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To identify and synthesise the content of knee bracing interventions in randomised controlled trials (RCTs) of knee osteoarthritis (OA). In this scoping review, three electronic databases (PubMed, Web of Science, Cochrane) were searched up to 10th June 2024. Nineteen previous systematic reviews of knee bracing for knee OA and four recent international clinical practice guidelines were also hand searched. Identified studies were screened for eligibility by two independent reviewers. Information on bracing interventions was extracted from included RCT reports, informed by Template for Intervention Description and Replication (TIDieR) guidelines. Data were synthesised narratively. Thirty-one RCTs testing 47 different bracing interventions were included. Braces were broadly grouped as valgus/varus, patellofemoral, sleeve, neutral hinged, or control/placebo knee braces. Brace manufacturer and models varied, as did amount of recommended brace use. Only three interventions specifically targeted brace adherence. Information on brace providers, setting, number of treatment sessions, and intervention modification over time was poorly reported. Adherence to brace use was described for 32 (68%) interventions, most commonly via self-report. Several mechanisms of action for knee braces were proposed, broadly grouped as biomechanical, neuromuscular, and psychological. Many different knee brace interventions have been tested for knee OA, with several proposed mechanisms of action, a lack of focus on adherence, and a lack of full reporting. These issues may be contributing to the heterogeneous findings and inconsistent guideline recommendations about the clinical effectiveness of knee bracing for knee OA to date.

Objective: To determine the reliability and agreement of manual and automated morphological measurements, and agreement in morphological diagnoses. Methods: Thirty pelvic radiographs were randomly selected from the World COACH consortium. Manual and automated measurements of acetabular depth-width ratio (ADR), modified acetabular index (mAI), alpha angle (AA), Wiberg center edge angle (WCEA), lateral center edge angle (LCEA), extrusion index (EI), neck-shaft angle (NSA), and triangular index ratio (TIR) were performed. Bland-Altman plots and intraclass correlation coefficients (ICCs) were used to test reliability. Agreement in diagnosing acetabular dysplasia, pincer and cam morphology by manual and automated measurements was assessed using percentage agreement. Visualizations of all measurements were scored by a radiologist. Results: The Bland-Altman plots showed no to small mean differences between automated and manual measurements for all measurements except for ADR. Intraobserver ICCs of manual measurements ranged from 0.26 (95%-CI 0–0.57) for TIR to 0.95 (95%-CI 0.87–0.98) for LCEA. Interobserver ICCs of manual measurements ranged from 0.43 (95%-CI 0.10–0.68) for AA to 0.95 (95%-CI 0.86–0.98) for LCEA. Intermethod ICCs ranged from 0.46 (95%-CI 0.12–0.70) for AA to 0.89 (95%-CI 0.78–0.94) for LCEA. Radiographic diagnostic agreement ranged from 47% to 100% for the manual observers and 63%–96% for the automated method as assessed by the radiologist. Conclusion: The automated algorithm performed equally well compared to manual measurement by trained observers, attesting to its reliability and efficiency in rapidly computing morphological measurements. This validated method can aid clinical practice and accelerate hip osteoarthritis research.

OBJECTIVE: The effect of physical activity on the risk of developing knee osteoarthritis (OA) is unclear. We undertook this study to examine the relationship between recreational physical activity and incident knee OA outcomes using comparable physical activity and OA definitions. METHODS: Data were acquired from 6 global, community-based cohorts of participants with and those without knee OA. Eligible participants had no evidence of knee OA or rheumatoid arthritis at baseline. Participants were followed up for 5-12 years for incident outcomes including the following: 1) radiographic knee OA (Kellgren-Lawrence [K/L] grade ≥2), 2) painful radiographic knee OA (radiographic OA with knee pain), and 3) OA-related knee pain. Self-reported recreational physical activity included sports and walking/cycling activities and was quantified at baseline as metabolic equivalents of task (METs) in days per week. Risk ratios (RRs) were calculated and pooled using individual participant data meta-analysis. Secondary analysis assessed the association between physical activity, defined as time (hours per week) spent in recreational physical activity and incident knee OA outcomes. RESULTS: Based on a total of 5,065 participants, pooled RR estimates for the association of MET days per week with painful radiographic OA (RR 1.02 [95% confidence interval (95% CI) 0.93-1.12]), radiographic OA (RR 1.00 [95% CI 0.94-1.07]), and OA-related knee pain (RR 1.00 [95% CI 0.96-1.04]) were not significant. Similarly, the analysis of hours per week spent in physical activity also showed no significant associations with all outcomes. CONCLUSION: Our findings suggest that whole-body, physiologic energy expenditure during recreational activities and time spent in physical activity were not associated with incident knee OA outcomes.

