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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.

Summary Objective There is a need to incorporate multiple tissues into in vitro OA models to evaluate novel therapeutics. This approach is limited by inherent donor variability. We present an optimized research tool: a human OA cartilage-synovium explant co-culture model (OA-EXM) that employs donor-matched lower and upper limit response controls combined with statistical approaches to address variability. Multiple rapid read-outs allow for evaluation of therapeutics while cataloguing cartilage-synovium interactions. Design 48-h human explant cultures were sourced from OA knee arthroplasties. An OA-like cartilage-synovium co-culture baseline was established relative to donor-matched upper limit supraphysiological pro-inflammatory cytokine and lower limit OA cartilage or synovium alone controls. 100 nM dexamethasone treatment validated possible “rescue effects” within the OA-EXM dual tissue environment. Gene expression, proteoglycan loss, MMP activity, and soluble protein concentrations were analyzed using blocking and clustering methods. Results The OA-EXM demonstrates the value of the co-culture approach as the addition of OA synovium increases OA cartilage proteoglycan loss and expression of MMP1, MMP3, MMP13, CXCL8, CCL2, IL6, and PTGS2, but not to the extent of supraphysiological stimulation. Conversely, OA cartilage does not affect gene expression or MMP activity of OA synovium. Dexamethasone shows dual treatment effects on synovium (pro-resolving macrophage upregulation, protease downregulation) and cartilage (pro-inflammatory, catabolic, and anabolic downregulation), and decreases soluble CCL2 levels in co-culture, thereby validating OA-EXM utility. Conclusions The OA-EXM is representative of late-stage OA pathology, captures dual interactions between cartilage and synovium, and combined with statistical strategies provides a rapid, sensitive research tool for evaluating OA therapeutics.

Objective MicroRNA‐34a‐5p (miR‐34a‐5p) expression is elevated in the synovial fluid of patients with late‐stage knee osteoarthritis (OA); however, its exact role and therapeutic potential in OA remain to be fully elucidated. This study was undertaken to examine the role of miR‐34a‐5p in OA pathogenesis. Methods Expression of miR‐34a‐5p was determined in joint tissues and human plasma (n = 71). Experiments using miR‐34a‐5p mimic or antisense oligonucleotide (ASO) treatment were performed in human OA chondrocytes, fibroblast‐like synoviocytes (FLS) (n = 7–9), and mouse OA models, including destabilization of the medial meniscus (DMM; n = 22) and the accelerated, more severe model of mice fed a high‐fat diet and subjected to DMM (n = 11). Wild‐type (WT) mice (n = 9) and miR‐34a–knockout (KO) mice (n = 11) were subjected to DMM. Results were expressed as the mean ± SEM and analyzed by t‐test or analysis of variance, with appropriate post hoc tests. P values less than 0.05 were considered significant. RNA sequencing was performed on WT and KO mouse chondrocytes. Results Expression of miR‐34a‐5p was significantly increased in the plasma, cartilage, and synovium of patients with late‐stage OA and in the cartilage and synovium of mice subjected to DMM. Plasma miR‐34a‐5p expression was significantly increased in obese patients with late‐stage OA, and in the plasma and knee joints of mice fed a high‐fat diet. In human OA chondrocytes and FLS, miR‐34a‐5p mimic increased key OA pathology markers, while miR‐34a‐5p ASO improved cellular gene expression. Intraarticular miR‐34a‐5p mimic injection induced an OA‐like phenotype. Conversely, miR‐34a‐5p ASO injection imparted cartilage‐protective effects in the DMM and high‐fat diet/DMM models. The miR‐34a–KO mice exhibited protection against DMM‐induced cartilage damage. RNA sequencing of WT and KO chondrocytes revealed a putative miR‐34a‐5p signaling network. Conclusion Our findings provide comprehensive evidence of the role and therapeutic potential of miR‐34a‐5p in OA.

Objectives Knee pain is the major driver for OA patients to seek healthcare, but after pursuing both conservative and surgical pain interventions, ∼20% of patients continue to report long-term pain following total knee arthroplasty (TKA). This study aimed to identify a metabolomic signature for sustained knee pain after TKA to elucidate possible underlying mechanisms. Methods Two independent cohorts from St John’s, NL, Canada (n = 430), and Toronto, ON, Canada (n = 495) were included in the study. Sustained knee pain was assessed using the WOMAC pain subscale (five questions) at least 1 year after TKA for primary OA. Those reporting any pain on all five questions were considered to have sustained knee pain. Metabolomic profiling was performed on fasted pre-operative plasma samples using the Biocrates Absolute IDQ p180 kit. Associations between metabolites and pair-wise metabolite ratios with sustained knee pain in each individual cohort were assessed using logistic regression with adjustment for age, sex and BMI. Random-effects meta-analysis using inverse variance as weights was performed on summary statistics from both cohorts. Results One metabolite, phosphatidylcholine (PC) diacyl (aa) C28:1 (odds ratio = 0.66, P = 0.00026), and three metabolite ratios, PC aa C32:0 to PC aa C28:1, PC aa C28:1 to PC aa C32:0, and tetradecadienylcarnitine (C14:2) to sphingomyelin C20:2 (odds ratios = 1.59, 0.60 and 1.59, respectively; all P Conclusions Though further investigations are needed, our results provide potential predictive biomarkers and drug targets that could serve as a marker for poor response and be modified pre-operatively to improve knee pain and surgical response to TKA.

