Nizar N. Mahomed

Purpose: This study aimed to identify metabolic biomarkers and pathways that might be associated with total joint arthroplasty (TJA) early revision for heterogeneous failure modes using an individual data meta-analysis of metabolomics. Methods: Two independent osteoarthritis (OA) cohorts were included. Revision records of patients with primary knee and hip OA were extracted at an average of 11.1 and 7.8 years after primary TJA, respectively. Preoperative fasting plasma was metabolomically profiled. Concentrations of metabolites/metabolism indicators were natural log-transformed, and their associations with early revision for all reasons in each individual cohort were assessed using logistic regression; the summary statistics from each cohort were then subjected to random-effects meta-analysis modelling. Results: Five hundred seventy-two patients with primary OA in The Newfoundland Osteoarthritis Study and 368 in the Longitudinal Evaluation in the Arthritis Program: Osteoarthritis Study were included. The revision rates were 4% and 6%, and mean times to revision were 1.7 and 2.1 years, respectively. No metabolite reached the prespecified significance threshold for multiple testing correction. However, 119 metabolites including choline, tryptophan betaine, indole, ornithine, three acylcarnitines, four cholesteryl esters, two lysophosphatidylcholines, five long-chain diglycerides, and 101 unsaturated (very) long-chain triglycerides were nominally significant with P < 0.05, suggesting potential links between these metabolites and early revision. Among these, indole and one acylcarnitine were positively associated with revision (odds ratio ≥1.73), while all others were negatively associated (odds ratio ≤0.73). Conclusion: Overactivation of the tryptophan-indole metabolic pathway may be associated with early revision after primary TJA. However, the findings were suggestive and represented a composite signal from heterogeneous failure modes.

Background: Despite broad calls to consider sex-specific effects in treatment/intervention studies, this remains a persistent gap. This study sought to identify presurgery factors associated with pain and physical function following hip and knee total joint arthroplasty (TJA) for osteoarthritis, specifically adopting a sex-stratified approach. Methods: Questionnaires were patient-completed presurgery: sociodemographic and health-related characteristics, anxiety and depression symptoms, neuropathic-like pain symptoms, multijoint involvement, and opioid use. Pain and physical function were captured presurgery and 1 year postsurgery. Study outcomes: pain and function status scores at 1 year and their percentage change (presurgery to 1 year postsurgery). Associations between presurgery factors and outcomes were assessed by sex-stratified multivariable linear regressions. Findings were contrasted against a sex-adjusted approach (i.e. one analysis in combined male/female sample). Results: Sample (45% hip, 55% knee): 787 female patients and 640 male patients. Among male patients only: Depressive symptoms were associated with worse pain and function status, and less pain improvement (β = −8.6% [−17.4%, 0.3%]), as were lower education and living alone. Among female patients only: Anxiety symptoms were associated with worse pain and function status and less pain (β = −7.7% [−14.3%, −1.0%) and functional improvement (β = −8.5% [−14.4%, −2.6%]), as was greater multijoint burden. The negative effect of neuropathic-like pain symptoms was greater in male patients than female patients. Sex-adjusted findings suggested sex had no consequence. Conclusions: Several factors uniquely influenced TJA outcomes by sex. Simple sex-adjustment may miss important effects. This has broad implications, including for patient education, decision making, prognostic/comparative effectiveness study design, and development/improvement of prediction algorithms. Though TJA focused, we hypothesize that sex differences are likely relevant in other clinical populations. Level of Evidence: Prognostic Level I . See Instructions for Authors for a complete description of levels of evidence.

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 examine the magnitude and costs of ambulatory primary care, specialist physician care, and hospital service use for musculoskeletal disorders (MSDs) in Canada’s largest province, Ontario.Methods.: Administrative health databases were analyzed for fiscal year 2013–2014 for adults aged ≥ 18 years, including data on physician services, emergency department (ED) visits, and hospitalizations. International Classification of Diseases diagnostic codes were used to identify MSD services. A validated algorithm was used to estimate direct medical costs. Person-visit rates and numbers of persons and visits were tabulated by care setting, age, sex, and physician specialty. Data were examined for all MSDs combined, as well as for specific diagnostic groupings.Results.: Overall, 3.1 million adult Ontarians (28.5%) made over 8 million outpatient physician visits associated with MSDs. These included 5.6 million primary care visits. MSDs accounted for 560,000 (12.3%) of all adult ED visits. Total costs for MSD-related care were $1.6 billion, with 12.6% of costs attributed to primary care, 9.2% to specialist care, 8.6% to ED care, 8.5% to day surgery, and 61.2% associated with inpatient hospitalizations. Costs due to arthritis accounted for 40% of total MSD care costs ($639 million). MSD-related imaging costs were $169 million, yielding a total cost estimate of $1.8 billion for MSDs overall.Conclusion.: MSDs place a significant and costly burden on the healthcare system. Health system planning needs to consider the large and escalating demand for care to reduce both the individual and population burden.

