NIHRDataInsights/HRCSData huggingface dataset:
Title: US- Ireland Partnership - Brendan Gilmore - Cold Plasma to Treat Post-Surgical Orthopedic Infection: A tripartite USA/Northern Ireland/Republic of Ireland Consortium
Funder: Public Health Agency, NI

Abstract: Infection following joint replacement is a devastating complication that occurs in up to 1-2% of cases. The incidence is even higher in patients with: diabetes, obesity, surgical site infections, inflammatory disorders, poor wound healing, or for those who smoke. Because of the increasing prevalence of multi-drug resistant bacteria, there is a critical need to develop new therapeutic interventions to avoid untreatable, life-threatening infections. Cold plasma is a non-antibiotic intervention that can eradicate bacteria and destroy bacterial biofilms. In this application, we propose to test the hypothesis that a multimodal cold plasma treatment applied during orthopaedic surgical procedures will eradicate existing bacteria and biofilm, thus preventing infection (or reinfection) and enhance surgical site healing and osseointegration. There are two Specific Aims. In SA1, we will determine the plasma treatment(s) protocol necessary to eliminate bacteria from (a) infected tissues and (b) bacterially contaminated hardware/implants/graft materials, using either direct cold plasma treatment and/or indirect treatment with plasma activated saline. We will also examine the effects of these treatments on the surrounding tissues. Based on our previous experiments, we propose that cold plasma treatments will foster tissue repair and new bone formation. The outcomes of the studies in SA1, will allow us to develop an integrated plasma treatment system that will protect the tissue and implant or allograft material against infection or reinfection after orthopaedic surgical procedures. In SA2, we will test the efficacy of the cold plasma treatment protocol developed in SA1, in two animal models that simulate either (a) Primary Surgery – with contaminated hardware or (b) Revision Surgery due to periprosthetic infection. Ultimately, we envision that cold plasma would be applied clinically during high-risk musculoskeletal tissue surgeries to protect against bacterial infection. Use of this powerful antimicrobial treatment will minimize induction of antibiotic resistance and improve orthopaedic surgery clinical outcomes, with the possibility of application to other general surgical procedures.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL;INFECTION
Title: Using evidence to reduce risk of healthcare acquired infection following primary hip replacement
Funder: Department of Health (England)

Abstract: Aim: to assess the cost-effectiveness of competing strategies that reduce risk of infection following hip replacement in an NHS hospital?Design: Decision analytic cost-effectiveness model informed by existing evidence. Target population: Patients undergoing primary hip replacement in NHS hospitals.Setting: NHS acute and community care services.Methods: State transition Markov models will be developed and updated with data that describe relevant parameters. Systematic reviews will be undertaken and the results meta-analysed. Other sources of evidence such as surgical registers will be assessed for quality and used to update model parameters. Uncertainties will be assessed by (i) probabilistic interpretation of parameter uncertainty (ii) important sources of variability will be considered. A Bayesian approach will allow external prior information (e.g. expert opinion) to be incorporated into the analysis. Markov Chain Monte Carlo (MCMC) re-sampling will be undertaken from each parameter distribution in the WinBugs environment. The result will be a joint distribution of cost and QALY outcomes. These points describe the joint uncertainty among model parameters. Net monetary benefits will be calculated and described and interpreted for the purpose of decision making.Expected output of research: A comprehensive policy for the management of infection risk among patients undergoing primary hip replacement in NHS hospitals. The policy will depend on the cost-effectiveness criterion. There will be intermediate outcomes as we progress toward this goal: estimates of the clinical effects of risk reducing interventions; estimates of the changes to economic cost outcomes; and estimates of the changes to health benefits. We will identify the efficient level of investment in infection control programmes and identify the best strategies to implement. If the decision is highly uncertain we will estimate the value of perfect information to inform future research efforts


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: MUSCULOSKELETAL;INFECTION
Title: Investigating the chondroprotective functions of TSG-6: towards novel therapeutics for arthritis (renewal)
Funder: Arthritis Research UK

Abstract: TSG-6 is an inflammation-associated protein, expressed in the cartilage and synovia of both OA and RA patients. There is increasing evidence that this multi-functional protein acts as an endogenous inhibitor of joint destruction during inflammation and also has homeostatic roles, e.g. in the regulation of bone turnover. We have made excellent progress in identifying new functions and ligands for TSG-6 and this renewal application is aimed at the development of a panel of mutant TSG-6 proteins with selectively restricted activities in vitro that will then be tested in mouse models. This approach, in combination with high-resolution structural studies, will enable us to fully characterise the molecular mechanisms that underlie the anti-inflammatory, chondroprotective and anti-resorptive properties of TSG-6. Furthermore, it will allow the identification of the best candidate molecules (e.g. wild-type or mutant TSG-6 proteins) for the development of new therapeutic approaches for the treatment of arthritic disease.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Role of osteoprotegerin autoantibodies in the pathogenesis of osteoporosis in rheumatic diseases
Funder: Arthritis Research UK