OBJECTIVE The influence of sex on post-total knee arthroplasty (TKA) outcomes has been variable in the literature. Though sex is often reported as an averaged effect, we undertook this study to investigate whether sex modified the influence of presurgery characteristics on post-TKA knee pain. METHODS This was a prospective study with data derived from 477 TKA osteoarthritis patients (279 women, 198 men). Questionnaires were completed presurgery and at 3 months postsurgery. The association between 3-month post-TKA knee pain and presurgery covariates (body mass index, comorbidity count, symptomatic joint count, low back pain, knee pain, and depressive symptoms) was assessed by linear regression. Sex-specific effects were evaluated using interactions. RESULTS Women had significantly worse presurgery knee pain, joint count, and depressive symptoms, and worse postsurgery knee pain, than men. With simple covariate adjustment, no sex effect on pain was found. However, sex was found to moderate the effects of comorbidities (worse for women [P = 0.013]), presence of low back pain (worse for men [P = 0.003]), and depressive symptoms (worse for men [P < 0.001]) on postsurgery pain. Worse presurgery pain was associated with worse postsurgery pain similarly for women and men. CONCLUSION The influence of some patient factors on early post-TKA pain cannot be assumed to be the same for women and men; average effects may mask underlying associations. Results suggest a need to consider sex differences in understanding TKA outcomes, which may have important implications for prognostic tool development in TKA.

BACKGROUND CONTEXT An important step in improving spinal care is understanding how current health-care resources and associated cost are being utilized and distributed across a health-care system. PURPOSE Our objective was to examine the magnitude and distribution of direct health care costs for spinal conditions across physician type and hospital setting. DESIGN/SETTING Cross-sectional analysis of administrative health data for the fiscal year 2013–2014 from the province of Ontario, Canada. PATIENT SAMPLE Adult population aged 18+ years (N=10,841,302). OUTCOME MEASURES Person visit rates and total number of people and visits by specific care settings were calculated for all spinal conditions as well as stratified by nontrauma and trauma-related conditions. Variation in rates by age and sex was examined. The proportion of patients seeing physicians of different specialties was calculated for each condition grouping. Direct medical costs were estimated and their percentage distribution by care setting calculated for nontrauma and trauma-related conditions. Additionally, costs for spinal imaging overall and stratified by type of scan were determined. METHODS Administrative health databases were analyzed, including data on physician services, emergency department visits, and hospitalizations. ICD-9 and -10 diagnostic codes were used to identify nontraumatic (degenerative or inflammatory) and traumatic spinal disorders. A validated algorithm was used to estimate direct medical costs. RESULTS Overall, 822,000 adult Ontarians (7.6%) made 1.6 million outpatient physician visits for spinal conditions; the majority (1.1 million) of these visits were for nontrauma conditions. Approximately, 86% of outpatient visits were in primary care. Emergency Department (ED) visits for nontrauma spinal conditions (130,000 out of 156,000 ED visits) accounted for 2.8% of all ED visits in the province. Total costs for spine-related care were $264 million (CDN) with 64% of costs due to nontrauma conditions. For these nontrauma conditions, ED visits cost $28 million for 130,000 visits ($215 per visit). For $32 million spent in primary care, 890,000 visits were made ($36 per visit). Spine imaging costs were $66.5 million, yielding a combined total of $330 million in health care spending for spinal conditions. CONCLUSIONS Spinal conditions place a large and costly burden on the health-care system. The disproportionate annual cost associated with ED visits represents a potential opportunity to redirect costs to fund more clinically and cost-effective models of care for nontraumatic spinal conditions.

OBJECTIVES To define the risk and incidence of post-traumatic ankle arthritis requiring ankle arthroplasty or fusion after ankle fracture in a large cohort and compare that rate to matched healthy patients from the general population. DESIGN Multiple databases were used to identify patients either treated surgically or nonsurgically for ankle fractures. Each patient was matched to 4 individuals from the general population (13.5 million) with no previous treatment for ankle fracture. Ankle fusion and replacement incidence was compared using the Kaplan-Meier analysis. MAIN OUTCOME MEASUREMENT Incidence of arthroplasty or fusion in all patients managed for rotational ankle fractures. RESULTS We identified 44,133 and 88,266 patients who had undergone operative management of ankle fracture (OAF) or nonoperative management of ankle fracture (NOAF) by an orthopaedic surgeon, respectively. Three hundred six (0.65%) patients who had OAF eventually underwent fusion or arthroplasty after a median 2.8 and 6.9 years, respectively. Among NOAF, n = 236 (0.17%) patients underwent fusion or arthroplasty after a median of 3.2 and 5.6 years, respectively. Surgical treatment, older age, comorbidity, and postinjury infection significantly increased the risk of fusion/arthroplasty. Compared with matched controls, the risk of fusion/arthroplasty was not independent of time, following an exponential decay pattern. OAF patient risk of fusion/arthroplasty was >20 times the general population in the 3 years after injury and approached the risk of NOAF by 14 years. CONCLUSIONS Compared with a matched control group, and after adjustment for medical comorbidity, rotational ankle fractures requiring surgical open reduction internal fixation increased the likelihood of arthroplasty or fusion by 3.5 times. This study allows for accurate prognostication of patient risk of arthroplasty or fusion, using patient- and injury-specific risk factors, both immediately after the initial injury and then subsequently during the follow up. LEVEL OF EVIDENCE Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Supplemental Digital Content is Available in the Text. Perineural local anesthetic and steroid injections do not confer an analgesic benefit for trauma- or compression-related peripheral neuropathic pain. A higher degree of catastrophizing reduces the analgesic benefit with treatments for neuropathic pain., 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.

