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Background Few clinical trials have investigated the safety and efficacy of mesenchymal stem cells for the management of post-traumatic osteoarthritis. The objectives of this pilot study were to determine the safety and tolerability and to explore the efficacy of a single intra-articular injection of allogeneic human mesenchymal precursor cells (MPCs) to improve clinical symptoms and retard joint structural deterioration over 24 months in patients following anterior cruciate ligament (ACL) reconstruction. Methods In this phase Ib/IIa, double-blind, active comparator clinical study, 17 patients aged 18–40 years with unilateral ACL reconstruction were randomized (2:1) to receive either a single intra-articular injection of 75 million allogeneic MPCs suspended in hyaluronan (HA) (MPC + HA group) ( n = 11) or HA alone ( n = 6). Patients were monitored for adverse events. Immunogenicity was evaluated by anti-HLA panel reactive antibodies (PRA) against class I and II HLAs determined by flow cytometry. Pain, function, and quality of life were assessed using the Knee Injury and Osteoarthritis Outcome Score (KOOS) and SF-36v2 scores. Joint space width was measured from radiographs, and tibial cartilage volume and bone area assessed from magnetic resonance imaging (MRI). Results Moderate arthralgia and swelling within 24 h following injection that subsided were observed in 4 out of 11 in the MPC + HA group and 0 out of 6 HA controls. No cell-related serious adverse effects were observed. Increases in class I PRA >10% were observed at week 4 in the MPC + HA group that decreased to baseline levels by week 104. Compared with the HA group, MPC + HA-treated patients showed greater improvements in KOOS pain, symptom, activities of daily living, and SF-36 bodily pain scores ( p < 0.05). The MPC + HA group had reduced medial and lateral tibiofemoral joint space narrowing ( p < 0.05), less tibial bone expansion (0.5% vs 4.0% over 26 weeks, p = 0.02), and a trend towards reduced tibial cartilage volume loss (0.7% vs –4.0% over 26 weeks, p = 0.10) than the HA controls. Conclusions Intra-articular administration of a single allogeneic MPC injection following ACL reconstruction was safe, well tolerated, and may improve symptoms and structural outcomes. These findings suggest that MPCs warrant further investigations as they may modulate some of the pathological processes responsible for the development of post-traumatic osteoarthritis following ACL reconstruction. Trial registration ClinicalTrials.gov ( NCT01088191 ) registration date: March 11, 2010

Background Arthroscopic surgery for femoroacetabular impingement syndrome (FAI) is known to lead to self-reported symptom improvement. In the context of surgical interventions with known contextual effects and no true sham comparator trials, it is important to ascertain outcomes that are less susceptible to placebo effects. The primary aim of this trial was to determine if study participants with FAI who have hip arthroscopy demonstrate greater improvements in delayed gadolinium-enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC) index between baseline and 12 months, compared to participants who undergo physiotherapist-led management. Methods Multi-centre, pragmatic, two-arm superiority randomised controlled trial comparing physiotherapist-led management to hip arthroscopy for FAI. FAI participants were recruited from participating orthopaedic surgeons clinics, and randomly allocated to receive either physiotherapist-led conservative care or surgery. The surgical intervention was arthroscopic FAI surgery. The physiotherapist-led conservative management was an individualised physiotherapy program, named Personalised Hip Therapy (PHT). The primary outcome measure was change in dGEMRIC score between baseline and 12 months. Secondary outcomes included a range of patient-reported outcomes and structural measures relevant to FAI pathoanatomy and hip osteoarthritis development. Interventions were compared by intention-to-treat analysis. Results Ninety-nine participants were recruited, of mean age 33 years and 58% male. Primary outcome data were available for 53 participants (27 in surgical group, 26 in PHT). The adjusted group difference in change at 12 months in dGEMRIC was -59 ms (95%CI − 137.9 to - 19.6) ( p  = 0.14) favouring PHT. Hip-related quality of life (iHOT-33) showed improvements in both groups with the adjusted between-group difference at 12 months showing a statistically and clinically important improvement in arthroscopy of 14 units (95% CI 5.6 to 23.9) ( p  = 0.003). Conclusion The primary outcome of dGEMRIC showed no statistically significant difference between PHT and arthroscopic hip surgery at 12 months of follow-up. Patients treated with surgery reported greater benefits in symptoms at 12 months compared to PHT, but these benefits are not explained by better hip cartilage metabolism. Trial registration details Australia New Zealand Clinical Trials Registry reference: ACTRN12615001177549 . Trial registered 2/11/2015.