Abstract: Osteoporosis is a recognised complication of inflammatory rheumatic diseases such as rheumatoid arthritis and SLE which is thought to occur as the result of multiple mechanisms including over production of pro-inflammatory cytokines; relative immobility and corticosteroid therapy. We have recently encountered a patient with coeliac disease who developed severe, high turnover osteoporosis in association with the development of neutralising antibodies to osteoprotegerin (OPG). In preliminary studies, we have found evidence of circulating antibodies to OPG in patients with rheumatoid arthritis and SLE, although their clinical significance is as yet unknown. The aim of this project will be to determine the frequency with which these antibodies occur; to determine if they have functional significance and to determine if the occurrence of OPG antibodies is related to the occurrence or severity of osteoporosis in rheumatic diseases.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Validating the genetic associations of ankylosing spondylitis
Funder: Arthritis Research UK

Abstract: Genome-wide association studies using panels of single nucleotide polymorphisms (SNPs) have already identified genes with relatively strong effects in ankylosing spondylitis (AS), such as ERAP1 and IL23R. Larger sample sizes will be necessary to detect weaker but potentially crucial biologic effects reliably. The Wellcome Trust and Australo-Anglo-American AS (TASC) consortia have identified 4 genomic regions of interest, containing important candidate genes (STAT3, ANTXR2, CARD9 and TRADD) that we wish to study further. Their associations will first be validated using a panel of tagging SNPs in a combined sample of at least 4,000 cases and controls. Some resequencing of these genes may be required to create a sufficiently comprehensive panel of SNPs for these analyses. Because STAT3 (already incriminated in Crohn's disease) and IL23R are both involved in Th17 lymphocyte functions we will also investigate other genes in the Th17 inflammatory pathway (eg. IL-10, IL6R). This will include comprehensive evaluation of the results from previous studies, the design of SNPs for replication/confirmation studies, some resequencing, and substantial genotyping and statistical analysis. Robust identification of AS-associated genes is an important precursor to detailed studies of their structure and function on which to base drug discovery programmes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Complement terminal pathway and susceptibility to rheumatological disease.
Funder: Arthritis Research UK

Abstract: Complement is a key component of the immune system with a central role of protecting against pathogenic infection. However, it also plays a role in propagating inflammation if activated excessively. Activation of the complement system leads to release of anaphylotoxins and assembly of the Membrane Attack Complex; which can lead to local inflammation and tissue damage._x000D_ _x000D_ Membrane Attack Complex assembly has been related to pathophysiology of several rheumatological diseases, including Rheumatoid Arthritis. The aim of this project is to investigate existing polymorphic variants of the components of complement and how different complotypes may lead to an increased susceptibility to disease. By looking at the kinetic and structural assembly of the Membrane Attack Complex, and how different polymorphisms affect this assembly, it will be possible to develop future strategies for modulation of this pathway.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: The role of inter-alpha-inhibitor in arthritis: friend or foe?
Funder: Arthritis Research UK

Abstract: The heavy chains (HC) from the serum protein inter-alpha-inhibitor (IαI) become covalently attached to hyaluronan (HA) to form HC•HA, where the levels of these complexes in synovial fluids correlate with disease severity in OA/RA. In addition to the effects of HC attachment on the hydrodynamic properties of HA, HC•HA have been implicated in a wide range of functional activities. However, it is not clear whether IαI/HC•HA have a protective or disease-promoting role; i.e. are they friend or foe? In this regard, HC•HA have been shown to have both pro- and anti-inflammatory effects, promoting leukocyte adhesion and macrophage apoptosis, while IαI inhibits complement activation. Furthermore, high MW HC•HA are anti-angiogenic, whereas IαI promotes the pro-angiogenic effects of low MW HA._x000D_ Currently, there are no data on how HA size and the level/nature of HC attachment affect the properties of HC•HA. Here we will address this by characterising the functional activities of defined HC•HA complexes (made in vitro, with known composition and hydrodynamic parameters) and comparing these with intact IαI and HC polypeptides. In combination with biophysical/structural analyses, this will provide important insights into the roles of HC•HA/IαI in arthritides (and the underlying molecular mechanisms), thus defining novel therapeutic targets.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Missed opportunities to improve the management of common musculoskeletal disorders in general practice
Funder: Arthritis Research UK

