NIHRDataInsights/HRCSData huggingface dataset:
Title: The Role of sIL-6R Mediated Trans-signaling in Cardiovascular Morbidity in Rheumatoid Arthritis
Funder: Arthritis Research UK

Abstract: Mortality is increased in RA patients mainly due to coronary artery disease (CAD), however the biologic mechanisms are unknown. Cardiovascular risk scores, even after modification as recommended by EULAR, underestimate risk in RA. My objective through this fellowship is to reduce cardiovascular mortality in RA by investigating biologic mechanisms and exploring potential biomarkers that can identify high-risk patients. Recent data from Cardiff Arthritis Research Group and elsewhere suggests soluble IL-6 receptor (sIL-6R) mediated trans-signaling is important in the pathogenesis of CAD in RA. Our preliminary work found sIL-6R levels are higher in RA patients with CAD than those without. Using the human primary cell based BioMAP® system, which included cell-types important in atherosclerosis, proteins regulated by sIL-6R were systematically identified. We have collectively called these sIL6R-regulated CAD Candidate Proteins (SCCPs). _x000D_ _x000D_ _x000D_ Key goals _x000D_ _x000D_ I hypothesise that sIL-6R-mediated trans-signaling is a major driver of CAD in RA. This will be demonstrated by:_x000D_ _x000D_ 1.Determining whether SCCPs are associated with progression of CAD using carotid intimal thickness(cIMT) as a surrogate marker._x000D_ _x000D_ 2.Investigating whether IL-6R-knockout mice are protected against vascular dysfunction in collagen-induced arthritis. _x000D_ _x000D_ 3.Determining whether IL-6 trans-signaling accelerates atherosclerosis, and whether sgp130(selective inhibitor of IL-6 trans-signaling) prevents development of atherosclerosis in Apo-E-/- mice.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;CARDIOVASCULAR
Title: The collective bioactivity of dietary flavonoids: importance of specific structural characteristics for cardiovascular benefits
Funder: Biotechnology and Biological Sciences Research Council

Abstract: We hypothesise that flavonoids share common biological activities, which are based on structural similarities between species and their reported 'health effects' are the result of multiple compounds working collectively. The bioactivity-directed screening model we have developed will use complimentary cell systems to investigate the structure-activity-relationships of flavonoids (objective 1), flavonoid metabolites (objective 2) and combinations of flavonoids and metabolites (objective 3), focusing on their effects on vascular and inflammatory markers (primary endpoints) and oxidative stress and anti-oxidant gene expression (secondary endpoints) in HUVEC, SMC and THP-1 cells. This model will test the flavonoids catechin, cyanidin, quercetin, naringenin, peonidin and hesperetin, and their common metabolic by-products (13 metabolites) at levels between 0.1 and 100uM. Our treatment matrix consists of 48 treatments across 5 concentrations and 3 replicates, for a combined 720 initial bioactivity screens. The model contains 5 levels of bioactivity: global cellular bioactivity utilising the WST-1 and H2DCFDA assays (Model Level 1); cardiovascular bioactivity relative to vascular, anti-inflammatory and anti-oxidant activity, utilising NADPH oxidase and eNOS bioactivity assays and the LPS induced pro-inflammatory cytokine assay (Model Level 2); biomarker gene (Model Level 3) and protein (Model Level 4) expression for eNOS, NADPH-oxidase, haem oxygenase-1, NQO1, glutathione regulating enzymes TNF-alpha, IL-1beta, tissue factor and VCAM-1; and DNA binding activity of the redox-sensitive transcription factors NF-kappaB or Nrf2 (Model Level 5). At each level of the model, as the more targeted assays become increasingly more time and resource 'expensive', the initial treatment numbers will be refined as the treatments displaying neutral or negative responses will not be taken to the next level of the model.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;CARDIOVASCULAR
Title: Coronary Artery Disease Evaluation in Rheumatoid Arthritis
Funder: Department of Health (England)

