressed on cholangiocytes in areas of ductular regeneration in the inflammed liver. This project will characterise the role of Fn14 and its ligand TWEAK in remodelling and differentiating intrahepatic bile ducts by cholangiocytes and their ductular reactive cell precursors. This will determine the Fn14/TWEAK system as a potential therapeutic target for chronic ductopenic liver diseases. Fundamental aims are to define: 1.Fn14/TWEAK expression in normal and ductopenic livers. 2.The functional role of Fn14/TWEAK in biliary remodelling by mature cholangiocytes. 3.The phenotype of ductular reactive cells allowing isolation and culturing of cholangiocyte precursors. 4.The role of Fn14/TWEAK in ductular reactive cell differentiation forming functional biliary architecture. Project design: (1)Human studies: cholangiocytes will be isolated from explanted livers. Detailed analysis of Fn14/TWEAK expression and functional outcome of Fn14/TWEAK interaction will utilise multicolour confocal microscopy, flow cytometry and cell IQ for cholangiocyte migration. (2)Isolation of human ductular reactive cells: by antibody phenotyping before positive and negative fluorescent cell-sorting. (3)Murine studies: to determine the effects of Fn14/TWEAK using wildtype and Fn14 knockout specimens in liver injury models including carbon tetrachloride fibrosis, bile duct ligation cholestasis and partial hepatectomy.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Discovering the importance of ITGB1 in liver fibrosis
Funder: Medical Research Council

Abstract: Despite significant progress in defining the molecular basis of liver fibrosis, there are currently no effective anti-fibrotic therapies for clinical use. Activation of quiescent hepatic stellate cells (HSCs) to proliferative myofibroblasts is the crucial step in initiating fibrosis. My preliminary data suggest that Itgb1 signalling plays a central role in HSC activation and liver fibrosis. The objective of my research is to unravel the role of Itgb1 in the development and function of activated HSCs in vitro, and test this in liver fibrosis in vivo. This will extend to testing whether small molecule integrin antagonists can block liver fibrosis in animal models. My specific aims are: 1. Define the temporal importance of Itgb1 during HSC activation in vitro 2. Identify the alpha-subunit(s) interacting with Itgb1 in activated HSCs 3. Define the temporal importance of Itgb1 during the onset of liver fibrosis in mice Methodology: I will utilise the techniques of immunoblotting, immunocytochemistry, expression microarray, real time-PCR, histology staining with haemotoxylin and eosin and Sirius red, cell transfection and co-immunoprecpitation. In vivo work will utilise Itgb1fl/fl;GFAPCreER+/- mice for conditional deletion of Itgb1 by intraperitoneal tamoxifen injection; before during and after induction of liver fibrosis by intraperitoneal CCl4 injection or bile duct ligation. Potential Scientific and Medical Outcome: Defining the role of Itgb1 signalling, and the effects of its blockade, will be a major advancement in our understanding of the pathophysiology of liver disease. Uncovering therapeutic potential for integrin-targeting compounds would be very exciting: there is an urgent need for anti-fibrotic agents, and discovering a new avenue for drug development would give hope to patients suffering with this condition, and clinicians frustrated by the lack of treatment options.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Interaction of endocytic vacuoles with cellular organelles as a trigger for the cell damage in acute pancreatitis.
Funder: Medical Research Council

