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Clinical trials conventionally test aggregate mean differences and assume homogeneous variances across treatment groups. However, significant response heterogeneity may exist. The purpose of this study was to model treatment response variability using gait speed change among older adults participating in caloric restriction (CR) trials. Eight randomized controlled trials (RCTs) with five- or six-month assessments were pooled, including 749 participants randomized to CR and 594 participants randomized to non-CR (NoCR). Statistical models compared means and variances by CR assignment and exercise assignment or select subgroups, testing for treatment differences and interactions for mean changes and standard deviations. Continuous equivalents of dichotomized variables were also fit. Models used a Bayesian framework, and posterior estimates were presented as means and 95% Bayesian credible intervals (BCI). At baseline, participants were 67.7 (SD = 5.4) years, 69.8% female, and 79.2% white, with a BMI of 33.9 (4.4) kg/m 2 . CR participants reduced body mass [CR: -7.7 (5.8) kg vs. NoCR: -0.9 (3.5) kg] and increased gait speed [CR: +0.10 (0.16) m/s vs. NoCR: +0.07 (0.15) m/s] more than NoCR participants. There were no treatment differences in gait speed change standard deviations [CR–NoCR: -0.002 m/s (95% BCI: -0.013, 0.009)]. Significant mean interactions between CR and exercise assignment [0.037 m/s (95% BCI: 0.004, 0.070)], BMI [0.034 m/s (95% BCI: 0.003, 0.066)], and IL-6 [0.041 m/s (95% BCI: 0.009, 0.073)] were observed, while variance interactions were observed between CR and exercise assignment [-0.458 m/s (95% BCI: -0.783, -0.138)], age [-0.557 m/s (95% BCI: -0.900, -0.221)], and gait speed [-0.530 m/s (95% BCI: -1.018, -0.062)] subgroups. Caloric restriction plus exercise yielded the greatest gait speed benefit among older adults with obesity. High BMI and IL-6 subgroups also improved gait speed in response to CR. Results provide a novel statistical framework for identifying treatment heterogeneity in RCTs.

Background Knee osteoarthritis (KOA) is increasingly more prevalent and significant number of patients require knee arthroplasty. Although knee arthroplasty is generally successful, it takes months to recover physical function. Preoperative physical function is known to predict postoperative outcomes and exercise can improve preoperative physical function. However, patients with KOA have difficulty exercise on land due to pain and stiffness, while water exercise can be better tolerated. We hypothesized that preoperative water exercise to improve preoperative physical function will improve postoperative outcomes after total knee arthroplasty (TKA). Methods We enrolled 43 participants who were scheduled for elective TKA in 4–8 weeks and scored at or below 50th percentile in mobility assessment tool-sf (MAT-sf). All enrolled participants were assessed on 1) clinical osteoarthritis symptom severity using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), 2) physical function using Short Physical Performance Battery (SPPB), 3) self-reported mobility using Mobility Assessment Tool-short form (MAT-sf), 4) depression using Geriatric Depression Scale-short form (GDS-sf), 5) cognitive function using Montreal Cognitive Assessment (MoCA). Blood samples for high-sensitivity-C-reactive protein (hs-CRP), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) were stored at − 80 °C then all samples were analyzed together. All the enrolled participants were randomly assigned to the aquatic exercise intervention (AEI) or usual care group. Sixty minute sessions of AEI was conducted three times a week for 4–8 weeks. Participants in both groups were evaluated within 1 week before their scheduled surgery, as well as 4 weeks after the surgery. Results The mean age was 67.1 (±6.2), 44% were female, 74% were White. There is no statistically significant difference in combined outcome of any complication, unscheduled ER visit, and disposition to nursing home or rehab facility by AEI. However, AEI was associated with more favorable outcomes: WOMAC scores ( p  < 0.01), chair-stand ( p  = 0.019), MAT-sf as well as improved depression ( p  = 0.043) and cognition ( p  = 0.008). Conclusion 4–8 weeks of aquatic exercise intervention resulted in improved functional outcomes as well as improved depression and cognition in elderly patients undergoing TKA. A larger study is warranted to explore the role of water exercise in clinical and functional outcomes of TKA.