Abstract: RESEARCH DESIGN: This study bolts on to the VEDERA trial a prospective longitudinal intervention study of patients with early RA randomized to either first-line anti-TNF therapy or conventional DMARD therapy. It isproposed that VEDERA patients undergo cardiovascular MRI at baseline 1 and 2 years. Baseline MRI results from the first 30 recruited patients will be compared with 30 matched controls. Changes in MRI findings between baseline and 1 year will be compared between VEDERA treatment groups.STUDY POPULATION: 100 patients from the VEDERA study and 30 controls. Inclusion criteria: diagnosis of RA according to 2010 ACR/EULAR criteria no prior therapy with disease modifying drugs early active disease and >1 poor prognostic factor.PLANNED INTERVENTIONS: Experimental treatment arm: immediate Etanercept (ETN) and Methotrexate (MTX) treatment. Control Treatment Arm: initial MTX monotherapy with Treat to Target (TT) regimen: escalation to combination DMARD therapy at or after 8 weeks if failing to meet pre-defined target and step-up to ETN and MTX at 24 weeks if failing to meet pre-defined target of remission.Proposed outcome measures: Primary: Aortic distensibility (MRI) Secondary: Myocardial perfusion reserve LV strain and twist LV Ejection fraction (all MRI) Exploratory: Extracellular volume fraction (MRI) and blood biomarkers.ASSESSMENT AND FOLLOW UP: MRI and biomarkers at baseline (pre treatment) and at 1 and 2 years of treatment. PROPOSED SAMPLE SIZE: A sample size of n=100 (50 in each group anticipating 10% lost to follow-up) will provide a power of 90% and a significance level of 5% to detect a difference of 2.46 cm2 dyne-110-6 or greater in the primary endpoint at 1 year.STATISTICAL ANALYSIS: The presence magnitude and 95% confidence interval of a difference between RA treated and RA non-treated patients will be determined.PROJECT TIMETABLE: Pre-award: Start acquisition of baseline MRI of VEDERA patients. Month 0-4: Design protocol establish the SMG and SSC obtain regulatory approvals. Month 3 - 19: Recruit patients. Month 15-49(54 if extension required): 1 year and 2 year follow-up MRI scans and analysis.RECRUITMENT STRATEGY: Patients to VEDERA are recruited from the local Rheumatology service where around 100 new cases of early RA are seen per year. Patients for this proposal are recruited from the VEDERA population.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;CARDIOVASCULAR
Title: IDENTIFICATION OF CELLULAR INFLAMMATION IN THE MYOCARDIUM USING MAGNETIC RESONANCE IMAGING
Funder: Chief Scientist Office (Scotland)

Abstract: "Ferumoxytol is a 'smart' magnetic resonance contrast agent consisting of ultrasmall superparamagnetic particles of iron oxide (USPIOs) that are taken up by macrophages. Concentration of USPIOs within macrophages changes the tissue relaxation properties and this can be detected by magnetic resonance imaging using R2* maps. In an early proof-of-concept study, we have recently demonstrated that macrophages can be detected by USPIOs in the penumbra and infarct zone of the myocardium in patients with a recent myocardial infarction. We therefore wish to establish whether USPIOs can be used to identify cellular inflammation within the myocardium in three distinct clinical conditions that currently lack a non-invasive diagnostic imaging test: cardiac allograft rejection, viral myocarditis and cardiac sarcoidosis. If successful, this would not only provide a useful diagnostic test but would also be a method of monitoring disease progression or response to therapy."


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;CARDIOVASCULAR
Title: Developmental clinical studies- Effect of elafin on myocardial injury and inflammation in coronary artery bypass surgery
Funder: Medical Research Council