Objective To examine patterns of depressive symptoms before and over the year following osteoarthritis (OA) surgery, stratified by joint and postsurgical outcome. Methods Participants were hip (n = 287), knee (n = 360), and lumbar spine (n = 100) OA patients scheduled for joint replacement or decompression surgery with or without fusion. One pre- and 4 postsurgery questionnaires were completed. Depressive symptoms were quantified using the Hospital Anxiety and Depression Scale (HADS). One-year outcomes were based on Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scores for hip and knee patients and Oswestry Disability Index (ODI) scores for spine patients and were categorized as "worse" (top score tertile) vs. "better" outcomes (first, second tertiles). Plots over time were generated by joint and outcome: 1) mean pain/disability and depression scores and 2) percentage of patients meeting HADS cut-off for depression "caseness," reporting depression diagnosis and treatment. Results There were notable decreases in depression scores for patients with better outcomes. For those with worse outcomes, decreases were smaller for hip patients and were not significant for knee and spine patients. Among those with poorer outcomes, 25% of spine and knee patients were depression "cases" pre- and postsurgery; an additional 16% of spine and 10% of knee patients developed new "caseness" postsurgery. The proportion of these patients deemed depression cases by score was much higher than the proportion reporting diagnosis/treatment. Conclusion Although depressive symptoms decrease overall in OA patients postsurgery, degrees of change vary by joint and surgical outcome. Greater attention to mental health postsurgery is warranted and may lead to improved surgical outcomes, particularly among knee and spine patients.

Patients with late-stage Kellgren-Lawrence knee osteoarthritis received a single intra-articular injection of 1, 10, or 50 million bone marrow mesenchymal stromal cells (BM-MSCs) in a phase I/IIa trial to assess safety and efficacy using a broad toolset of analytical methods. Besides safety, outcomes included patient-reported outcome measures (PROMs): Knee Injury and Osteoarthritis Outcome Score (KOOS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC); contrast-enhanced magnetic resonance imaging (MRI) for cartilage morphology (Whole Organ MRI Scores [WORMS]), collagen content (T2 scores), and synovitis; and inflammation and cartilage turnover biomarkers, all over 12 months. BM-MSCs were characterized by a panel of anti-inflammatory markers to predict clinical efficacy. There were no serious adverse events, although four patients had minor, transient adverse events. There were significant overall improvements in KOOS pain, symptoms, quality of life, and WOMAC stiffness relative to baseline; the 50 million dose achieved clinically relevant improvements across most PROMs. WORMS and T2 scores did not change relative to baseline. However, cartilage catabolic biomarkers and MRI synovitis were significantly lower at higher doses. Pro-inflammatory monocytes/macrophages and interleukin 12 levels decreased in the synovial fluid after MSC injection. The panel of BM-MSC anti-inflammatory markers was strongly predictive of PROMs over 12 months. Autologous BM-MSCs are safe and result in significant improvements in PROMs at 12 months. Our analytical tools provide important insights into BM-MSC dosing and BM-MSC reduction of synovial inflammation and cartilage degradation and provide a highly predictive donor selection criterion that will be critical in translating MSC therapy for osteoarthritis. Stem Cells Translational Medicine 2019;8:746–757

Interest in postoperative healthcare utilization has increased following the implementation of episode-of-care funding for elective orthopedic surgery. Most efforts have focused on readmission; however, little has been reported on emergency department (ED) presentation. We analyzed elective, primary total hip or knee arthroplasty (THA and TKA) cases to determine the rate, reasons, risk factors, timing, and hospital cost associated with 30-day ED presentations.An observational study of patients who underwent primary, elective TKA and THA between January 1, 2016, and December 31, 2017, was performed. The primary outcome was an ED visit within 30-days of the index operation. Secondary outcomes included reasons, risk factors, timing, and hospital cost of ED visits. A multivariable logistic regression was undertaken to determine patient factors associated with ED presentation.Overall, 1690 patients were included, of which 9.2% presented to the ED within 30-days of surgery. Approximately two-thirds of the visits were after-hours, and most were discharged home without readmission (81.4%). The most commonly reported reasons were wound concerns (30.1%) and pain (20.5%). Older age (OR 1.1, P = .03) and preoperative dyspnea (OR 2.1, P.001) increased the odds of ED visits. The mean cost of an ED visit was significantly greater after-hours (P = .015).Overall, 1 in 10 patients undergoing TKA/THA presented to the ED within 30-days of surgery, of which over 80% were not readmitted, and most occurred after-hours where cost is greatest. Our observations suggest ED visits following TKA/THA are common, and most are likely preventable. Future efforts should focus on developing interventions to reduce these visits.