Abstract: Primary care ‘deals with most health problems for most people most of the time’, an observation that holds true for the majority of musculoskeletal disorders. In the UK, one in five general practice consultations is for a rheumatological complaint and whilst effective care in this setting can make a substantial contribution to individuals, their families and society as a whole, evidence to support clinicians is lacking._x000D_ _x000D_ Early diagnosis in primary care is challenging. The diagnostic value of symptoms, signs and investigation depends on disease prevalence (and therefore the setting), and since the evolution of disease is often poorly understood, research on diagnosis in general practice must take place in primary care rather than hospital settings. Furthermore, general practice patients seldom have disease in isolation. Research conducted in primary care has the unique potential for exploiting the ‘collateral benefit’ of patient centred care when managing patients with multi-morbidity._x000D_ _x000D_ Using a variety of methodologies (qualitative, GP consultation database analysis, cross-sectional survey, cluster randomised trial) this fellowship will address critical but neglected ‘missed opportunities’ in general practice for early diagnosis, effective primary care management and monitoring, and collateral benefits of person-focused care for selected musculoskeletal disorders (polymyalgia rheumatica, rheumatoid arthritis, osteoarthritis).


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Aberrant chondrocyte primary cilia structure and function drives cartilage degradation in response to IL-1
Funder: Arthritis Research UK

Abstract: Primary cilia are poorly understood cytoskeletal organelles that projects into the extracellular milieu. The chondrocytes cilium acts as a centre for Hedgehog (Hh) signalling which has recently been shown to be up-regulated in osteoarthritis where it drives cartilage degradation . However the mechanisms leading to aberrant Hh signalling have not been identified. Preliminary data show that the inflammatory cytokine, IL-1β, which is up-regulated in osteoarthritis, triggers a significant increase in primary cilia length. We hypothesise that this cytokine-mediated ciliogenesis activates changes in cilia function, including Hh signalling. We will therefore identify the underlying mechanisms through which cytokines modulate cilia length, including the involvement of adenyly cyclise, calcium signalling and the actin remodelling. We will then determine the consequences for cilia-mediated Hh signalling, and downstream cartilage matrix synthesis and catabolism. Studies will utilise isolated primary chondrocytes and cartilage explants as well as transgenic chondrocytes that lack primary cilia. We will ultimately determine whether manipulation of ciliogenesis can down-regulate cytokine-induced changes in primary cilia function and thus identify novel cilia-related therapeutic targets to attenuate cartilage degradation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: An Investigation into the Cultural Educational Gap Between What Community Pharmacists (CP) Give and What Patients Want in the Treatment of Arthritis
Funder: Arthritis Research UK

Abstract: Around 99% of the population has access to a pharmacy within 20 minutes by car. Pharmacists therefore represent an enormous untapped resource for identification of symptoms and signposting, monitoring and improving medicine adherence from patients suffering with arthritis. Our project will evaluate the discrepancy between the provision given by pharmacists and what patients want. We will achieve this by developing case studies about patients with arthritis using an expert reference group. The case studies will then be evaluated by pharmacists, detailing the clinical approach they would use. Finally, patients will evaluate the pharmacist's approach, utilising their own experiences of living with the disease. This will identify gaps between information given by CP and the patients' wants and needs and how to reduce perceived barriers between the patient and healthcare professional. Our research will enhance the best practice and ensure a world-class workforce in primary care.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Transient receptor potential canonical (TRPC) 5: a role in joint pain and inflammation?
Funder: Arthritis Research UK

Abstract: The mechanisms that contribute to pain in arthritis are unclear and patients commonly complain of poor pain relief from traditional therapies. Our research has focussed on determining at a fundamental level the role of transient receptor potential (TRP) receptors in murine models of joint pain and inflammation. We have elucidated mechanisms by which TRP vanilloid 1 (TRPV1) and TRP ankyrin1 (TRPA1) channels contribute to arthritic pain. We hypothesise that the TRP canonical 5 (TRPC5) channel, has a protective role. This project will use a range of experimental tools including wild type and TRPC5 knockout (TRPC5KO) mice, to address the following questions: 1) How does TRPC5 influence hyperalgesia and joint inflammatio in arthritis? 2) What influence does TRPC5 have on known arthritic mechanisms associated with pain such as involving TNFα, TRPV1 and TRPA1? 3) Can TRPC5 influence inflammatory mediator and matrix metallo-proteinase expression in activated fibroblast-like synoviocytes (FLS) taken from the mouse and from patients with rheumatoid and osteo- arthritis? These studies involve molecular and cell biology, histological analysis and an integrated physiology approach to studying arthritic mechanisms They are essential and timely for the evaluation of TRPC5 as a novel therapeutic target for the treatment of arthritic pain.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Helping more people to ESCAPE-pain: Early development of an online exercise-based rehabilitation programme for people with chronic knee and hip pain.
Funder: Arthritis Research UK

