Quantitative analysis of effectiveness and associated factors of exercise on symptoms in osteoarthritis: a pharmacodynamic model-based meta-analysis.

OBJECTIVE: This study aims to evaluate the time point and magnitude of peak effectiveness of exercise and the effects of various exercise modalities for osteoarthritis (OA) symptoms and to identify factors that significantly affect the effectiveness of exercise. DESIGN: Pharmacodynamic model-based meta-analysis (MBMA). DATA SOURCES: Embase, PubMed, Cochrane Library, Web of Science and Scopus were searched for randomised controlled trials (RCTs) examining the effect of exercise for OA from inception to 20 November 2023. ELIGIBILITY CRITERIA: RCTs of exercise interventions in patients with knee, hip or hand OA, using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) subscales or Visual Analogue Scale (VAS) pain scores as outcome measures, were included. The minimum clinically important difference (MCID) for WOMAC total, pain, stiffness, function and VAS pain was 9.0, 1.6, 0.8, 5.4 and 0.9, respectively. RESULTS: A total of 186 studies comprising 12 735 participants with symptomatic or radiographic knee, hip or hand OA were included. The effectiveness of exercise treatments peaked at 1.6-7.2 weeks after initiation of exercise interventions. Exercise was more effective than the control, but the differences in the effects of exercise compared with control on all outcomes were only marginally different with the MCID (7.5, 1.7, 1.0, 5.4 and 1.2 units for WOMAC total, pain, stiffness, function and VAS pain, respectively). During a 12-month treatment period, local exercise (strengthening muscles and improving mobilisations of certain joints) had the best effectiveness (WOMAC pain decreasing by 42.5% at 12 weeks compared with baseline), followed by whole-body plus local exercise. Adding local water-based exercise (eg, muscle strengthening in warm water) to muscle strengthening exercise and flexibility training resulted in 7.9, 0.5, 0.7 and 8.2 greater improvements in the WOMAC total score, pain, stiffness and function, respectively. The MBMA models revealed that treatment responses were better in participants with more severe baseline symptom scores for all scales, younger participants for the WOMAC total and pain scales, and participants with obesity for the WOMAC function. Subgroup analyses revealed participants with certain characteristics, such as female sex, younger age, knee OA or more severe baseline symptoms on the WOMAC pain scale, benefited more from exercise treatment. CONCLUSION: Exercise reaches peak effectiveness within 8 weeks and local exercise has the best effectiveness, especially if local water-based exercise is involved. Patients of female sex, younger age, obesity, knee OA or more severe baseline symptoms appear to benefit more from exercise treatment than their counterparts.

A combined program of education plus exercise versus general advice for ankle osteoarthritis: A feasibility randomised controlled trial.

BACKGROUND: Unlike hip and knee OA, there is little evidence to guide the management of ankle osteoarthritis (OA) and there are no clinical guidelines for ankle OA. Regardless of the body region, guidelines for treating OA typically include education, weight loss and exercise as the key components of management. Such an intervention has not been investigated in people with ankle OA. OBJECTIVES: To determine the feasibility of conducting a randomised controlled trial (RCT) that compares physiotherapist-delivered education plus exercise to physiotherapist-delivered general advice for people with ankle OA. Secondarily, to inform planning for future RCTs. DESIGN: A randomised parallel-group feasibility trial. METHOD: Study participants were recruited, assessed for eligibility, and randomised using 1:1 concealed allocation to receive either physiotherapist-delivered education plus exercise, or physiotherapist-delivered general advice. Primary feasibility outcomes were evaluated based on predetermined feasibility criteria. Secondary participant-reported and physical outcomes were collected to inform the design of future RCTs. RESULTS: Thirty participants (67% (n = 20) women, mean (standard deviation) age: 66.1 (11.5) years) were randomised. Data for key feasibility outcomes met a priori feasibility criteria: consent rate (97%), participant adherence with their allocated intervention arm (71%), fidelity of the intervention (94%) and rate of completion of outcome measures at 3 months (87%). CONCLUSIONS: This study demonstrates that it is feasible to run an adequately powered RCT comparing physiotherapist-delivered education plus exercise versus physiotherapist-delivered general advice for people with ankle OA. Study data will inform the planning of a full-scale RCT.