Background The Intensive Diet and Exercise for Arthritis (IDEA) trial was a randomized trial conducted to evaluate the effects of diet and exercise on osteoarthritis (OA), the most prevalent form of arthritis. Various risk factors, including obesity and sex, contribute to OA’s debilitating nature. While diet and exercise are known to improve OA symptoms, cellular and molecular mechanisms underlying these interventions, as well as effects of participant sex, remain elusive. Methods Serum was obtained at three timepoints from IDEA participants assigned to groups of diet, exercise, or combined diet and exercise ( n  = 10 per group). A randomly selected subset of serum samples were extracted and analyzed via liquid chromatography-mass spectrometry combined with metabolomic profiling to unveil mechanisms associated with types of intervention and disease. Extracted serum was pooled and fragmentation patterns were analyzed to identify metabolites that statistically differentially regulated between groups. Results Changes in metabolism across male and female IDEA participants after 18-months of diet, exercise, and combined diet and exercise intervention mapped to lipid, amino acid, carbohydrate, vitamin, and matrix metabolism. The diverse metabolic landscape detected across IDEA participants shows that intervention type differentially impacts the serum metabolome of OA individuals. Moreover, dissimilarities in the serum metabolome corresponded with participant sex. Conclusions These findings suggest that intensive weight loss among males and females offers potential metabolic benefits for individuals with knee OA. This study provides a deeper understanding of dysregulation occurring during OA development in parallel with various interventions, potentially paving the way for improved interventions, treatments, and quality of life of those impacted by OA. Trial Registration clinicaltrials.gov Identifier NCT00381290, Registered, 9/25/2006.

Background The aim of this systematic review was to identify principles of exercise interventions associated with improved physical function, weight management or musculoskeletal pain relief among young and middle-aged adults with obesity and propose an evidence-based exercise prescription that could assist in secondary prevention of osteoarthritis. Methods A structured electronic review was conducted using MEDLINE, PubMed, and SPORTDiscus. The search string included 1) “obes*” AND “exercise” AND “interven*” AND “musculoskeletal pain OR knee pain OR hip pain”. Studies 1) were randomized controlled trials of humans, with a non-exercise control, 2) included participants aged 18–50 years, and 3) had outcomes that included physical function, musculoskeletal pain, and/or body composition. Studies were excluded if participants had peri-menopausal status, cancer, or obesity-related co-morbidities. A recommended exercise prescription was developed based on common principles used in the included exercise interventions with greatest change in function or pain. Results Seven studies were included. Similarities in exercise intensity (40–80% VO 2max ), frequency (three times per week), duration (30–60 min), and exercise mode (treadmill, cross-trainer, stationary bike, aquatic exercise) were observed in exercise interventions that resulted in improved physical function and/or pain, compared to non-exercise control groups. Conclusion Common principles in exercise prescription for improvements in weight management, physical function and pain relief among otherwise healthy people with obesity. Exercise prescription including moderate intensity exercise for 30–60 min, three times per week can be considered an effective treatment for weight management and obesity-related musculoskeletal symptoms. Exercise should be recommended to at-risk individuals as part of secondary prevention of osteoarthritis.

The Intensive Diet and Exercise for Arthritis (IDEA) trial was an 18-month randomized controlled trial that enrolled 454 overweight and obese older adults with symptomatic and radiographic knee osteoarthritis (OA). Participants were randomized to either exercise (E), intensive diet-induced weight loss (D), or intensive diet-induced weight loss plus exercise (D + E) interventions. We previously reported that the clinical benefits of D + E were significantly greater than with either intervention alone (e.g., greater pain reduction, and better function, mobility, and health-related quality of life). We now test the hypothesis that D + E has greater overall benefit on gait mechanics compared to either intervention alone. Knee joint loading was analyzed using inverse dynamics and musculoskeletal modeling. Analysis of covariance determined the interventions’ effects on gait. The D + E group walked significantly faster at 18-month follow-up (1.35 m s−1) than E (1.29 m s−1, p = 0.0004) and D (1.31 m s−1, p = 0.0007). Tibiofemoral compressive impulse was significantly lower (p = 0.0007) in D (1069 N s) and D + E (1054 N s) compared to E (1130 N s). D had significantly lower peak hip external rotation moment (p = 0.01), hip abduction moment (p = 0.0003), and peak hip power production (p = 0.016) compared with E. Peak ankle plantar flexion moment was significantly less (p < 0.0001) in the two diet groups compared with E. There also was a significant dose-response to weight loss; participants that lost >10% of baseline body weight had significantly (p = 0.0001) lower resultant knee forces and lower muscle (quadriceps, hamstring, and gastrocnemius) forces than participants that had less weight loss. Compared to E, D produces significant load reductions at the hip, knee, and ankle; combining D with E attenuates these reductions, but most remain significantly better than with E alone.