We investigated the association between serum levels of C-reactive protein (CRP) and the extent of multijoint pain among individuals with hip/knee osteoarthritis (OA) and determined whether the association differs by sex.Serum CRP and cartilage oligomeric matrix protein (COMP) were determined by enzyme-linked immunosorbent assay (ELISA) in 189 individuals (101 female, 88 male) scheduled for total hip/knee arthroplasty for OA. Patients indicated on a homunculus all painful joints; a summed count was derived. A series of negative binomial regression models was used to investigate the cross-sectional association between painful joint count (outcome) and serum CRP concentrations, adjusting for age, sex, body mass index (BMI), comorbidity count and COMP. An interaction between sex and these biomarkers was tested.Mean age: 66 among women, 65 among men. Women had higher mean joint count (3.7 vs 2.5, P 0.01; 4+ joint count reported by 37% women, 25% men). Median CRP concentration was higher in women (15.4 mg/l vs 9.3, P = 0.07). From adjusted analyses, the effects of both ln(CRP) and ln(COMP) were modified by sex (P 0.05). Increasing ln(CRP) was associated with greater painful joint count among women, but not men.There may be a dose-response association between painful joint burden in OA and systemic inflammation, and it appears the association is sex-specific, which may in part explain inconsistent findings in the literature. Our results underline the importance of showing sex-specific associations in OA, especially when studying the influence of inflammation.

Background 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. Methods 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. Results 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. Conclusion 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. Electronic supplementary material The online version of this article (10.1186/s13075-018-1798-2) contains supplementary material, which is available to authorized users.

Background & Aim Osteoarthritis (OA) is a joint disease affecting > 5 million Canadians. Patients have limited palliative and joint-replacement surgical options, emphasizing the need for new curative therapies. Stromal cell therapy is emerging as a compelling treatment for OA. Our first-in-Canada Ph1/2 trial with bone marrow mesenchymal stromal cells (BM-MSCs) in OA patients showed significant improvements in patient outcomes. Although, MSCs showed beneficial effects in all the patients, we found variabilities in MSCs efficacy among participants. The goal of this study is to identify novel microRNAs (miRs) that correlate with therapeutic efficacy of MSCs in the context of OA. Methods, Results & Conclusion We have identified a panel of predictive anti-inflammatory markers (i.e. IL10, HGF, IL6, TSG6, PGE2) on MSCs that is strongly indicative of clinical efficacy in OA. To expend this panel, we conducted an unbiased miR sequencing on our clinical trial MSC samples. We are correlating differential miR expression with patient outcomes. We identified 25 miRs differentially expressed between MSCs from responder (5/5 on KOOS sub-scale responses are clinically significant) and mild responder (2-3/5 KOOS sub-scale responses are clinically significant) participants. Amongst these, 12 miRs showed higher expression in MSCs from responder participants and 13 miRs appeared to be expressed at lower level when compared to those levels in MSCs from mild responder participants. Interestingly, miR target and pathway analysis revealed that the identified miRs are associated with Toll like receptors, IL-4, IL-13, IL12, IL-1 and IL-10 cascades; as well as TGF-β, wnt and Smad signaling. Thus, contributing to immune response, fibrosis and consequently OA pathology. We have selected 10 miRs out of 25 differentially expressed miRs based on the relevance of their targets to OA pathology for further analysis. Currently, we are verifying these miRs by qPCR and their significance in OA pathology will be confirmed via knock down/overexpression experiments. This will help us to better understand and predict potent MSCs, and/or OA patients that are responders to MSC therapies. In conclusion, microRNA profile of MSCs contributes to therapeutic efficacy of MSCs. Understanding therapeutically relevant mechanism of action of MSCs will help to develop enhanced MSCs; and define potency criterion for screening effective MSCs in OA patients. This in turn will enable a successful MSC pivotal clinical trial in OA.