Race, Ethnicity, and Sex in Pediatric Eye Disease Investigator Group Clinical Studies.

Importance: Racial, ethnic, and sex disparities exist in US clinical study enrollment, and the prevalence of these disparities in Pediatric Eye Disease Investigator Group (PEDIG) clinical studies has not been thoroughly assessed. Objective: To evaluate racial, ethnic, and sex representation in PEDIG clinical studies compared with the 2010 US Census pediatric population. Design, Setting, and Participants: This cross-sectional analysis examined PEDIG clinical studies based in the US from December 1, 1997 to September 12, 2022, 41 of which met inclusion criteria of a completed study, a study population younger than 18 years, and 1 or more accompanying publication. Data analysis was performed between November 2023 and February 2024. Exposure: Study participant race, ethnicity, and sex for each clinical study, as collected from peer-reviewed publications, patient-enrollment datasets, and ClinicalTrials.gov. Main Outcomes and Measures: Median enrollment percentages of female, White, Black, Hispanic, Asian, and other race participants were calculated and compared with the 2010 US Census pediatric population using a 1-sample Wilcoxon rank test. Proportionate enrollment was defined as no difference on a 1-sample Wilcoxon rank test if P ≥ .05. If P < .05, we determined if the median enrollment percentage was greater than or less than 2010 US Census proportion to determine if enrollees were underrepresented or overrepresented. To calculate the magnitude of overrepresentation or underrepresentation, enrollment-census difference (ECD) was defined as the difference between groups' median enrollment percentage and percentage representation in the 2010 US Census. Compound annual growth rate (CAGR) was used to measure temporal trends in enrollment, and logistic regression analysis was used to analyze factors that may have contributed to proportionate representation outcomes. Results: A total of 11 658 study participants in 41 clinical studies were included; mean (SD) participant age was 5.9 (2.8) years and 5918 study participants (50.8%) were female. In clinical studies meeting inclusion criteria, White participants were overrepresented (ECD, 0.19; 95% CI, 0.10-0.28; P < .001). Black participants (ECD, -0.07; 95% CI, -0.10 to -0.03; P < .001), Asian participants (ECD, -0.03; 95% CI, -0.04 to -0.02; P < .001), and Hispanic participants (ECD, -0.09; 95% CI, -0.13 to -0.05; P < .001) were underrepresented. Female participants were represented proportionately (ECD, 0.004; 95% CI, -0.036 to 0.045; P = .21). White and Asian participants demonstrated a decreasing trend in study enrollment from 1997 to 2022 (White: CAGR, -1.5%; 95% CI, -2.3% to -0.6%; Asian: CAGR, -1.7%; 95% CI, -2.0% to -1.4%), while Hispanic participants demonstrated an increasing enrollment trend (CAGR, 7.2%; 95% CI, 3.7%-10.7%). Conclusions and Relevance: In this retrospective cross-sectional study of PEDIG clinical studies from December 1, 1997 to September 12, 2022, Black, Hispanic, and Asian participants were underrepresented, White participants were overrepresented, and female participants were represented proportionally. Trends suggested increasing enrollment of Hispanic participants and decreasing enrollment of White participants over time. This study demonstrates an opportunity to advocate for increased enrollment of underrepresented groups in pediatric ophthalmology clinical studies.

Comparison of weight loss interventions in overweight and obese adults with knee osteoarthritis: A systematic review and network meta-analysis of randomized trials.