Determine the safety and initial efficacy of a novel biofeedback intervention to improve landing mechanics in patients following anterior cruciate ligament reconstruction (ACLR). Forty patients post-ACLR (age: 16.9 ± 2.0 years) were randomly allocated to a biofeedback intervention or an attention control group. Patients in the biofeedback group completed 12 sessions over six-weeks that included bilateral unweighted squats with visual and tactile biofeedback. Patients in the control group completed a six-week educational program. Lower extremity mechanics were collected during a bilateral stop jump at baseline, six-weeks, and 12-weeks post-intervention. Linear mixed-effects models adjusted for sex and graft type determined the main effects of and interactions between group and time. No group by time interaction existed for peak knee extension moment symmetry. A group by time interaction existed for peak vertical ground reaction force symmetry (p = 0.012), where patients in the biofeedback group had greater improvements in symmetry between baseline and post-intervention that were not maintained through the retention assessments. This novel biofeedback program did not reduce risk factors for second ACL injuries. Future work could develop and test multidisciplinary interventions for reducing second ACL injury risk factors. (NCT03273673) •Squat biofeedback can improve loading symmetry in landing.•Squat biofeedback does not improve knee extension moment symmetry in landing.•Squat biofeedback is not sufficient to decrease 2nd ACL injury risk factors.•Combined mental and physical interventions need to be explored.

ObjectivesTo evaluate mediating factors for the effect of therapeutic exercise on pain and physical function in people with knee/hip osteoarthritis (OA).MethodsFor Subgrouping and TargetEd Exercise pRogrammes for knee and hip OsteoArthritis (STEER OA), individual participant data (IPD) were sought from all published randomised controlled trials (RCTs) comparing therapeutic exercise to non-exercise controls in people with knee/hip OA. Using the Counterfactual framework, the effect of the exercise intervention and the percentage mediated through each potential mediator (muscle strength, proprioception and range of motion (ROM)) for knee OA and muscle strength for hip OA were determined.ResultsData from 12 of 31 RCTs of STEER OA (1407 participants) were available. Within the IPD data sets, there were generally statistically significant effects from therapeutic exercise for pain and physical function in comparison to non-exercise controls. Of all potential mediators, only the change in knee extension strength was statistically and significantly associated with the change in pain in knee OA (β −0.03 (95% CI −0.05 to −0.01), 2.3% mediated) and with physical function in knee OA (β −0.02 (95% CI −0.04 to −0.00), 2.0% mediated) and hip OA (β −0.03 (95% CI −0.07 to −0.00), no mediation).ConclusionsThis first IPD mediation analysis of this scale revealed that in people with knee OA, knee extension strength only mediated ±2% of the effect of therapeutic exercise on pain and physical function. ROM and proprioception did not mediate changes in outcomes, nor did knee extension strength in people with hip OA. As 98% of the effectiveness of therapeutic exercise compared with non-exercise controls remains unexplained, more needs to be done to understand the underlying mechanisms of actions.