Background It has been suggested that total knee replacement is being performed in people with less-severe osteoarthritis. We aimed to determine whether there were differences in the presurgery profile, symptoms and disability of 2 cohorts who underwent total knee replacement over a 10-year period. Methods Patients aged 18-85 years undergoing primary total knee replacement for osteoarthritis at 1 of 4 sites in Toronto and Strathroy, Ontario, were recruited in a cohort study during 2006-2008 (cohort 1) and 2012-2015 (cohort 2). Patients undergoing unicompartmental or revision arthroplasty were excluded. Demographic and health (body mass index [BMI], comorbidity) variables and osteoarthritis severity, as assessed with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the disability component of the Late-Life Function and Disability Instrument (LLFDI-D), were collected before surgery. We calculated proportions, means and standard deviations with 95% confidence intervals (CIs) for all data. We constructed density plots by tertile score for the WOMAC pain and physical function subscales and the LLFDI-D limitation scale. Results There were 494 patients in cohort 1 and 251 patients in cohort 2. There were no differences in age, sex, education, living status, BMI, comorbidity, pain severity or disability between the cohorts based on overlapping 95% CIs and the density plots. More patients in cohort 1 than in cohort 2 were single (176 [35.6%], 95% CI 32.5%-41.1% v. 63 [25.1%], 95% CI 20.3%-31.0%). Patients in cohort 2 reported less limitation in higher-demand activities than did those in cohort 1 (mean score on LLFDI-D 62.3 [95% CI 60.7-63.9] v. 59.2 [95% CI 58.2-60.2]). Interpretation The patient profile and reported osteoarthritis severity were similar in 2 cohorts that had total knee replacement over a 10-year period. This suggests that increasing total knee replacement volumes over this period likely were not driven by these factors.

OBJECTIVE To evaluate rates of prescription opioid use among patients with presurgical knee, hip, and spine osteoarthritis (OA) and associations between use and sociodemographic and health status characteristics. METHODS Participants were patients with presurgical, end-stage OA of the knee (n = 77), hip (n = 459), and spine (n = 168). Data were collected on current use of opioids and other pain medications, as well as measures of sociodemographic and health status variables and depression and pain (0-10 numeric rating scale). Rates of opioid use were calculated by sex, age, and surgical site. Multivariable logistic regression was used to examine associations between opioid use (sometimes/daily versus never) and other study variables. RESULTS The mean age of participants was 65.6 years; 55.5% were women, 15% of patients reported "sometimes" using opioids, and 15% reported "daily use." Use of opioids was highest among patients with spine OA (40%) and similar among patients with knee and hip OA (28% and 30%, respectively). Younger women (ages

ObjectivesWe recently identified microRNA-181a-5p (miR-181a-5p) as a critical mediator involved in the destruction of lumbar facet joint (FJ) cartilage. In this study, we tested if locked nucleic acid (LNA) miR-181a-5p antisense oligonucleotides (ASO) could be used as a therapeutic to limit articular cartilage degeneration.MethodsWe used a variety of experimental models consisting of both human samples and animal models of FJ and knee osteoarthritis (OA) to test the effects of LNA-miR-181a-5p ASO on articular cartilage degeneration. Histopathological analysis including immunohistochemistry and in situ hybridisation were used to detect key OA catabolic markers and microRNA, respectively. Apoptotic/cell death markers were evaluated by flow cytometry. qPCR and immunoblotting were applied to quantify gene and protein expression.ResultsmiR-181a-5p expression was increased in human FJ OA and knee OA cartilage as well as injury-induced FJ OA (rat) and trauma-induced knee OA (mouse) cartilage compared with control cartilage, correlating with classical OA catabolic markers in human, rat and mouse cartilage. We demonstrated that LNA-miR-181a-5p ASO in rat and mouse chondrocytes reduced the expression of cartilage catabolic and chondrocyte apoptotic/cell death markers in vitro. Treatment of OA-induced rat FJ or mouse knee joints with intra-articular injections of in vivo grade LNA-miR-181a-5p ASO attenuated cartilage destruction, and the expression of catabolic, hypertrophic, apoptotic/cell death and type II collagen breakdown markers. Finally, treatment of LNA-miR-181a-5p ASO in cultures of human knee OA chondrocytes (in vitro) and cartilage explants (ex vivo) further demonstrated its cartilage protective effects.ConclusionsOur data demonstrate, for the first time, that LNA-miR-181a-5p ASO exhibit cartilage-protective effects in FJ and knee OA.

Summary Objective To determine factors associated with orthopaedic surgeons' decision to recommend total joint replacement (TJR) in people with knee and hip osteoarthritis (OA). Design Cross-sectional study in eleven countries. For consecutive outpatients with definite hip or knee OA consulting an orthopaedic surgeon, the surgeon's indication of TJR was collected, as well as patients' characteristics including comorbidities and social situation, OA symptom duration, pain, stiffness and function (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]), joint-specific quality of life, Osteoarthritis Research Society International (OARSI) joint space narrowing (JSN) radiographic grade (0–4), and surgeons' characteristics. Univariable and multivariable logistic regressions were performed to identify factors associated with the indication of TJR, adjusted by country. Results In total, 1905 patients were included: mean age was 66.5 (standard deviation [SD], 10.8) years, 1082 (58.0%) were women, mean OA symptom duration was 5.0 (SD 7.0) years. TJR was recommended in 561/1127 (49.8%) knee OA and 542/778 (69.7%) hip OA patients. In multivariable analysis on 516 patients with complete data, the variables associated with TJR indication were radiographic grade (Odds Ratio, OR for one grade increase, for knee and hip OA, respectively: 2.90, 95% confidence interval [1.69–4.97] and 3.30 [2.17–5.03]) and WOMAC total score (OR for 10 points increase: 1.65 [1.32–2.06] and 1.38 [1.15–1.66], respectively). After excluding radiographic grade from the analyses, on 1265 patients, greater WOMAC total score was the main predictor for knee and hip OA; older age was also significant for knee OA. Conclusion Radiographic severity and patient-reported pain and function play a major role in surgeons' recommendation for TJR.

Background & Aim Monocytes/macrophages (MΦs) are innate immune cells that exist on a spectrum of pro-inflammatory to inflammation-resolving phenotypes. Their polarization is mediated in vivo through the local microenvironment or ex vivo through exogenous factors. Such ex vivo polarized cells have been used in early clinical trials for a variety of immunosuppressive or reparative indications (e.g. spinal cord injury, liver cirrhosis, transplant rejection). Manufacturing protocols have been variable between studies with similarities in 7-day duration and surface marker characterization. We aim to develop an abbreviated (i.e. Methods, Results & Conclusion Peripheral blood MΦs are isolated by density centrifugation and CD14 magnetic beads, then treated with in-house cytokine cocktail or small molecule inhibitors for 24-48h. Polarized MΦs are co-cultured with late stage osteoarthritic explants to test phenotypic stability. MΦs are characterized through: flow cytometry (surface markers, viability, dextran endocytosis), qRT-PCR and/or immunoassay (inflammatory/chemotactic/catabolic mediators), and T cell proliferation. Treatment phenotype is compared against 7-day treatment with M-CSF and against naive 48h MΦs. 48h polarized MΦs demonstrate a similar phenotypic profile to 7-day polarized MΦs. Gene expression of anti-inflammatory IL-10 is upregulated in both groups relative to naive controls. Surface expression of scavenger receptors CD163 and CD206, markers of an inflammation-suppressive phenotype, are higher in both the 48h and 7d groups relative to control. Pro-inflammatory markers CD86 and HLA-DR are not highly expressed in either group. 48h polarized MΦs maintain a similar surface marker profile after co-culture with osteoarthritic explant tissue for up to 7 days. Preliminary results demonstrate that the 48h polarization protocol yields a similar phenotypic profile to 7d polarized MΦs. With further functional assay and protocol optimization using small molecule agents, we aim to develop an efficient, well-characterized inflammation suppressive MΦ phenotype that can be easily translated for clinical use.

Background: Clinical studies of shoulder dislocations typically include adult patients (>16 years of age). Only small case series of patients aged 10 to 16 years are available to guide management. Purpose: Using a cohort of patients aged 10 to 16 years, this study sought to determine (1) the incidence density rate (IDR) of primary anterior shoulder dislocations requiring closed reduction (CR) and (2) the rate of and risk factors for repeat shoulder CR. Study Design: Cohort study (prognosis); Level of evidence, 2. Methods: With use of administrative databases, patients aged 10 to 16 years who underwent CR of a primary anterior shoulder dislocation in Ontario, Canada, between April 2002 and September 2010 were gathered. IDRs for the entire cohort and demographic subgroups were calculated. The main outcome, repeat shoulder CR, was sought until September 2012. The cumulative incidence of repeat CR was calculated at multiple time points for the entire cohort and age subgroups. A competing risk model identified risk factors for repeat CR (reported as hazard ratios [HRs] with 95% CIs). Results: There were 1937 patients aged 10 to 16 years who underwent primary CR (median age, 15.0 years; 79.7% male). The incidence of primary CR was highest among male patients aged 16 years (164.4 per 100,000 person-years), but primary dislocations were rare in 10- to 12-year-old children (n = 115; 5.9% of all dislocations). Repeat CR was observed in 740 patients (38.2%) after a median of 0.8 years; however, the rate of repeat CR was age dependent: it was highest among 14- to 16-year-old patients (37.2%-42.3%) and considerably lower among 10- to 13-year-old patients (0%-25.0%). Male sex (HR, 1.2 [95% CI, 1.0-1.5]; P = .04) and older patient age (HR, 1.2 [95% CI, 1.1-1.3]; P < .001) significantly increased the odds of repeat CR. Conclusion: Among 14- to 16-year-old patients, the rate of primary and recurrent shoulder CR mirrors that of high-risk adults (17-20 years of age) from previously published data; however, the rate of shoulder CR (primary or recurrent) is considerably lower among 10- to 13-year-olds. In addition to older patient age, male sex increased the odds of repeat shoulder CR. Going forward, clinicians should counsel male patients and those aged 14 to 16 years regarding their increased risk of recurrence after the nonoperative management of a primary anterior shoulder dislocation.