OBJECTIVE: To ascertain the comparative effectiveness of weight-loss strategies for osteoarthritis (OA) to develop rational treatment algorithms aimed at improving OA-related symptoms in overweight/obese individuals. DESIGN: Medline, Embase, CINAHL, Scopus, and Web of Science were searched from inception to June 2023 for observational studies and randomized trials. Network meta-analyses were performed using a frequentist approach. Effect sizes for pain and function were computed as standardized mean differences, while change in body weight was computed as mean differences. RESULTS: 13 RCTs on knee OA (KOA) (2800 participants) with 7 interventions: diet (D); exercise (E); diet and exercise (DE); pharmacological (L); psychological (P); psychological, diet, and exercise (PDE); and Mediterranean diets (M) were networked. For weight change (kg), all interventions significantly outperformed control comparators, with effect sizes ranging from -11.2 (95% CI, -16.0, -6.5 kg) for the most effective approach (PDE) to -4.7 (95% CI, -6.7, -2.7 kg) for the least effective approach (DE). In terms of pain (0-20 scale), only DE outperformed control comparators (-2.2, 95% CI: -4.1, -0.21), whereas PDE was not superior to control comparators (-3.9, 95% CI: -8.4, 0.5) in improving the pain. Regardless of the chosen intervention, prediction intervals from meta-regression analysis indicate that significant pain relief may be anticipated when patients achieve at least a weight reduction of 7%. CONCLUSIONS: PDE and DE interventions may offer the most effective approach for weight loss, potentially leading to improvements in pain and physical function among overweight/obese individuals with KOA if they achieve more than 7% weight loss.

Gene identification for ocular congenital cranial motor neuron disorders using human sequencing, zebrafish screening, and protein binding microarrays.

Purpose: To functionally evaluate novel human sequence-derived candidate genes and variants for unsolved ocular congenital cranial dysinnervation disorders (oCCDDs). Methods: Through exome and genome sequencing of a genetically unsolved human oCCDD cohort, we previously identified variants in 80 strong candidate genes. Here, we further prioritized a subset of these (43 human genes, 57 zebrafish genes) using a G0 CRISPR/Cas9-based knockout assay in zebrafish and generated F2 germline mutants for seventeen. We tested the functionality of variants of uncertain significance in known and novel candidate transcription factor-encoding genes through protein binding microarrays. Results: We first demonstrated the feasibility of the G0 screen by targeting known oCCDD genes phox2a and mafba. 70-90% of gene-targeted G0 zebrafish embryos recapitulated germline homozygous null-equivalent phenotypes. Using this approach, we then identified three novel candidate oCCDD genes (SEMA3F, OLIG2, and FRMD4B) with putative contributions to human and zebrafish cranial motor development. In addition, protein binding microarrays demonstrated reduced or abolished DNA binding of human variants of uncertain significance in known and novel sequence-derived transcription factors PHOX2A (p.(Trp137Cys)), MAFB (p.(Glu223Lys)), and OLIG2 (p.(Arg156Leu)). Conclusions: This study nominates three strong novel candidate oCCDD genes (SEMA3F, OLIG2, and FRMD4B) and supports the functionality and putative pathogenicity of transcription factor candidate variants PHOX2A p.(Trp137Cys), MAFB p.(Glu223Lys), and OLIG2 p.(Arg156Leu). Our findings support that G0 loss-of-function screening in zebrafish can be coupled with human sequence analysis and protein binding microarrays to aid in prioritizing oCCDD candidate genes/variants.

Intravenous fluorescein overdose in a child undergoing fluorescein angiography.

Fluorescein angiography is a fluorescent dye-based imaging procedure, most commonly indicated in the pediatric setting to evaluate peripheral retinal vascular lesions. Fluorescein dye is organic, water soluble, and largely excreted renally, with a reassuring safety profile at therapeutic doses. While toxicity with intrathecal overdose has been reported, the effect of intravenous exposure to supratherapeutic levels has not been previously documented in the literature. We report the case of a 10-month-old girl with incontinentia pigmenti who received more than four times the recommended dosage of fluorescein during scheduled fluorescein angiography and developed marked yellowing of skin, sclera, stool, and urine. She was seen by the toxicology team and underwent monitoring for 8 hours before being discharged, with no adverse consequences detected during follow-up.