Background Hip osteoarthritis (OA) is a leading cause of musculoskeletal pain. Exercise is a core recommended treatment. Despite some clinical guidelines also recommending weight loss for hip OA, there is no evidence from randomised controlled trials (RCT) to substantiate these recommendations. This superiority, 2-group, parallel RCT will compare a combined diet and exercise program to an exercise only program, over 6 months. Methods One hundred people with symptomatic and radiographic hip OA will be recruited from the community. Following baseline assessment, participants will be randomly allocated to either, i) diet and exercise or; ii) exercise only. Participants in the diet and exercise group will have six consultations with a dietitian and five consultations with a physiotherapist via videoconferencing over 6 months. The exercise only group will have five consultations with a physiotherapist via videoconferencing over 6 months. The exercise program for both groups will include prescription of strengthening exercise and a physical activity plan, advice about OA management and additional educational resources. The diet intervention includes prescription of a ketogenic very low-calorie diet with meal replacements and educational resources to support weight loss and healthy eating. Primary outcome is self-reported hip pain via an 11-point numeric rating scale (0 = ‘no pain’ and 10 = ‘worst pain possible’) at 6 months. Secondary outcomes include self-reported body weight (at 0, 6 and 12 months) and body mass index (at 0, 6 and 12 months), visceral fat (measured using dual energy x-ray absorptiometry at 0 and 6 months), pain, physical function, quality of life (all measured using subscales of the Hip Osteoarthritis Outcome Scale at 0, 6 and 12 months), and change in pain and physical activity (measured using 7-point global rating of change Likert scale at 6 and 12 months). Additional measures include adherence, adverse events and cost-effectiveness. Discussion This study will determine whether a diet intervention in addition to exercise provides greater hip pain-relief, compared to exercise alone. Findings will assist clinicians in providing evidence-based advice regarding the effect of a dietary intervention on hip OA pain. Trial registration ClinicalTrials.gov . Identifier: NCT04825483 . Registered 31st March 2021.

Docosahexaenoic acid (DHA) is an essential fatty acid (FA) important for health and neurodevelopment. Premature infants are at risk of DHA deficiency and circulating levels directly correlate with health outcomes. Most supplementation strategies have focused on increasing DHA content in mother’s milk or infant formula. However, extremely premature infants may not reach full feedings for weeks and commercially available parenteral lipid emulsions do not contain preformed DHA, so blood levels decline rapidly after birth. Our objective was to develop a DHA supplementation strategy to overcome these barriers. This double-blind, randomized, controlled trial determined feasibility, tolerability and efficacy of daily enteral DHA supplementation (50 mg/day) in addition to standard nutrition for preterm infants (24–34 weeks gestational age) beginning in the first week of life. Blood FA levels were analyzed at baseline, full feedings and near discharge in DHA ( n  = 31) or placebo supplemented ( n  = 29) preterm infants. Term peers ( n  = 30) were analyzed for comparison. Preterm infants had lower baseline DHA levels ( p  < 0.0001). Those receiving DHA had a progressive increase in circulating DHA over time (from 3.33 to 4.09 wt% or 2.88 to 3.55 mol%, p  < 0.0001) while placebo-supplemented infants (receiving standard neonatal nutrition) had no increase over time (from 3.35 to 3.32 wt% or 2.91 to 2.87 mol%). Although levels increased with additional DHA supplementation, preterm infants still had lower blood DHA levels than term peers (4.97 wt% or 4.31 mol%) at discharge ( p  = 0.0002). No differences in adverse events were observed between the groups. Overall, daily enteral DHA supplementation is feasible and alleviates deficiency in premature infants.

Physical activity decreases the risk of osteoarthritis (OA)-related disability; however, pain and lack of confidence represent barriers for older adults with knee OA. The purpose of this study was to examine (a) the baseline associations among self-efficacy and physical activity, function, and pain; (b) longitudinal changes in self-efficacy; and (c) whether self-efficacy mediates treatment effects on clinical outcomes. The Intensive Diet and Exercise for Arthritis (IDEA) trial was a single-blind, randomized controlled 18-month study including 454 overweight/obese older adults (M age = 66 years) with knee OA. Participants were randomized to one of three interventions: exercise (E), diet-induced weight loss (D), or both (D+E). Self-efficacy for gait, balance, and walking duration were assessed at baseline, 6 months, and 18 months. Baseline associations were tested using Pearson correlations, and group least squares means were compared using mixed linear models at follow-up. Participants with higher self-efficacy reported significantly better physical function and less knee pain at baseline, walked farther (6-min walk), and were more physically active (all |r| > 0.12, all p < .01). Significant differences between groups were detected for all self-efficacy measures at 18 months; the D+E group reported significantly (all p < .005) higher self-efficacy for gait, walking duration, and balance compared with the D- or E-only groups. Self-efficacy significantly (p < .05) mediated treatment effects on physical function and pain at 18 months. A combined intervention of diet-induced weight loss and exercise is the treatment of choice to maximize self-efficacy, improve physical function, and reduce pain in overweight/obese adults with knee OA. Keywords Self-efficacy, Exercise, Physical activity, Weight loss, Knee osteoarthritis