Introduction: Trauma and compression are common causes of peripheral neuropathic pain (NP) refractory to conventional medical management (CMM). The role of perineural interventions in relieving this type of pain is unclear. Objectives: The objectives of this retrospective study were to determine the analgesic benefits of adding a combination of perineural local anesthetic and steroids (LA-S) to CMM compared with CMM alone in patients who had moderate-to-severe refractory NP after trauma to the ankle and the foot. Methods: Health care records of 60 patients in exposed (3 injections of perineural LA-S at weekly intervals with CMM) and 60 in unexposed (CMM) cohorts were reviewed. Data on patient characteristics, pain, and mental and physical function were extracted at baseline and at the postintervention follow-up. Data were analyzed to evaluate analgesic benefit from the study interventions and the impact of baseline characteristics. Results: Perineural LA-S with CMM cohort had lower pain numerical rating scale scores at 1 to 3 months after the intervention as compared to the CMM alone cohort (5.50 [interquartile range 4.00–7.00] and 7.00 [interquartile range 5.00–8.00], respectively; P < 0.01). However, multivariable analysis did not show an independent beneficial analgesic effect with the addition of perineural LA-S to CMM compared with CMM alone. A greater severity of preintervention catastrophizing (each unit increase in pain catastrophizing score increased pain score at follow-up by 0.04, 95% confidence interval: 0.01–0.07) was associated with reduction in the analgesic benefit. Conclusion: Perineural local anesthetic and steroid injections do not confer an analgesic benefit for trauma- or compression-related peripheral NP.

Chronic, low-grade inflammation of the synovium (synovitis) is a hallmark of osteoarthritis (OA), thus understanding of OA immunobiology, mediated by immune effectors, is of importance. Specifically, monocytes/macrophages (MΦs) are known to be abundantly present in OA joints and involved in OA progression. However, different subsets of OA MΦs have not been investigated in detail, especially in terms of their relationship with patient-reported outcome measures (PROMs). We hypothesized that levels of synovial fluid (SF) MΦ subsets are indicative of joint function and quality of life in patients with OA, and can therefore serve as biomarkers and therapeutic targets for OA. In this cohort study, synovial fluid leukocytes (SFLs, N = 86) and peripheral blood mononuclear cells (n = 53) from patients with knee OA were characterized. Soluble MΦ receptors and chemokine (sCD14, sCD163, CCL2, CX3CL1) levels were detected in SF using immunoassays. Linear models, adjusted for sex, age and body mass index, were used to determine associations between SF MΦs and soluble factors with PROMs (N = 83). Pearson correlation was calculated to determine correlation between MΦ subsets, T cells and soluble factors. SF MΦs were the most abundant SFLs. Within these, the double-positive CD14+CD16+-MΦ subset is enriched in knee OA SF compared to the circulation. Importantly, MΦ subset ratios correlated with PROMs, specially stiffness, function and quality of life. Interestingly, the SF CD14+CD16+-MΦ subset ratio correlated with SF chemokine (C-C motif) ligand 2 (CCL2) levels but not with levels of sCD163 or sCD14; we found no association between PROMs and either SF CCL2, sCD163, sCD14 or CX3CL1 (which was below detection levels). All SF MΦs displayed high levels of HLA-DR, suggesting an activated phenotype. Correlation between OA SF MΦ subsets and activated CD4+ T cell subsets suggests modulation of CD4+ T cell activation by MΦs. SF MΦ subsets are associated with knee OA PROMs and display an activated phenotype, which may lead to modulation of CD4+ T cell activation. Knee OA SF MΦ subsets could serve as knee OA function biomarkers and as targets of novel therapeutics.