Progression of Bone Marrow Lesions and the Development of Knee Osteoarthritis: Osteoarthritis Initiative Data.

Background Bone marrow lesions (BMLs) are a known risk factor for incident knee osteoarthritis (OA), and deep learning (DL) methods can assist in automated segmentation and risk prediction. Purpose To develop and validate a DL model for quantifying tibiofemoral BML volume on MRI scans in knees without radiographic OA and to assess the association between longitudinal BML changes and incident knee OA. Materials and Methods This retrospective study included knee MRI scans from the Osteoarthritis Initiative prospective cohort (February 2004-October 2015). The DL model, developed between August and October 2023, segmented the tibiofemoral joint into 10 subregions and measured BML volume in each subregion. Baseline and 4-year follow-up MRI scans were analyzed. Knees without OA at baseline were categorized into three groups based on 4-year BML volume changes: BML-free, BML regression, and BML progression. The risk of developing radiographic and symptomatic OA over 9 years was compared among these groups. Results Included were 3869 non-OA knees in 2430 participants (mean age, 59.5 years ± 9.0 [SD]; female-to-male ratio, 1.3:1). At 4-year follow-up, 2216 knees remained BML-free, 1106 showed an increase in BML volume, and 547 showed a decrease in BML volume. BML progression was associated with a higher risk of developing radiographic knee OA compared with remaining BML-free (hazard ratio [HR] = 3.0; P < .001) or BML regression (HR = 2.0; P < .001). Knees with BML progression also had a higher risk of developing symptomatic OA compared with BML-free knees (HR = 1.3; P < .001). Larger volume changes in BML progression were associated with a higher risk of developing both radiographic OA (HR = 2.0; P < .001) and symptomatic OA (HR = 1.7; P < .001). In almost all subchondral plates, especially the medial femur and tibia, BML progression was associated with a higher risk of developing both radiographic and symptomatic OA compared with remaining BML-free. Conclusion Knees with BML progression, according to subregion and extent of volume changes, were associated with an increased risk of OA compared with BML-free knees and knees with BML regression, highlighting the potential utility of monitoring BML volume changes in evaluating interventions to prevent OA development. ClinicalTrials.gov Identifier: NCT00080171 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Said and Sakly in this issue.

Efficacy and safety of an oral complementary medicine combination in people with symptomatic knee osteoarthritis: Protocol for the double-blind, randomized, placebo-controlled ATLAS trial.

Objective: To investigate the efficacy and safety of an oral complementary medicine combination formulation relative to placebo, on changes in pain intensity from baseline to week 12, in people with knee osteoarthritis (OA). Design: A placebo-controlled, double-blind, two-arm, superiority, phase II, Randomized Controlled Trial (RCT) (ACTRN12623000380695). We will recruit 82 participants (∼41 per arm), aged ≥40 years, with a clinical diagnosis of symptomatic knee OA and radiographic change on x-ray (Kellgren-Lawrence Grade ≥2). Participants will be randomly allocated to receive either a complementary medicine formulation containing a daily dose of Boswellia serrata extract (Boswellin® Super, 250 â€‹mg/day), pine bark extract (Fenoprolic™ 70 Organic 100 â€‹mg/day), curcumin (500 â€‹mg/day), piperine (5 â€‹mg/day), and methylsulfonylmethane (MSM, 1500 â€‹mg/day), or placebo, for 12-weeks. The primary endpoint will be change from baseline in average knee pain intensity at 12-weeks (visual analogue scale). Secondary endpoints will include change in knee pain from baseline to 12-weeks in the Knee Injury and Osteoarthritis Outcome Score (KOOS), global assessment of disease activity, global rating of change, and health-related quality of life (AQoL-8D). Ethics and dissemination: This protocol has been approved by the University of Sydney Human Research Ethics Committee (#2021/877). Dissemination will occur through lay summaries, infographics, conference abstracts, oral presentations, theses, and scientific publications. Conclusion: This RCT will provide credible evidence about the efficacy and safety of this complementary medicine combination and inform updates to international clinical practice standards on the use of complementary medicines in the management of symptomatic knee OA.

Association of serum calcium, vitamin D, and C-reactive protein with all-cause and cause-specific mortality in an osteoarthritis population in the UK: a prospective cohort study.

BACKGROUND: Osteoarthritis is a prevalent musculoskeletal condition, but the role of specific serum biomarkers, such as calcium, vitamin D, and C-reactive protein (CRP), in predicting mortality among individuals with osteoarthritis remains unclear. METHODS: This observational study analyzed longitudinal data from over 500,000 participants in the UK Biobank, identifying those with osteoarthritis using ICD-9/10 codes or self-reported history. We performed multivariable cox-regression and flexible parametric survival model (FPSM) for survival analysis, with adjustments made through the inverse probability of treatment weight (IPTW) for baseline covariates identified by directed acyclic graphs (DAGs). RESULTS: Of the 49,082 osteoarthritis population, the average age was 60.69 years, with 58.7% being female. During the follow-up period exceeding 15 years, a total of 5,522 people with osteoarthritis died. High serum calcium levels, compared to normal serum calcium levels, were significantly associated with all-cause mortality (hazard ratio (HR) 1.33, 95% confidence interval (CI) 1.11, 1.59), cardiovascular diseases (CVD)-related deaths (HR 1.55, 95% CI 1.05, 2.29), and other deaths (HR 1.59, 95% CI 1.20, 2.11). Low serum calcium levels, compared to normal serum calcium levels, was linked with CVD-related deaths (HR 2.06, 95% CI 1.02, 4.14). Vitamin D insufficiency, compared to sufficient vitamin D levels, was correlated with all-cause mortality (HR 1.22, 95% CI 1.13, 1.33), CVD-related deaths (HR 1.43, 95% CI 1.20, 1.72), and other deaths (HR 1.26, 95% CI 1.09, 1.45) but not with cancer-related deaths. High serum CRP levels, compared to normal CRP levels, were associated with all outcomes (all-cause mortality: HR 1.22, 95% CI 1.12, 1.33; CVD-related death: HR 1.24, 95%CI 1.03, 1.49; cancer-related death: HR 1.23, 95% CI 1.09, 1.40; other deaths: HR 1.19, 95%CI 1.03, 1.38). CONCLUSIONS: Both high and low serum calcium levels, elevated CRP, and vitamin D insufficiency are potential predictors of increased mortality risk in the osteoarthritis population. These findings emphasize the importance of monitoring and possibly addressing these serum biomarkers in osteoarthritis populations to improve long-term outcomes. Further studies are needed to understand the underlying mechanisms and to propose therapeutic interventions.

Tissue Radiologic and Pathologic Response to Biphasic Pulsed Electric Field Technology in a Porcine Model.

PURPOSE: To evaluate the radiologic, pathologic, and safety characteristics of a commercially available pulsed electric field (PEF) ablation system in a porcine model. MATERIALS AND METHODS: Monopolar biphasic PEF ablation was delivered to the liver, kidney, and longissimus dorsi muscle through a single needle via a percutaneous or open approach with the AliyaTM System. Six animals were ablated and evaluated in two cohorts (Day 3 and Day 28). Muscle, kidney, and liver were ablated in each animal. Intraprocedural Cone Beam CT, follow-up weekly CT, blood serology, gross pathology, and histopathology were performed to characterize the radiographic evolution and tissue response. RESULTS: There were no adverse events, no findings of ECG abnormalities, and serological values returned to baseline by day 28. Ablation zones were visible on non-contrast CT images during follow-up. Most identified zones became radiographically smaller over time, with some fully resolved by day 28. The relative decrease in gross ablation zone volume in the liver and skeletal muscle was 20%, and 26%, respectively, while kidney sites grew by 22%. Ablation sites were focal and were contained within the intended target tissue without extension to non-target tissues or collateral structures. CONCLUSION: The biphasic PEF system evaluated here resulted in a safe and predictable ablation response, with preservation of structural tissues in an animal model, offering an alternative to thermal ablative modalities, particularly near critical structures.

Genetic Polymorphisms and Genetic Risk Scores Contribute to the Risk of Coronary Artery Disease (CAD) in a North Indian Population.

Coronary artery disease (CAD) is the leading cause of death in India. Many genetic polymorphisms play a role in regulating oxidative stress, blood pressure and lipid metabolism, contributing to the pathophysiology of CAD. This study examined the association between ten polymorphisms and CAD in the Jat Sikh population from Northern India, also considering polygenic risk scores. This study included 177 CAD cases and 175 healthy controls. The genetic information of GSTM1 (rs366631), GSTT1 (rs17856199), ACE (rs4646994), AGT M235T (rs699), AGT T174M (rs4762), AGTR1 A1166C (rs5186), APOA5 (rs3135506), APOC3 (rs5128), APOE (rs7412) and APOE (rs429358) and clinical information was collated. Statistical analyses were performed using SPSS version 27.0 and SNPstats. Significant independent associations were found for GST*M1, GST*T1, ACE, AGT M235T, AGT T174M, AGTR1 A1166C and APOA5 polymorphisms and CAD risk (all p < 0.05). The AGT CT haplotype was significantly associated with a higher CAD risk, even after controlling for covariates (adjusted OR = 3.93, 95% CI [2.39-6.48], p < 0.0001). The APOA5/C3 CC haplotype was also significantly associated with CAD (adjusted OR = 1.86, 95% CI [1.14-3.03], p < 0.05). A higher polygenic risk score was associated with increased CAD risk (adjusted OR = 1.98, 95% CI [1.68-2.34], p < 0.001). Seven polymorphisms were independently associated with an increase in the risk of CAD in this North Indian population. A considerable risk association of AGT, APOA5/C3 haplotypes and higher genetic risk scores is documented, which may have implications for clinical and public health applications.

Exploring antidiabetic drug targets as potential disease-modifying agents in osteoarthritis.

BACKGROUND: Osteoarthritis is a leading cause of disability, and disease-modifying osteoarthritis drugs (DMOADs) could represent a pivotal advancement in treatment. Identifying the potential of antidiabetic medications as DMOADs could impact patient care significantly. METHODS: We designed a comprehensive analysis pipeline involving two-sample Mendelian Randomization (MR) (genetic proxies for antidiabetic drug targets), summary-based MR (SMR) (for mRNA), and colocalisation (for drug-target genes) to assess their causal relationship with 12 osteoarthritis phenotypes. Summary statistics from the largest genome-wide association meta-analysis (GWAS) of osteoarthritis and gene expression data from the eQTLGen consortium were utilised. FINDINGS: Seven out of eight major types of clinical antidiabetic medications were identified, resulting in fourteen potential drug targets. Sulfonylurea targets ABCC8/KCNJ11 were associated with increased osteoarthritis risk at any site (odds ratio (OR): 2.07, 95% confidence interval (CI): 1.50-2.84, P < 3 × 10-4), while PPARG, influenced by thiazolidinediones (TZDs), was associated with decreased risk of hand (OR: 0.61, 95% CI: 0.48-0.76, P < 3 × 10-4), finger (OR: 0.50, 95% CI: 0.35-0.73, P < 3 × 10-4), and thumb (OR: 0.49, 95% CI: 0.34-0.71, P < 3 × 10-4) osteoarthritis. Metformin and GLP1-RA, targeting GPD1 and GLP1R respectively, were associated with reduced risk of knee and finger osteoarthritis. In the SMR analyses, gene expression of KCNJ11, GANAB, ABCA1, and GSTP1, targeted by antidiabetic drugs, was significantly linked to at least one osteoarthritis phenotype and was replicated across at least two gene expression datasets. Additionally, increased KCNJ11 expression was related to decreased osteoarthritis risk and co-localised with at least one osteoarthritis phenotype. INTERPRETATION: Our findings suggest a potential therapeutic role for antidiabetic drugs in treating osteoarthritis. The results indicate that certain antidiabetic drug targets may modify disease progression, with implications for developing targeted DMOADs. FUNDING: This study was funded by the Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant (2022), the Shanghai Municipal Health Commission Health Industry Clinical Research Project (Grant No. 20224Y0139), Beijing Natural Science Foundation (Grant No. 7244458), and the Postdoctoral Fellowship Program (Grade C) of China Postdoctoral Science Foundation (Grant No. GZC20230130).

Role of Selected Genetic Polymorphisms in the Development of Rheumatoid Arthritis in a British White Population.

BACKGROUND: Rheumatoid arthritis (RA) is a complex autoimmune disease that negatively affects synovial joints, leading to the deterioration of movement and mobility of patients. This chronic disease is considered to have a strong genetic inheritance, with genome-wide association studies (GWAS) highlighting many genetic loci associated with the disease. Moreover, numerous confounding and non-genetic factors also contribute to the risk of the disease. AIMS: This study investigates the association of selected genetic polymorphisms with rheumatoid arthritis risk and develops a polygenic risk score (PRS) based on selected genes. METHODS: A case-control study recruited fully consenting participants from the East Midlands region of the UK. DNA samples were genotyped for a range of polymorphisms and genetic associations were calculated under several inheritance models. PRS was calculated at crude (unweighted) and weighted levels, and its associations with clinical parameters were determined. RESULTS: There were significant associations with the risk of RA at six genetic markers and their associated risk alleles (TNRF2*G, TRAF1*A, PTPN22*T, HLA-DRB1*G, TNFα*A, and IL4-590*T). The TTG haplotype at the VDR locus increased the risk of RA with an OR of 3.05 (CI 1.33-6.98, p = 0.009). The GA haplotype of HLADRB1-TNFα-308 was a significant contributor to the risk of RA in this population (OR = 2.77, CI 1.23-6.28, p = 0.01), although linkage disequilibrium was low. The polygenic risk score was significantly higher in cases over controls in both unweighted (mean difference = 1.48, t285 = 5.387, p < 0.001) and weighted (mean difference = 2.75, t285 = 6.437, p < 0.001) results. CONCLUSION: Several genetic loci contribute to the increased risk of RA in the British White sample. The PRS is significantly higher in those with RA and can be used for clinical applications and personalised prevention of disease.

The Flare-OA-16 questionnaire measuring flare in knee and hip osteoarthritis in the patient perspective: scale reduction and validation using a Rasch model.

OBJECTIVES: The recent Flare-OA questionnaire measuring flare in knee and hip osteoarthritis (OA) (19 items in 5 domains, numerical rating scale) showed good psychometric properties along with classical test theory. This study aimed to determine its scaling properties by Rasch analysis and to present evidence for a refined scalable version. STUDY DESIGN AND SETTING: The participants were 398 subjects (mean age 64 years [standard deviation = 8.1], 70.4% women) recruited from Australia, France, and the United States, with clinically and radiologically symptomatic knee or hip OA, who completed an online survey. The sample was split into derivation and validation subsamples, stratified by country and joint. Rasch analysis examined differential item functioning (DIF) for sex, age, country, and joint. A confirmatory factor analysis and an analysis of convergent validity were performed to document the psychometric properties of the short version. RESULTS: To fit the Rasch model, we reordered thresholds of answering modalities when necessary. Two items were removed. A local dependency between 2 items was solved by combining items modalities into a super-item. A uniform DIF (expected and nonremoved) was identified for one item that was split by joint, and a nonuniform DIF for one item for age and country (removed). The person-item threshold distribution showed a well-focused scale; the confirmatory factor analysis and the analysis of convergent validity showed good fit indicators for the short version. CONCLUSION: The Rasch analysis was helpful in guiding the decision to refine the measurement instrument. After analysis, the 16-item Flare-OA self-report questionnaire is available for use in clinical research.