Introduction Simple elbow dislocations treated by closed reduction are thought to result in a satisfactory return of function in most patients. Little, however, is known about how many patients ultimately proceed to subsequent surgical treatment due to the low patient numbers and significant loss to follow-up in the current literature. The purpose of this study was to establish the rate of and risk factors for subsequent surgical treatment after closed reduction of a simple elbow dislocation at a population level. Patients and methods All patients aged 16 years or older who underwent closed reduction of a simple elbow dislocation between 1994 and 2010 were identified using a population database. Subsequent procedures performed for joint contractures, instability or arthritis were recorded. Outcomes were modelled as a function of age, sex, income quintile, co-morbidity, urban/rural status, physician speciality performing the initial reduction and whether orthopaedic consultation and/or post-reduction radiograph was performed within 28 days of the injury, in a time-to-event analysis. Results We identified 4878 elbow dislocations with a minimum 2-year follow-up: stabilisation surgery was performed in 112 (2.3%) at a median time of 1 month, contracture release in 59 (1.2%) at median 9 months and arthroplasty in seven (0.1%) at median 25 months. Admission to hospital for the initial reduction was associated with an increased risk of undergoing stabilisation (hazard ratio (HR), 2.50; 95% confidence interval (CI), 1.67–3.74) and contracture release (HR, 1.93; CI, 1.08–3.44). Multiple reduction attempts increased the risk of requiring contracture release (HR, 3.71; CI, 1.22–11.29). Survival analysis demonstrated that all subsequent procedures had taken place by 4–5 years. Conclusion Few patients with simple elbow dislocations develop complications requiring surgery, but those that do most commonly undergo soft-tissue stabilisation or contracture release within 4 years of the injury. Contrary to current thinking, surgery for instability is performed more often than joint contracture release, albeit with slightly different time patterns.

Objectives We have previously shown that peroxisome proliferator-activated receptor gamma (PPARγ), a transcription factor, is essential for the normal growth and development of cartilage. In the present study, we created inducible cartilage-specific PPARγ knockout (KO) mice and subjected these mice to the destabilisation of medial meniscus (DMM) model of osteoarthritis (OA) to elucidate the specific in vivo role of PPARγ in OA pathophysiology. We further investigated the downstream PPARγ signalling pathway responsible for maintaining cartilage homeostasis. Methods Inducible cartilage-specific PPARγ KO mice were generated and subjected to DMM model of OA. We also created inducible cartilage-specific PPARγ/mammalian target for rapamycin (mTOR) double KO mice to dissect the PPARγ signalling pathway in OA. Results Compared with control mice, PPARγ KO mice exhibit accelerated OA phenotype with increased cartilage degradation, chondrocyte apoptosis, and the overproduction of OA inflammatory/catabolic factors associated with the increased expression of mTOR and the suppression of key autophagy markers. In vitro rescue experiments using PPARγ expression vector reduced mTOR expression, increased expression of autophagy markers and reduced the expression of OA inflammatory/catabolic factors, thus reversing the phenotype of PPARγ KO mice chondrocytes. To dissect the in vivo role of mTOR pathway in PPARγ signalling, we created and subjected PPARγ-mTOR double KO mice to the OA model to see if the genetic deletion of mTOR in PPARγ KO mice (double KO) can rescue the accelerated OA phenotype observed in PPARγ KO mice. Indeed, PPARγ-mTOR double KO mice exhibit significant protection/reversal from OA phenotype. Significance PPARγ maintains articular cartilage homeostasis, in part, by regulating mTOR pathway.

Research to understand predictors of poor outcomes after total knee arthroplasty (TKA) has largely focused on presurgery factors. We examined whether pain and function 3-month postsurgery were predictive of longer-term outcomes ascertained 2 years after TKA.Western Ontario McMaster University Osteoarthritis Index pain and physical function scores (scaled 0-20 and 0-68; higher = worse) were recorded pre-TKA and 3, 12, and 24 months post-TKA. A sequential series of regression models was used to examine the relative contribution of baseline score and baseline to 3-month and 3 to 12-month change score to explaining variability (RData from 560 patients were analyzed. Mean pain and function scores improved significantly presurgery to 2 years postsurgery; 10-4 and 33-16 (P.001), respectively. Considerable variability in 2-year scores was observed. Overall, 80.3% and 79.9% of changes in pain and function scores over the 2 years occurred within the first 3 months. Change over these 3 months explained the greatest proportion of variability in 2-year scores, 16% and 23% for pain and function, respectively. The influences of these early changes were similar to those of baseline status.Changes in patient-reported pain and function occurring within the first 3 months post-TKA strongly determine pain and function status at 2 years. Research to identify pre-/intra-/early postoperative factors associated with change in this early postoperative period that may be amenable to modification or used to better inform education and decision-making is warranted.

Metabolic changes induced by high fat diet (HFD) that contribute to osteoarthritis (OA) are poorly understood. We investigated longitudinal changes to metabolites and their contribution to OA pathogenesis in response to HFD. HFD-fed mice exhibited acceleration of spontaneous age-related and surgically-induced OA compared to lean diet (LD)-fed mice. Using metabolomics, we identified that HFD-fed mice exhibited a distinct and sustained plasma metabolite signature rich in phosphatidylcholines (PC) and lysophosphatidylcholines (lysoPCs), even after resumption of normal chow diet. Using receiver operator curve analysis and prediction modelling, we showed that the concentration of these identified metabolites could efficiently predict the type of diet and OA risk with an accuracy of 93%. Further, longitudinal evaluation of knee joints of HFD- compared to LD- fed mice showed a greater percentage of leptin-positive chondrocytes. Mechanistic data showed that leptin-treated human OA chondrocytes exhibited enhanced production of lysoPCs and expression of autotaxin and catabolic MMP-13. Leptin-induced increased MMP13 expression was reversed by autotaxin inhibition. Together, this study is the first to describe a distinct and sustained HFD-induced metabolite signature. This study suggests that in addition to increased weight, identified metabolites and local leptin-signaling may also contribute in part, towards the accelerated OA-phenotype observed in HFD mice.