Abstract: During coronary artery bypass graft surgery, the myocardium receives an immediate ischaemic insult, exacerbated by post-ischaemic inflammatory responses following reperfusion that lead to increased myocardial injury. Elafin is a potent endogenous anti-elastase with wide ranging anti-inflammatory properties that inhibit destructive post-ischaemic inflammatory pathways. We hypothesise that elafin will reduce peri-operative ischaemic myocardial injury and systemic inflammation in elective coronary artery bypass graft surgery. Myocardial injury will be quantified over the first 48 hours using serial measurements of plasma troponin T concentrations. Subsequent myocardial infarct volume will be quantified by cardiac magnetic resonance imaging. This proof-of-concept study will establish whether elafin has cardioprotective effects in a clinical model of predictable myocardial injury. It has implications for the treatment of ischaemic heart disease, myocardial infarction and other diseases of ischaemic origin.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;CARDIOVASCULAR
Title: Feasibility study - treatment of fatigue with physical activity and behavioural change support in vasculitis (FAB-V)
Funder: Versus Arthritis

Abstract: Fatigue in patients with rheumatic diseases is a major life-affecting symptom. Currently it is under-diagnosed and inadequately treated (ARUK workshop report 2013). Fatigue in ANCA-associated vasculitis (AAV) is related to biological and psychosocial mediators, including depression, pain, and sleep deprivation. Studies in rheumatoid arthritis and chronic fatigue syndrome have suggested that fatigue maybe amenable to treatment through increased physical activity.


Research activity codes: 6.7 PHYSICAL;6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;CARDIOVASCULAR
Title: Investigating premature mortality in people with ANCA-associated vasculitis
Funder: Versus Arthritis

Abstract: Background: ANCA-associated vasculitis has the highest mortality of the Rheumatic diseases, with 11-14% of people affected dying within 1 year. As it is rare, with incidence estimated as 20/million person-years, previous studies are small, and there are limited data about mortality and its causes.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;CARDIOVASCULAR
Title: Predicting cardiovascular risk in Rheumatoid arthritis patients: Addition of microparticle and immunological biomarkers to current cardiovascular risk scores
Funder: Department of Health (England)

Abstract: Rheumatoid arthritis (RA) is an autoimmune disease that affects 600,000 people in the UK. The biggest cause of death in these patients is cardiovascular disease (CVD). Microparticles are small vesicles produced by cells in the vessels when the body is stressed. In this study, levels of microparticles and immune function will be assessed in patients with established RA plus cardiovascular disease and compared to controls. Signature microparticle and immune function profiles will be assessed in predicting cardiovascular disease in new RA patients. Better evaluation of early RA patients could lead to earlier intervention and decrease in morbidity and mortality from CVD.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;CARDIOVASCULAR
Title: Ageing and the maladapted innate immune response: implications for recovery from cardiac surgery
Funder: The Dunhill Medical Trust

Abstract: Demographic trends, including aging of the “baby-boomer” generation, suggest health issues related to an increasingly elderly population will impact on resources of Western societies. In this context, the age of individuals presenting for complex cardiac surgery is increasing and we have shown that post-operative recovery is compromised. We have preliminary data indicating that expression on neutrophils of RAGE, a pro-inflammatory pattern recognition receptor; PRR) increases with age (Pearson’s r2=0.7, p< 0.05). Also, we have shown that RAGE ligands are increased during cardiac surgery; together, these data suggest greater potential for deleterious, enhanced innate-immune responses in the elderly. We propose to investigate using neutrophils from patients undergoing cardiac surgery: 1) Age-related RAGE expression; and for comparison other PRR i.e. toll-like receptors 2) Functional consequences of RAGE activation 3) Inhibitory stratagems of potential therapeutic importance. Greater understanding of the RAGE axis in neutrophils has important implications for reducing the burden of age-related-disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;CARDIOVASCULAR
Title: Investigating and targeting monocyte-macrophage cellular effectors in ANCA associated vasculitis
Funder: Wellcome Trust

Abstract: The pathophysiology of ANCA associated vasculitis remains incompletely understood but with the development of novel animal models we have the tools to investigate the key processes initiating and propogating disease. Monocytes/macrophages are frequently found in affected organs. However, the precise role they play and the effect their differental states of activation play in disease are still unclear. This proposal seeks to investigate the role of monocyte/macrophage activation and polarisation in ANCA associated disease, using our autoimmune immunised rat model and patient material. Our hypothesis is that the state of macrophage activation dictates disease phenotype and outcome. As such targeting the key processes in macrophage activation should provide a novel rational therapeutic approach. We will make use of the model we have developed to investigate the genetic predisposition to disease using a series of congenic animals we have generated, the role of signalling pathways in vivo a nd the macrophage phenotype. These results will be compared with patients and the correlation between macrophage activation and disease phenotype will be made.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;CARDIOVASCULAR
Title: A System for Quantitative Measurement of Nailfold Capillary Structure and Function using Image Analysis.
Funder: Wellcome Trust