Background/hypothesis Shoulder pain in elite swimmers is common, and its pathogenesis is uncertain. Hypothesis/study design The authors used a crosssectional study design to test Jobe’s hypothesis that repetitive forceful swimming leads to shoulder laxity, which in turn leads to impingement pain. Methods Eighty young elite swimmers (13–25 years of age) completed questionnaires on their swimming training, pain and shoulder function. They were given a standardised clinical shoulder examination, and tested for glenohumeral joint laxity using a non-invasive electronic laxometer. 52/80 swimmers also attended for shoulder MRI. Results 73/80 (91%) swimmers reported shoulder pain. Most (84%) had a positive impingement sign, and 69% of those examined with MRI had supraspinatus tendinopathy. The impingement sign and MRIdetermined supraspinatus tendinopathy correlated strongly (rs=0.49, p<0.00001). Increased tendon thickness correlated with supraspinatus tendinopathy (rs=0.37, p<0.01). Laxity correlated weakly with impingement pain (rs=0.23, p<0.05) and was not associated with supraspinatus tendinopathy (rs=0.14, p=0.32). The number of hours swum/week (rs=0.39, p<0.005) and weekly mileage (rs=0.34, p=0.01) both correlated significantly with supraspinatus tendinopathy. Swimming stroke preference did not. Conclusions These data indicate: (1) supraspinatus tendinopathy is the major cause of shoulder pain in elite swimmers; (2) this tendinopathy is induced by large amounts of swimming training; and (3) shoulder laxity per se has only a minimal association with shoulder impingement in elite swimmers. These findings are consistent with animal and tissue culture findings which support an alternate hypothesis: the intensity and duration of load to tendon fibres and cells cause tendinopathy, impingement and shoulder pain.

Background Thumb-base osteoarthritis (OA) is a common cause of pain and disability This study aimed to investigate the associations of musculoskeletal ultrasound OA pathologies with the extent of pain, function, radiographic scores, and muscle strength in symptomatic thumb-base osteoarthritis. Methods This is a cross-sectional study of an ongoing clinical trial with eligibility criteria including thumb-base pain on Visual Analogue Scale (VAS) ≥40 (0 to 100 mm), Functional Index for Hand OA (FIHOA) ≥ 6 (0 to 30) and Kellgren Lawrence (KL) grade ≥ 2. The most symptomatic side was scanned to measure synovitis and osteophyte severity using a 0–3 semi-quantitative score, power Doppler and erosion in binary score. A linear regression model was used for associations of ultrasound findings with VAS pain, FIHOA and hand grip and pinch strength tests after adjusting for age, gender, body mass index, disease duration and KL grade as appropriate. For correlation of ultrasound features with KL grade, OARSI ((Osteoarthritis Research Society International) osteophyte and JSN scores, Eaton grades, Spearman coefficients were calculated, and a significant test defined as a p -value less than 0.05. Results The study included 93 participants (mean age of 67.04 years, 78.5% females). Presence of power Doppler has a significant association with VAS pain [adjusted β coefficient = 11.29, P  = 0.02] while other ultrasound pathologies revealed no significant associations with all clinical outcomes. In comparison to radiograph, ultrasonographic osteophyte score was significantly associated with KL grade [r s  = 0.44 ( P  < 0.001)], OARSI osteophyte grade [r s  = 0.35 ( P  = 0.001)], OARSI JSN grade [r s  = 0.43 (P < 0.001)] and Eaton grade [r s  = 0.30 ( P  < 0.01)]. Ultrasonographic erosion was significantly related with radiographic erosion [r s  = − 0.49 (P = 0.001)]. Conclusion From a clinical perspective the significant relationship of power Doppler with pain severity in thumb base OA suggests this might be a useful tool in understanding pain aetiology. It is important to recognise that power Doppler activity was only detected in 14% of the study so this might be an important subgroup of persons to monitor more closely. Trial registration Registered at Australian New Zealand Clinical Trials Registry (ANZCTR), http://www.anzctr.org.au/ , ACTRN12616000353493.