Obesity is a global pandemic, but there is yet no effective measure to control it. Recent metabolomics studies have identified a signature of altered amino acid profiles to be associated with obesity, but it is unclear whether these findings have actionable clinical potential. The aims of this study were to reveal the metabolic alterations of obesity and to explore potential strategies to mitigate obesity. We performed targeted metabolomic profiling of the plasma/serum samples collected from six independent cohorts and conducted an individual data meta-analysis of metabolomics for body mass index (BMI) and obesity. Based on the findings, we hypothesized that restriction of branched-chain amino acids (BCAAs), phenylalanine, or tryptophan may prevent obesity and tested our hypothesis in a dietary restriction trial with eight groups of 4-week-old male C57BL/6J mice (n = 5/group) on eight different types of diets, respectively, for 16 weeks. A total of 3397 individuals were included in the meta-analysis. The mean BMI was 30.7 ± 6.1 kg/m2, and 49% of participants were obese. Fifty-eight metabolites were associated with BMI and obesity (all p ≤ 2.58 × 10-4), linked to alterations of the BCAA, phenylalanine, tryptophan, and phospholipid metabolic pathways. The restriction of BCAAs within a high-fat diet (HFD) maintained the mice's weight, fat and lean volume, subcutaneous and visceral adipose tissue weight, and serum glucose and insulin at levels similar to those in the standard chow group, and prevented obesity, adipocyte hypertrophy, adipose inflammation, and insulin resistance induced by HFD. Our data suggest that four metabolic pathways, BCAA, phenylalanine, tryptophan, and phospholipid metabolic pathways, are altered in obesity and restriction of BCAAs within a HFD can prevent the development of obesity and insulin resistance in mice, providing a promising strategy to potentially mitigate diet-induced obesity.

Objective: To summarize proceedings of a workshop convened to discuss the current state of science in the disease of osteoarthritis (OA), identify the knowledge gaps, and examine the developmental and regulatory challenges in bringing these products to market. Design: Summary of the one-day workshop held virtually on June 22nd, 2021. Results: Speakers selected by the Planning Committee presented data on the current approach to assessment of OA therapies, biomarkers in OA drug development, and the assessment of disease progression and long-term benefit. Conclusions: Demonstrated by numerous failed clinical trials, OA is a challenging disease for which to develop therapeutics. The challenge is magnified by the slow time of onset of disease and the need for clinical trials of long duration and/or large sample size to demonstrate the effect of an intervention. The OA science community, including academia, pharmaceutical companies, regulatory agencies, and patient communities, must continue to develop and test better clinical endpoints that meaningfully reflect disease modification related to long-term patient benefit.

Objective: To summarize available evidence on the association between hip shape as quantified by statistical shape modeling (SSM) and the incidence or progression of hip osteoarthritis. Design: We conducted a systematic search of five electronic databases, based on a registered protocol (available: PROSPERO CRD42020145411). Articles presenting original data on the longitudinal relationship between radiographic hip shape (quantified by SSM) and hip OA were eligible. Quantitative meta-analysis was precluded because of the use of different SSM models across studies. We used the Newcastle–Ottawa Scale (NOS) for risk of bias assessment. Results: Nine studies (6,483 hips analyzed with SSM) were included in this review. The SSM models used to describe hip shape ranged from 16 points on the femoral head to 85 points on the proximal femur and hemipelvis. Multiple hip shape features and combinations thereof were associated with incident or progressive hip OA. Shape variants that seemed to be consistently associated with hip OA across studies were acetabular dysplasia, cam morphology, and deviations in acetabular version (either excessive anteversion or retroversion). Conclusions: Various radiographic, SSM-defined hip shape features are associated with hip OA. Some hip shape features only seem to increase the risk for hip OA when combined together. The heterogeneity of the used SSM models across studies precludes the estimation of pooled effect sizes. Further studies using the same SSM model and definition of hip OA are needed to allow for the comparison of outcomes across studies, and to validate the found associations.

Background Brace effectiveness for knee osteoarthritis (OA) remains unclear and international guidelines offer conflicting recommendations. Our trial will determine the clinical and cost-effectiveness of adding knee bracing (matched to patients' clinical and radiographic presentation and with adherence support) to a package of advice, written information and exercise instruction delivered by physiotherapists. Methods and analysis A multicentre, pragmatic, two-parallel group, single-blind, superiority, randomised controlled trial with internal pilot and nested qualitative study. 434 eligible participants with symptomatic knee OA identified from general practice, physiotherapy referrals and self-referral will be randomised 1:1 to advice, written information and exercise instruction and knee brace versus advice, written information and exercise instruction alone. The primary analysis will be intention-to-treat comparing treatment arms on the primary outcome (Knee Osteoarthritis Outcomes Score (KOOS)-5) (composite knee score) at the primary endpoint (6 months) adjusted for prespecified covariates. Secondary analysis of KOOS subscales (pain, other symptoms, activities of daily living, function in sport and recreation, knee-related quality of life), self-reported pain, instability (buckling), treatment response, physical activity, social participation, self-efficacy and treatment acceptability will occur at 3, 6, and 12 months postrandomisation. Analysis of covariance and logistic regression will model continuous and dichotomous outcomes, respectively. Treatment effect estimates will be presented as mean differences or ORs with 95% CIs. Economic evaluation will estimate cost-effectiveness. Semistructured interviews to explore acceptability and experiences of trial interventions will be conducted with participants and physiotherapists delivering interventions. Ethics and dissemination North West Preston Research Ethics Committee, the Health Research Authority and Health an