Abstract: Our proposal is to develop a new technology to measure the small blood vessels (capillaries) of the finger nailfold. Nailfold capillaries are almost always abnormal in the multisystem disease scleroderma ( systemic sclerosis ), and their early detection by nailfold capillaroscopy (nailfold examination under a microscope) helps clinicians distinguish primary (benign) Raynaud s phenomenon (episodic discoloration of the fingers in cold weather) and scleroderma-associated Raynaud s. Patients with scleroderma can have very severe finger problems with scarring, ulcers and even gangrene, so early diagnosis is important. With the new technology, researchers will be able not only to detect if capillaries are normal or abnormal, but also to quantify the degree of abnormality and measure change over time, or in response to drug treatment. Current treatments for scleroderma-associated Raynaud s are unsatisfactory, because our present inability to measure the disease process accurately has hamp ered clinical trials of new treatments. The capillaroscopy system we have developed in Manchester measures abnormality and tracks change over time, but needs major refinement to make it use-friendly , fast, and completely automatic. Once developed, the new technology will be used by clinicians across different countries to research scleroderma and other diseases such as diabetes in which abnormalities of small blood vessels occur.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;CARDIOVASCULAR
Title: Immunomodulatory role of platelets ITAM receptors in systemic inflammation and sepsis associated with cardiovascular diseases
Funder: Wellcome Trust

Abstract: Sepsis is a dysregulated response to infection that has a high mortality. It is associated with low platelet count, a dysfunctional inflammatory response and multiple organ failure. Patients with cardiovascular disease have a higher risk of developing sepsis with worse outcomes, particularly in the elderly. In this project we will investigate whether cardiovascular diseases and ageing induce a pro-inflammatory and prothrombotic state during sepsis that is mediated by upregulation of platelet activity. We will determine whether this is ameliorated by inhibition of platelet immune receptors GPVI, CLEC-2 and Fc&gamma;RIIa, which modulate inflammation and pathogenic thrombosis but have a minimal role in haemostasis. We will investigate these mechanisms in platelets and immune cells from patients with cardiovascular disease and validate these observations in clinically relevant experimental sepsis models associated with chronic cardiovascular diseases (e.g. atherosclerosis and heart failure). We will inhibit the platelet receptors GPVI, CLEC-2 and Fc&gamma;RIIa using a range of different approaches and determine effects on sepsis progression and outcome. This work will help understanding the influence of cardiovascular disease and age on sepsis and provides a novel approach for targeting platelet-immune cell interactions in sepsis using new drugs that target platelet immune receptors.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;CARDIOVASCULAR;INFECTION
Title: Antibiotics and antiseptics for venous leg ulcers (review update)
Funder: Department of Health (England)