Background Strategies to enhance clinicians’ adherence to validated imaging decision rules and increase the appropriateness of imaging remain unclear. Objective To evaluate the effectiveness of various implementation strategies for increasing clinicians’ use of five validated imaging decision rules (Ottawa Ankle Rules, Ottawa Knee Rule, Canadian C-Spine Rule, National Emergency X-Radiography Utilization Study and Canadian Computed Tomography Head Rule). Design Systematic review. Methods The inclusion criteria were experimental, quasi-experimental study designs comprising randomised controlled trials (RCTs), non-randomised controlled trials, and single-arm trials (i.e. prospective observational studies) of implementation interventions in any care setting. The search encompassed electronic databases up to March 11, 2024, including MEDLINE (via Ovid), CINAHL (via EBSCO), EMBASE (via Ovid), Cochrane CENTRAL, Web of Science, and Scopus. Two reviewers assessed the risk of bias of studies independently using the Cochrane Effective Practice and Organization of Care Group (EPOC) risk of bias tool. The primary outcome was clinicians’ use of decision rules. Secondary outcomes included imaging use (indicated, non-indicated and overall) and knowledge of the rules. Results We included 22 studies (5-RCTs, 1-non-RCT and 16-single-arm trials), conducted in emergency care settings in six countries (USA, Canada, UK, Australia, Ireland and France). One RCT suggested that reminders may be effective at increasing clinicians’ use of Ottawa Ankle Rules but may also increase the use of ankle radiography. Two RCTs that combined multiple intervention strategies showed mixed results for ankle imaging and head CT use. One combining educational meetings and materials on Ottawa Ankle Rules reduced ankle injury imaging among ED physicians, while another, with similar efforts plus clinical practice guidelines and reminders for the Canadian CT Head Rule, increased CT imaging for head injuries. For knowledge, one RCT suggested that distributing guidelines had a limited short-term impact but improved clinicians’ long-term knowledge of the Ottawa Ankle Rules. Conclusion Interventions such as pop-up reminders, educational meetings, and posters may improve adherence to the Ottawa Ankle Rules, Ottawa Knee Rule, and Canadian CT Head Rule. Reminders may reduce non-indicated imaging for knee and ankle injuries. The uncertain quality of evidence indicates the need for well-conducted RCTs to establish effectiveness of implementation strategies.

IntroductionKnee osteoarthritis (KOA) is a highly prevalent disabling joint disease. Intra-articular stem cell therapy is increasingly being used for treating KOA with little high-quality evidence to support its use. The aim of this study is to investigate the efficacy, safety and cost-effectiveness of allogeneic mesenchymal stem cells (Cymerus MSCs) for treating symptomatic tibiofemoral KOA and improving knee structure over 24 months.Methods and analysisThe Stem Cell injections for symptomatic relief and strUctural improvement in people with Tibiofemoral knee OsteoaRthritis study is a phase III, multi-centre, parallel, superiority, randomised, double-blind, placebo-controlled trial, which will be conducted in Sydney and Hobart, Australia. 440 participants (220 per arm) aged over 40 years with painful KOA and mild to moderate structural change on X-ray (Kellgren and Lawrence grade 2 or 3) with medial minimum joint space width between 1 and 4 mm in the study knee will be recruited from the community and randomly allocated to receive either intra-articular MSCs or saline at baseline, week 3 and week 52. The coprimary outcomes will be the proportion of participants achieving patient-acceptable symptom state for knee pain at 24 months and quantitative central medial femorotibial compartment cartilage thickness change from baseline to 24 months. Main secondary outcomes include change in knee pain, Patient Global Assessment, physical function, quality of life and other structural changes. Additional data for cost-effectiveness analysis will also be recorded. Adverse events will be monitored throughout the study. The primary analysis will be conducted using modified intention-to-treat.Ethics and disseminationThis protocol has been approved by The University of Sydney (USYD) Human Research Ethics Committee (HREC) #: 2020/119 and The University of Tasmania (UTAS) HREC #: H0021868. All participants will be required to provide informed consent. Dissemination will occur through conferences, social media, and scientific publications.Trial registration numbersAustralian New Zealand Clinical Trials Registry (ACTRN12620000870954); U1111-1234-4897.

IntroductionKnee osteoarthritis (OA) is the most prevalent arthritis type and a leading cause of chronic mobility disability. While pain medications provide only symptomatic pain relief; growing evidence suggests pentosan polysulfate sodium (PPS) is chondroprotective and could have anti-inflammatory effects in knee OA. This study aims to explore the efficacy and safety of oral PPS in symptomatic knee OA with dyslipidaemia.Methods and analysisMaRVeL is a phase II, single-centre, parallel, superiority trial which will be conducted at Royal North Shore Hospital, Sydney, Australia. 92 participants (46 per arm) aged 40 and over with painful knee OA and mild to moderate structural change on X-ray (Kellgren and Lawrence grade 2 or 3) will be recruited from the community and randomly allocated to receive two cycles of either oral PPS or placebo for 5 weeks starting at baseline and week 11. Primary outcome will be the 16-week change in overall average knee pain severity measured using an 11-point Numeric Rating Scale. Main secondary outcomes include change in knee pain, patient global assessment, physical function, quality of life and other structural changes. A biostatistician blinded to allocation groups will perform the statistical analysis according to the intention-to-treat principle.Ethics and disseminationThe protocol has been approved by the NSLHD Human Research Ethics Committee (HREC) (2021/ETH00315). All participants will provide written informed consent online. Study results will be disseminated through conferences, social media and academic publications.Trial registration numbersAustralian New Zealand Clinical Trial Registry (ACTRN12621000654853); U1111-1265-3750.