Background Despite recent advances in the understanding of the genetic architecture of osteoarthritis (OA), only two genetic loci have been identified for OA of the hand, in part explained by the complexity of the different hand joints and heterogeneity of OA pathology. Methods We used data from the Rotterdam Study (RSI, RSII and RSIII) to create three hand OA phenotypes based on clustering patterns of radiographic OA severity to increase power in our modest discovery genome-wide association studies in the RS (n=8700), and sought replication in an independent cohort, the Framingham Heart Study (n=1203). We used multiple approaches that leverage different levels of information and functional data to further investigate the underlying biological mechanisms and candidate genes for replicated loci. We also attempted to replicate known OA loci at other joint sites, including the hips and knees. Results We found two novel genome-wide significant loci for OA in the thumb joints. We identified WNT9A as a possible novel causal gene involved in OA pathogenesis. Furthermore, several previously identified genetic loci for OA seem to confer risk for OA across multiple joints: TGFa, RUNX2, COL27A1, ASTN2, IL11 and GDF5 loci. Conclusions We identified a robust novel genetic locus for hand OA on chromosome 1, of which WNT9A is the most likely causal gene. In addition, multiple genetic loci were identified to be associated with OA across multiple joints. Our study confirms the potential for novel insight into the genetic architecture of OA by using biologically meaningful stratified phenotypes.

Objective: To summarize available evidence on the association between hip shape as quantified by statistical shape modeling (SSM) and the incidence or progression of hip osteoarthritis. Design: We conducted a systematic search of five electronic databases, based on a registered protocol (available: PROSPERO CRD42020145411). Articles presenting original data on the longitudinal relationship between radiographic hip shape (quantified by SSM) and hip OA were eligible. Quantitative meta-analysis was precluded because of the use of different SSM models across studies. We used the Newcastle–Ottawa Scale (NOS) for risk of bias assessment. Results: Nine studies (6,483 hips analyzed with SSM) were included in this review. The SSM models used to describe hip shape ranged from 16 points on the femoral head to 85 points on the proximal femur and hemipelvis. Multiple hip shape features and combinations thereof were associated with incident or progressive hip OA. Shape variants that seemed to be consistently associated with hip OA across studies were acetabular dysplasia, cam morphology, and deviations in acetabular version (either excessive anteversion or retroversion). Conclusions: Various radiographic, SSM-defined hip shape features are associated with hip OA. Some hip shape features only seem to increase the risk for hip OA when combined together. The heterogeneity of the used SSM models across studies precludes the estimation of pooled effect sizes. Further studies using the same SSM model and definition of hip OA are needed to allow for the comparison of outcomes across studies, and to validate the found associations.

OBJECTIVES: Further knowledge about typical hand osteoarthritis (OA) characteristics is needed for the development of new classification criteria for hand OA. METHODS: In a cross-sectional multi-centre international study, a convenience sample of patients from primary and secondary/tertiary care with a physician-based hand OA diagnosis (n = 128) were compared with controls with hand complaints due to inflammatory or non-inflammatory conditions (n = 70). We examined whether self-reported, clinical, radiographic and laboratory findings were associated with hand OA using logistic regression analyses. Discrimination between groups was assessed by calculating the area under receiver operating curves (AUC). RESULTS: Strong associations with hand OA were observed for radiographic osteophytes (OR = 1.62, 95% CI 1.40 to 1.88) and joint space narrowing (JSN) (OR = 1.57, 95% CI 1.36 to 1.82) in the distal interphalangeal (DIP) joints with excellent discrimination (AUC = 0.82 for both). For osteophytes and JSN, we found acceptable discrimination between groups in the proximal interphalangeal joints (AUC = 0.77 and 0.78, respectively), but poorer discrimination in

Objective In rheumatoid arthritis, composite outcomes constructed from a combination of outcome measures are widely used to enhance responsiveness (sensitivity to change) and comprehensively summarize response. WOMAC pain is the primary outcome measure in many osteoarthritis (OA) trials. Information from other outcomes, such as rescue medication use, and other WOMAC subscales, could be added to create composite outcomes, but the sensitivity of such a composite has not been tested. Method We used data from a completed trial of Tanezumab for knee OA (NCT00733902). The WOMAC questionnaire and rescue medication use were measured at multiple time points, up to 16 weeks. Pain and rescue medication outcomes were standardised and combined into 3 composite outcomes via principal components analysis to produce one score (composite outcome) and their responsiveness was compared to WOMAC pain, the standard. We pooled all treatment doses of Tanezumab into one ‘treatment’ group, for simplicity, and compared this to the control group (placebo). Results The composite outcomes showed modestly but not statistically significantly greater responsiveness when compared to WOMAC pain alone. Adding information on rescue medication to the composite improved responsiveness. While improvements in sensitivity were modest, the required sample sizes for trials using composites was 20- 40% less than trials using WOMAC pain alone Page 4 of 55 Page 4 of 23 Conclusion Combining information from related, but distinct, outcomes considered relevant to a particular treatment improved responsiveness, could reduce sample size requirements in OA trials and might offer a way to better detect treatment efficacy in OA trials.