Abstract: Chronic joint pain affects 8.5 million people, causing enormous personal and socioeconomic hardship. Our programme, Enabling Self-management and Coping of Arthritic Pain through Exercise, ESCAPE-pain, helps people understand how exercise can be used to improve physical and psychosocial well-being. Developing an online version of ESCAPE-pain would enable many more people to benefit._x000D_ _x000D_ However, online programmes often produce unwanted, unusable, “high tech but low impact” programmes with poor uptake, effectiveness, adherence and implementation, because they are developed without input from potential users. To avoid this we plan to interview potential user’s to establish their needs and wants, and work with web-designers to incorporate these into a prototype online version of ESCAPE-pain programme._x000D_ _x000D_ The groundwork prepared by this preliminary study is essential for developing a online version ESCAPE-pain that people suffering joint pain will find relevant, useful, usable, accessible and effective, thereby improving uptake and implementation.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Development of small population prevalence models for the Arthritis Research UK ‘MSK Calculator’
Funder: Arthritis Research UK

Abstract: The overall aim of the project is to develop four (osteoarthritis (OA), rheumatoid arthritis (RA), back pain and high fracture risk (HFR)) small population estimates of prevalence and need for healthcare, and to relate this to actual and expected activity and costs, and where possible intervention thresholds and cost-effectiveness. We propose in the first instance to utilise classical logistic regression modelling, possibly using multiple imputation for missing data and multilevel modelling for clustered data e.g. survey households. Once odds ratios (ORs) have been obtained, internal validation will be carried out using areas under receiver operating characteristics (ROC) curves and prediction probabilities, and derived ORs will then be used to estimate prevalence in small population subgroups, with confidence intervals.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES);2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Improving the safety and patient experience in the magnetic resonance imaging of arthritis: Magnetic resonance imaging of synovitis without the use of intraveous gadolinium
Funder: Department of Health (England)

Abstract: Currently, the assessment of synovitis (inflammation within the joint) with MRI requires intravenous contrast, which is associated with discomfort, cost and potential patient complications. In order to reduce these risks, the aim of this study is to develop and validate MRI in patients with arthritis using novel MRI scans that do not require intravenous administration of contrast agents. Utilising the Leeds patient and imaging infrastructure, we will (i) develop novel MRI sequences to image the presence and extent of synovitis; (ii) refine and assess these novel MRI techniques; (iii) validate the techniques against the gold standard of MRI using intravenous contrast; and (iv) explore the feasibility and utility of the techniques for assessing the effect of biologic therapy. In doing this, we will develop a validated MRI protocol that will be sensitive and specific for assessing synovitis without the need for intravenous administration of contrast.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Forefoot complications in patients with rheumatoid arthritis: identification, impact and intervention
Funder: Department of Health (England)

Abstract: Objectives: 1: to validate the use of ultrasound (US) to assess forefoot health in patients with rheumatoid arthritis (RA). 2: to determine the impact of such forefoot complications 3: to determine the feasibility of a randomised controlled trial (RCT) of targeted intervention, informed by studies 1 and 2. Design: A programme of three interlinking multicentre or internationally collaborative research phases. Expected outcomes: 1: a validated US assessment tool. 2: new information about the prevalence and impact of forefoot complications in patients with RA. 3: a piloted and evidence-based RCT proposal for targeted intervention of forefoot complications in patients with RA.


Research activity codes: 4.3 INFLUENCES AND IMPACT;1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Cachexia, sarcopenia, inflammation and clinical outcome in hospitalised older people
Funder: Department of Health (England)

Abstract: Hospitalised older people are understudied and poorly characterised despite rising admission numbers. Muscle weakness is a common cause of disability in older-adults; associated with disease and reduced life-expectancy. Sarcopenia and cachexia are the commonest causes, possibly due to age-related changes to the immune system, called inflammaging. We will characterise 150 hospitalised older-adults in terms of sarcopenia, cachexia and inflammaging and link with clinical outcomes after 12 months.We will gain a detailed understanding of this group, including causes and consequences of sarcopenia and cachexia, the role of inflammaging, predicting those who will deteriorate and facilitating recovery with early, effective intervention.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM