Application of Heterogeneity of Treatment-Effects Methods: Exploratory Analyses of a Trial of Exercise-Based Interventions for Knee Osteoarthritis

Objective: To evaluate heterogeneity of treatment effects in a trial of exercise-based interventions for knee osteoarthritis (OA). Methods: Participants (n = 350) were randomized to standard physical therapy (PT; n = 140), internet-based exercise training (IBET; n = 142), or wait list (WL; n = 68) control. We applied qualitative interaction trees (QUINT), a sequential partitioning method, and generalized unbiased interaction detection and estimation (GUIDE), a regression tree approach, to identify subgroups with greater improvements in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score over 4 months. Predictors included 24 demographic, clinical, and psychosocial characteristics. We conducted internal validation to estimate optimism (bias) in the range of mean outcome differences among arms. Results: Both QUINT and GUIDE indicated that for participants with lower body mass index (BMI), IBET was better than PT (improvements of WOMAC ranged from 6.3 to 9.1 points lower), and for those with higher BMI and a longer duration of knee OA, PT was better than IBET (WOMAC improvement was 6.3 points). In GUIDE analyses comparing PT or IBET to WL, participants not employed had improvements in WOMAC ranging from 1.8 to 6.8 points lower with PT or IBT versus WL. From internal validation, there were large corrections to the mean outcome differences among arms; however, after correction, some differences remained in the clinically meaningful range. Conclusion: Results suggest there may be subgroups who experience greater improvement in symptoms from PT or IBET, and this finding could guide referrals and future trials. However, uncertainty persists for specific treatment-effects size estimates and how they apply beyond this study sample

Biomarkers and longitudinal changes in lumbar spine degeneration and low back pain: the Johnston County Osteoarthritis Project

Objective: To determine if baseline biomarkers are associated with longitudinal changes in the worsening of disc space narrowing (DSN), vertebral osteophytes (OST), and low back pain (LBP). Design: Paired baseline (2003–2004) and follow-up (2006–2010) lumbar spine radiographs from the Johnston County Osteoarthritis Project were graded for severity of DSN and OST. LBP severity was self-reported. Concentrations of analytes (cytokines, proteoglycans, and neuropeptides) were quantified by immunoassay. Pressure-pain threshold (PPT), a marker of sensitivity to pressure pain, was measured with a standard dolorimeter. Binary logistic regression models were used to estimate odd ratios (OR) and 95% confidence intervals (CI) of biomarker levels with DSN, OST, or LBP. Interactions were tested between biomarker levels and the number of affected lumbar spine levels or LBP. Results: We included participants (n = 723) with biospecimens, PPT, and paired lumbar spine radiographic data. Baseline Lumican, a proteoglycan reflective of extracellular matrix changes, was associated with longitudinal changes in DSN worsening (OR = 3.19 [95% CI 1.22, 8.01]). Baseline brain-derived neuropathic factor, a neuropeptide, (OR = 1.80 [95% CI 1.03, 3.16]) was associated with longitudinal changes in OST worsening, which may reflect osteoclast genesis. Baseline hyaluronic acid (OR = 1.31 [95% CI 1.01, 1.71]), indicative of systemic inflammation, and PPT (OR = 1.56 [95% CI 1.02, 2.31]) were associated with longitudinal increases in LBP severity. Conclusion: These findings suggest that baseline biomarkers are associated with longitudinal changes occurring in structures of the lumbar spine (DSN vs OST). Markers of inflammation and perceived pressure pain sensitivity were associated with longitudinal worsening of LBP

Relationship of joint hypermobility with low Back pain and lumbar spine osteoarthritis

Background: Chronic low back pain (cLBP) affects millions of Americans and costs billions. Studies suggest a link between cLBP and joint hypermobility. Methods: We conducted cross-sectional primary analyses of joint hypermobility and cLBP, lumbar spine osteoarthritis (OA), and lumbar facet joint OA (FOA) in 3 large studies - the Generalized Osteoarthritis Study, Genetics of Generalized Osteoarthritis Study, and Johnston County Osteoarthritis Project (total n = 5072). Associations of joint hypermobility and Beighton trunk flexion with cLBP and lumbar OA were estimated using separate adjusted logistic regression models. Adjusted pooled odds ratios (pORs) and 95% confidence intervals (CIs) were then summarized - using random effect univariate, multivariate crude, and adjusted models - and heterogeneity was determined (I 2 statistic). Results: In univariate models, hypermobility was associated with symptomatic FOA (pOR = 0.64 [95% CI 0.44, 0.93]) but this result was not found in the multivariate models. In multivariate adjusted models, hypermobility was not significantly associated with cLBP and lumbar OA, but trunk flexion was inversely associated with cLBP (pOR = 0.40 [95% 0.26, 0.62]), spine OA (pOR = 0.66 [95% CI 0.50, 0.87]), symptomatic spine OA (pOR = 0.39 [95% CI 0.28, 0.53]), and symptomatic FOA (pOR = 0.53 [95% CI 0.37, 0.77]). Generally, between-study heterogeneity was moderate-high. Conclusions: Hypermobility was not associated with cLBP or lumbar OA. The inverse association of trunk flexion with cLBP and lumbar OA may indicate a role for a flexible spine in avoiding or managing these conditions. © 2019 The Author(s)

Relationship of joint hypermobility with ankle and foot radiographic osteoarthritis and symptoms in a community-based cohort

Objective. To explore associations of joint hypermobility (a condition where range of motion is greater than normal) with ankle and foot radiographic osteoarthritis (OA) and symptoms in a large community-based cohort of African American and white adults ages 55-94 years old. Methods. Ankle and foot radiographs and joint hypermobility data (Beighton score for joint hypermobility criteria) were available for 848 participants (from 2003 to 2010) in this cross-sectional study. General joint hypermobility was defined as a Beighton score ≥4 (range 0-9); knee hypermobility was defined as hyperextension of at least 1 knee. Standing anteroposterior and lateral foot radiographs were read with standard atlases for Kellgren-Lawrence grade, osteophytes, and joint space narrowing (JSN) at the tibiotalar joint, and for osteophytes and JSN to define OA at 5 foot joints. Ankle or foot symptoms were self-reported. Separate person-based logistic regression models were used to estimate associations of ankle and foot OA and symptom outcomes with hypermobility measures, adjusting for age, sex, race, body mass index, and history of ankle/foot injury. Results. This sample cohort included 577 women (68%) and 280 African Americans (33%). The mean age of the participants was 71 years, with a mean body mass index of 31 kg/m2. The general joint hypermobility of the participants was 7% and knee hypermobility was 4%. Having a history of ankle injury was 11.5%, and foot injury was 3.8%. Although general joint hypermobility was not associated with ankle and foot outcomes, knee hypermobility was associated with ankle symptoms, foot symptoms, and talonavicular OA (adjusted odds ratios of 4.4, 2.4, and 3.0, respectively). Conclusion. Knee joint hypermobility may be related to talonavicular OA and to ankle and foot symptoms

Predictors of Lumbar Spine Degeneration and Low Back Pain in the Community: The Johnston County Osteoarthritis Project

Objective: To determine the incidence and worsening of lumbar spine structure and low back pain (LBP) and whether they are predicted by demographic characteristics or clinical characteristics or appendicular joint osteoarthritis (OA). Methods: Paired baseline (2003–2004) and follow-up (2006–2010) lumbar spine radiographs from the Johnston County Osteoarthritis Project were graded for osteophytes (OST), disc space narrowing (DSN), spondylolisthesis, and presence of facet joint OA (FOA). Spine OA was defined as at least mild OST and mild DSN at the same level for any level of the lumbar spine. LBP, comorbidities, and back injury were self-reported. Weibull models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) of spine phenotypes accounting for potential predictors including demographic characteristics, clinical characteristics, comorbidities, obesity, and appendicular OA. Results: Obesity was a consistent and strong predictor of incidence of DSN (HR 1.80 [95% CI 1.09–2.98]), spine OA (HR 1.56 [95% CI 1.01–2.41]), FOA (HR 4.99 [95% CI 1.46–17.10]), spondylolisthesis (HR 1.87 [95% CI 1.02–3.43]), and LBP (HR 1.75 [95% CI 1.19–2.56]), and worsening of DSN (HR 1.51 [95% CI 1.09–2.09]) and LBP (HR 1.51 [95% CI 1.12–2.06]). Knee OA was a predictor of incident FOA (HR 4.18 [95% CI 1.44–12.2]). Spine OA (HR 1.80 [95% CI 1.24–2.63]) and OST (HR 1.85 [95% CI 1.02–3.36]) were predictors of incidence of LBP. Hip OA (HR 1.39 [95% CI 1.04–1.85]) and OST (HR 1.58 [95% CI 1.00–2.49]) were predictors of LBP worsening. Conclusion: Among the multiple predictors of spine phenotypes, obesity was a common predictor for both incidence and worsening of lumbar spine degeneration and LBP

Inflammatory, Structural, and Pain Biochemical Biomarkers May Reflect Radiographic Disc Space Narrowing: The Johnston County Osteoarthritis Project

The purpose of this work is to determine the relationship between biomarkers of inflammation, structure, and pain with radiographic disc space narrowing (DSN) in community-based participants. A total of 74 participants (37 cases and 37 controls) enrolled in the Johnston County Osteoarthritis Project during 2006–2010 were selected. The cases had at least mild radiographic DSN and low back pain (LBP). The controls had neither radiographic evidence of DSN nor LBP. The measured analytes from human serum included N-cadherin, Keratin-19, Lumican, CXCL6, RANTES, IL-17, IL-6, BDNF, OPG, and NPY. A standard dolorimeter measured pressure-pain threshold. The coefficients of variation were used to evaluate inter- and intra-assay reliability. Participants with similar biomarker profiles were grouped together using cluster analysis. The binomial regression models were used to estimate risk ratios (RR) and 95% confidence intervals (CI) in propensity score-matched models. Significant associations were found between radiographic DSN and OPG (RR = 3.90; 95% CI: 1.83, 8.31), IL-6 (RR = 2.54; 95% CI: 1.92, 3.36), and NPY (RR = 2.06 95% CI: 1.62, 2.63). Relative to a cluster with low levels of biomarkers, a cluster representing elevated levels of OPG, RANTES, Lumican, Keratin-19, and NPY (RR = 3.04; 95% CI: 1.22, 7.54) and a cluster representing elevated levels of NPY (RR = 2.91; 95% CI: 1.15, 7.39) were significantly associated with radiographic DSN. Clinical Significance: These findings suggest that individual and combinations of biochemical biomarkers may reflect radiographic DSN. This is just one step toward understanding the relationships between biochemical biomarkers and DSN that may lead to improved intervention delivery

Racial Differences in Performance-Based Function and Potential Explanatory Factors Among Individuals With Knee Osteoarthritis

Objective: In individuals with knee osteoarthritis (OA), self-reported physical function is poorer in African Americans than in whites, but whether this difference holds true for objective assessments is unclear. The purpose of this study was to examine racial differences in performance-based physical function as well as potential underlying factors contributing to these racial differences. Methods: Participants with knee OA from a randomized controlled trial completed the 2-minute step test (2MST), timed-up-and-go (TUG), and 30-second chair stand (30s-CST) at baseline. Race differences in performance-based function were assessed by logistic regression. Separate models were adjusted for sets of demographic, socioeconomic, psychological health, and physical health variables. Results: In individuals with knee OA (n = 322; 72% women, 22% African American, mean ± SD age 66 ± 11 years, mean ± SD body mass index 31 ± 8 kg/m2), African Americans (versus whites) had greater unadjusted odds of poorer function (30s-CST odds ratio [OR] 2.79 [95% confidence interval (95% CI) 1.65–4.72], 2MST OR 2.37 [95% CI 1.40–4.03], and TUG OR 3.71 [95% CI 2.16–6.36]). Relationships were maintained when adjusted for demographic and psychological health covariates, but they were either partially attenuated or nonsignificant when adjusted for physical health and socioeconomic covariates. Conclusion: African American adults with knee OA had poorer unadjusted performance-based function than whites. Physical health and socioeconomic characteristics diminished these differences, emphasizing the fact that these factors may be important to consider in mitigating racial disparities in function

Association of Biomarkers with Individual and Multiple Body Sites of Pain: The Johnston County Osteoarthritis Project

Introduction: Biochemical biomarkers may provide insight into musculoskeletal pain reported at individual or multiple body sites. The purpose of this study was to determine if biomarkers or pressure-pain threshold (PPT) were associated with individual or multiple sites of pain. Methods: This cross-sectional analysis included 689 community-based participants. Self-reported symptoms (ie, pain, aching, or stiffness) were ascertained about the neck, upper back/thoracic, low back, shoulders, elbows, wrist, hands, hips, knees, ankles, and feet. Measured analytes included CXCL-6, RANTES, HA, IL-6, BDNF, OPG and NPY. A standard dolorimeter measured PPT. Logistic regression was used determine the association between biomarkers and PPT with individual and summed sites of pain. Results: Increased IL-6 and HA were associated with knee pain (OR=1.30, 95% CI 1.03, 1.64) and (OR=1.32, 95% CI 1.01, 1.73) respectively; HA was also associated with elbow/wrist/hand pain (OR=1.60, 95% CI 1.22, 2.09). Those with increased NPY levels were less likely to have shoulder pain (OR=0.56, 95% CI 0.33, 0.93). Biomarkers HA (OR=1.50, 95% CI 1.07, 2.10), OPG (OR=1.74, 95% CI 1.00, 3.03), CXCL-6 (OR=1.75, 95% CI 1.02, 3.01) and decreased PPT (OR=3.97, 95% CI 2.22, 7.12) were associated with multiple compared to no sites of pain. Biomarker HA (OR=1.57, 95% CI 1.06, 2.32) and decreased PPT (OR=3.53, 95% CI 1.81, 6.88) were associated with multiple compared to a single site of pain. Conclusion: Biomarkers of inflammation (HA, OPG, IL-6 and CXCL-6), pain (NPY) and PPT may help to understand the etiology of single and multiple pain sites

The Similarity Hypothesis in General Relativity

Self-similar models are important in general relativity and other fundamental theories. In this paper we shall discuss the ``similarity hypothesis'', which asserts that under a variety of physical circumstances solutions of these theories will naturally evolve to a self-similar form. We will find there is good evidence for this in the context of both spatially homogenous and inhomogeneous cosmological models, although in some cases the self-similar model is only an intermediate attractor. There are also a wide variety of situations, including critical pheneomena, in which spherically symmetric models tend towards self-similarity. However, this does not happen in all cases and it is it is important to understand the prerequisites for the conjecture.Comment: to be submitted to Gen. Rel. Gra