Abstract: Venous leg ulcers (VLUs) have been estimated to affect 0.1 to 1.1% of people in developed countries.1 VLUs are painful and lead to restriction of work and leisure activities and social isolation.2 They are also costly to treat: a recent evaluation conducted in Germany estimated the total mean annual cost of illness for leg ulcers as EUR 9060 per patient (price year 2006).3 It is thought that the presence of infection leads to delayed healing; it is thus crucial to assess the effectiveness of interventions designed to combat infection on VLU healing.Our Cochrane review ‘Antibiotics and antiseptics for venous leg ulcers’ was last updated in 2010. We included 25 trials reporting 32 comparisons and found a lack of reliable evidence in relation to systemic antibiotics for promoting healing in VLUs. We found some evidence to support cadexomer iodine but no good quality evidence regarding other topical preparations. We know that there have been at least 15 new trials published since 2010. We believe it is necessary to update this highly accessed review (3864 abstract downloads in 2012) to provide decision-makers with the most up-to-date evidence in this complex high-cost area.1.Graham ID Harrison MB Nelson EA Lorimer K Fisher A. Prevalence of lower-limb ulceration: a systematic review of prevalence studies. Advances in Skin and Wound Care 2003;16(6):305-16.2.Herber OR Schnepp W Rieger MA. A systematic review on the impact of leg ulceration on patients quality of life. Health and Quality of Life Outcomes 2007;5(44).3.Augustin M Brocatti LK Rustenbach SJ Schäfer I Herberger K. Cost-of-illness of leg ulcers in the community. International Wound Journal 2012:doi: 10.1111/j.1742-481X.2012.01089.x.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;CARDIOVASCULAR;SKIN
Title: Educating adolescents at Risk of Anaphylaxis and their Future Doctors (ERA+FD)
Funder: Department of Health (England)

Abstract: Background: Anaphylaxis is a life-threatening allergic reaction. Adolescent patients and doctors lack knowledge and skill in anaphylaxis management. This must be addressed through improved education, to ensure better patient care. Modern technology can support innovative educational methods. Objectives/Design: 1. To develop an anaphylaxis education programme, making use of modern technology, including smartphones. 2. To integrate user views & experiences into the programme, using qualitative methods and participatory design. 3. To adapt and deliver the resource to medical students, performing a pilot randomised controlled trial of its implementation. Outcomes: Improved self-care of nut-allergic adolescents and clinical skills of future doctors.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;7.1 INDIVIDUAL CARE NEEDS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;DISPUTED AETIOLOGY AND OTHER
Title: Identifying the biological fingerprints of fatigue
Funder: Medical Research Council

Abstract: This study aims to identify the biological fingerprints of fatigue using primary Sjogren's syndrome (PSS), an autoimmune condition with several clinical and biological features similar to chronic fatigue syndrome (CFS) including intense fatigue, as a disease model. We will then test whether these biological fingerprints are also present in patients with CFS. We will perform whole blood gene expression profiling (using genome-wide microarray) and measure serum markers of immune dysregulation (using fluorescent bead-based multiplex technology) of an existing biobanked samples from a large cohort of clinically well-characterized PSS patients (the UK PSS registry). Further information concerning the cohort can be found on the cohort website www.sjogrensregistry.org and Annex 1. The data from these experiments will be analyzed using various bioinformatics techniques in order to identify a biological profile of fatigue, which will be validated using a second blinded test cohort of PSS patients. We will also investigate whether the biological profile changes over time and responds to biological treatment of fatigue in PSS patients. The data from these investigations will then be integrated to identify a set of biomarkers that will maximally discriminate fatigued subjects from non-fatigued individuals. Finally, we will test whether these biomarkers of fatigue are present in CFS patients and if so, whether they can be used to correctly classify CFS from active or sedentary healthy individuals.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;DISPUTED AETIOLOGY AND OTHER
Title: Regulation of monocyte function by iNKT cells in normal subjects and sarcoidosis.
Funder: Wellcome Trust

Abstract: Sarcoidosis is a multisystem disease of unknown cause, predominantly affecting the lungs. It affects between 5 and 10 per 100 000 of the population in the United Kingdom. The course of the disease is unpredictable and there is no satisfactory treatment. Poor understanding of the mechanisms underlying this condition has hampered the development of more effective therapies. By contrast, in other diseases, a clearer understanding of the underlying cellular and molecular abnormalities has lead to the development of novel, targeted, therapies. This includes therapy targeting the inflammatory mediator tumour necrosis factor alpha (anti-TNF&#945;) for the treatment of inflammatory joint and bowel diseases, and targets against leukotriene- receptors for the treatment of asthma. Complex immune-mediated pathways are important in the development of sarcoidosis. In this study I will investigate an immune defect implicated in the development of disease in sarcoidosis. It is hoped that th is study will improve understanding of this disease and reveal potential targets for therapeutic intervention.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;DISPUTED AETIOLOGY AND OTHER