Abstract: Acute pancreatitis (AP) is a severe, debilitating and sometimes fatal disease. Its incidence has escalated dramatically in recent years, however, no specific therapy exists. We have found that inducers of AP trigger formation of large endocytic vacuoles in pancreatic acinar cells within which trypsinogen activation occurs. Our preliminary experiments revealed rupture of these vacuoles and fusion of the vacuoles with the basal and lateral regions of the plasma membrane. In order to understand the pathophysiology of AP and develop translational approaches, we will investigate the mechanisms responsible for the intravacuolar trypsinogen activation, rupture of the vacuoles and fusion of the vacuoles with the plasma membrane. We will test if intravacuolar trypsinogen activation and the rupture of the vacuoles are important for the damage of acinar cells. We will determine if trypsinogen is activated in the vacuoles as a result of the interaction of the vacuoles with autophagosomes / lysosomes / endosomes and whether these organelle interactions are required for the rupture of the vacuoles. We will determine if the cells could be damaged as a result of the fusion of the vacuoles with basolateral membrane and release of trypsin into the extracellular milieu (experiments on undissociated pancreatic tissue will be essential for this part of the project). We hope to determine the sequence of events starting from aberrant signalling and organelle interactions to trypsinogen activation and cell damage. The project will involve confocal and two-photon microscopy of live pancreatic cells and tissues (the primary technical strength of our laboratory), and will be supplemented with immunocytochemistry, molecular biology, electrophysiology and electron microscopy. The project will be closely coordinated with the work of the Liverpool NIHR Pancreas Biomedical Research Unit so that any technical or conceptual developments could benefit the translational efforts of the Unit.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Pathogenesis of Ulcerative Colitis: the role of Claudin-8 in epithelial barrier function and inflammation
Funder: Medical Research Council

Abstract: Title Pathogenesis of Ulcerative Colitis: the role of Claudin-8 in epithelial barrier function and inflammation Background Ulcerative Colitis (UC) is a chronic Inflammatory Bowel Disease affecting 120,000 people in the UK. There is evidence that abnormal epithelial barrier function could drive aberrant immune responses in genetically susceptible individuals. Studies in humans and animals have shown that the composition of several tight-junction molecules, in particular members of the claudin (CLDN) family, become altered in active colitis. Recent work in our laboratory, the only study investigating UC patients in clinical remission, revealed a significant reduction in CLDN8 expression in colonic samples of UC patients. In contrast, the expression of other CLDN proteins was not altered in our study. Further analysis of our data revealed that reduced expression of CLDN8 mirrored the disease distribution in the colon. Aims: 1. Determine the functional significance of CLDN8 in bowel homeostasis and inflammation 2. Define the changes in CLDN expression levels in individual UC patients in longitudinal studies Methodology: The changes in the structure, epithelial turnover and permeability of the colon will be studied in a CLDN8 knockout mouse model. Several models of inflammation, including acute and chronic colitis, will also be used in the mutant mice to assess the role of CLDN8 in inflammation. In addition, colonic biopsies will be taken during relapse and remission of UC in the same patients. This will be used to determine the changes in CLDN8 expression, and possible compensatory changes in the expression of other CLDNs as the disease reverts or relapses. Scientific and Medical opportunities If CLDN8 is shown to be aetiologically implicated in UC, it might prove beneficial to treat the condition by elevating the levels of the molecule in the colonic mucosa, for example by the induction of gene expression, or gene therapy, delivered by enema


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Improved Delivery and Function of Myoblasts via Soluble TIPS Microcarriers
Funder: Medical Research Council

Abstract: The project aims to demonstrate proof of principle for an innovative therapeutic system for functional restoration of injured muscle using a combination of cell therapy and a novel degradable cell microcarrier device. The novelty of this approach is the use of TIPS microspheres for cell expansion and delivery, utilizing their advantageous features and avoiding the need for proteolytic cell detachment prior to delivery. Optimal conditions for muscle progenitor cell attachment to TIPS microspheres with different porosities will be identified with primary cultures of myoblasts and mesoangioblasts derived from mouse and human tissues at different seeding densities using a range of dynamic and/or static regimens. External anal sphincter injury will be modelled in a pilot investigation by creating a transverse incision in the tibialis anterior of mice and evaluating the healing response. Delivery of the cellularized microspheres and repair of muscle injury will be investigated in three injury groups simulating repair at different stages after obstetric injury and compared with delivery of cell suspensions or microspheres alone. The muscle will be resected at 2 and 4 weeks after treatment and contractile properties measured using an organ bath and electrical field stimulation. Integration of transplanted cells with host muscle at the injury site and remodelling of tissue will be determined by histology combined with morphometric analysis of fibrosis and angiogenesis. The findings from the experimental component of the project, combined with feedback from patient user groups, will contribute to the developmental pathway of the therapeutic system. The use of quality qualified TIPS microspheres combined with cell types currently being trialled in humans as advanced therapeutic medicinal products will accelerate future translation of the system into the clinic.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: ORAL AND GASTROINTESTINAL