Background Knee osteoarthritis (OA) causes substantial pain, physical dysfunction and impaired quality of life. There is no cure for knee OA, and for some people, the disease may involve progressive symptomatic and structural deterioration over time. Platelet-rich plasma (PRP) is a therapeutic agent that aims to address underlying biological processes responsible for OA pathogenesis. As such, it has the potential to improve both symptoms and joint structure. The aim of this clinical trial is to determine whether a series of injections of PRP into the knee joint will lead to a significantly greater reduction in knee pain, and less loss of medial tibial cartilage volume over 12 months when compared to a series of placebo saline injections in people with knee OA. Methods This will be a two-group, superiority, randomised, participant-, interventionist- and assessor-blinded, placebo-controlled trial. Two hundred and eighty-eight participants aged over 50 years with painful knee OA and mild to moderate structural change on x-ray (Kellgren and Lawrence grade 2 and 3) will be randomly allocated to receive either three PRP injections or three normal saline injections into the knee joint at weekly intervals. The primary outcomes will be 12-month change in average overall knee pain severity (numeric rating scale) and medial tibial cartilage volume (magnetic resonance imaging (MRI)). Secondary outcomes include additional measures of knee pain and other symptoms, function in daily living and sport and recreation, quality of life, participant-perceived global ratings of change, and other MRI structural outcomes including meniscal and cartilage morphology, synovitis, effusion, bone marrow lesions and cartilage defects. A range of additional measures will be recorded, and a separate health economic evaluation will be performed. Discussion The findings from this study will help determine whether PRP improves both clinical and structural knee OA outcomes over 12 months when compared to a series of placebo saline injections. Trial registration Australian New Zealand Clinical Trials Registry reference: ACTRN12617000853347 . Prospectively registered 9th of June 2017.

BackgroundSeveral validated decision rules are available for clinicians to guide the appropriate use of imaging for patients with musculoskeletal injuries, including the Canadian CT Head Rule, Canadian C-Spine Rule, National Emergency X-Radiography Utilization Study (NEXUS) guideline, Ottawa Ankle Rules and Ottawa Knee Rules. However, it is unclear to what extent clinicians are aware of the rules and are using these five rules in practice.ObjectiveTo determine the proportion of clinicians that are aware of five imaging decision rules and the proportion that use them in practice.DesignSystematic review.MethodsThis was a systematic review conducted in accordance with the ‘Preferred reporting items for systematic reviews and meta-analyses’ (PRISMA) statement. We performed searches in MEDLINE (via Ovid), CINAHL (via EBSCO), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science and Scopus databases to identify observational and experimental studies with data on the following outcomes among clinicians related to five validated imaging decision rules: awareness, use, attitudes, knowledge, and barriers and facilitators to implementation. Where possible, we pooled data using medians to summarise these outcomes.ResultsWe included 39 studies. Studies were conducted in 15 countries (e.g. the USA, Canada, the UK, Australasia, New Zealand) and included various clinician types (e.g. emergency physicians, emergency nurses and nurse practitioners). Among the five decision rules, clinicians’ awareness was highest for the Canadian C-Spine Rule (84%, n = 3 studies) and lowest for the Ottawa Knee Rules (18%, n = 2). Clinicians’ use was highest for NEXUS (median percentage ranging from 7 to 77%, n = 4) followed by Canadian C-Spine Rule (56–71%, n = 7 studies) and lowest for the Ottawa Knee Rules which ranged from 18 to 58% (n = 4).ConclusionOur results suggest that awareness of the five imaging decision rules is low. Changing clinicians’ attitudes and knowledge towards these decision rules and addressing barriers to their implementation could increase use.

Knee Osteoarthritis is a prevalent and disabling condition that impacts activities of daily living, participation in work and family roles, and overall quality of life. With population growth and ageing, an increasing number of Australians are living with knee osteoarthritis (over 1.9 million people in 2019, representing 126% growth relative to 1990 numbers). National estimates indicate that knee osteoarthritis is associated with over 59 000 years lived with disability annually, exceeding the disability burden of dementia, stroke or ischaemic heart disease. Knee osteoarthritis also has a major economic impact in Australia, with over dollar 3.5 billion spent annually on osteoarthritis-related hospital admissions and an estimated productivity loss of dollar 424 billion. International clinical guidelines consistently recommend non-surgical modalities as the mainstay of knee osteoarthritis management, with referral for consideration of joint replacement surgery reserved for people with late-stage disease. Concerningly, low value care (care that is wasteful, ineffective and/or harmful) persists across the knee osteoarthritis journey. This is often fuelled by misconceptions about osteoarthritis, including inaccurate beliefs around diagnosis and management, that are amenable to change through education and effective communication.