Summary Objective We investigated whether pain at rest and pain on activity were differentially associated with neuropathic pain scores in individuals with end-stage hip and knee OA. Design Study participants were 843 patients with hip or knee OA scheduled for total joint arthroplasty. In pre-surgery questionnaires, measures of socio-demographics, health status, medication use, neuropathic pain (painDETECT), pain at rest and pain on activity (WOMAC pain items), depression (HADS) and pain catastrophizing (PCS) were collected. Multivariable linear regression models were estimated for men and women separately to examine the association between neuropathic pain scores (outcome) and study measures, entered in blocks. Results Sample mean age was 65.1 years (SD: 9.6); 57.1% were women. Mean painDETECT scores were significantly higher ( P ≤ 0.001) for women (11.2 ± 6.6 out of 38) than men (9.3 ± 7.0), with 35.6% of women and 27.7% of men meeting cut-offs for possible or likely neuropathic pain. In the final regression model for women, the coefficients for both types of pain were statistically significant, although the coefficient for pain at rest was 1.6 times greater than that for pain on activity. For men, only pain at rest was significantly associated with neuropathic pain scores. Conclusions Findings support that possible neuropathic pain is experienced by a notable proportion of patients with end-stage hip and knee OA and is more strongly associated with pain at rest than pain on activity, particularly in men. Clinical presentation of pain at rest may warrant more thorough evaluation for potential neuropathic pain and have implications for appropriate pain management.

Background Multijoint involvement in osteoarthritis (OA) has long been documented clinically and in the literature. Even so, the vast majority of OA research has focused on OA in individual joints, particularly the knees, hips or hands. In many “joint-specific” studies, the presence of multijoint symptoms are either ignored or peripherally considered in descriptive and analytical work. The implicit assumption is often that OA is OA, irrespective of whether a single joint or several joints are involved. Objectives To document the occurrence of multijoint symptoms in a clinical sample of individuals with knee and hip OA scheduled for orthopaedic surgery. To examine the joint sites involved and investigate whether the extent of joint involvement is related to demographic and health characteristics. Methods Patients scheduled for total knee or hip replacement for end-stage OA were consecutively recruited from an academic hospital in Toronto, Canada. A health questionnaire completed prior to surgery captured demographic characteristics (age, sex), symptomatic joints other than the surgical joint (right and left shoulders, elbows, wrists, hands, hips, knees, feet, ankle, neck and back), body mass index (BMI), comorbidities (hypertension, depression, diabetes, migraine headaches, cancer, respiratory disease, heart disease, stomach/bowel disease, stroke) and WOMAC hip- and knee-specific pain and function. Results Study questionnaires were completed by 366 hip and 407 knee patients. The mean age of the sample was 65 years (SD=9.2; range 38–89 years), 57% were female. The most frequently reported symptomatic joints among knee patients were the contralateral knee (53.2%), one or both hands (32.1%), and the upper-, mid- or lower-back (31.0%), and among hip patients were one or both knees (49.4%), the back (36.6%), and the contralateral hip (21.3%). The overall mean number of symptomatic joints other than the surgical joint was 3.0 (SD=3.2; range 0–17). Only 19.0% reported the surgical joint as the only symptomatic joint; 23.0% reported 5 or more additional symptomatic joints. Mean hip/knee-specific pain and function scores were significantly worse with increasing symptomatic joint count (p Conclusions In this clinical OA sample, the “average” patient reported multiple symptomatic joints. Increasing age was not associated with increasing frequency of symptomatic joints. Irrespective of age and obesity, multiple symptomatic joints were the rule, not the exception. It was notable that the frequency of co-occurring conditions increased with increasing symptomatic joint count. This may suggest a need to re-examine how OA is characterized and perhaps its underlying etiology as it relates to single vs. multi-joint involvement. Disclosure of Interest None declared

Background: Reoperation rates following open reduction and internal fixation (ORIF) of midshaft clavicle fractures have been described, but reported rates of nonunion, malunion, infection, and implant removal have varied. We sought to establish baseline rates of, and risk factors for, reoperations following clavicle ORIF in a large population cohort. Methods: Administrative databases were used to identify patients sixteen to sixty years of age who had undergone an ORIF of a closed, midshaft clavicle fracture from April 2002 to April 2010. The primary outcome was a reoperation within two years (isolated implant removal, irrigation and debridement [deep infection], pseudarthrosis reconstruction [nonunion], or clavicle osteotomy [malunion]). The secondary outcome was rare perioperative complications, including pneumothorax, subclavian vasculature injury, and brachial plexus injury. A multivariable logistic regression analysis was performed to determine the influence of patient and provider factors on these outcomes. Results: We identified 1350 patients who underwent midshaft clavicle ORIF (median age, thirty-two years [interquartile range, twenty-one to forty-four years]; 81.3% male). One in four patients (24.6%) underwent at least one clavicle reoperation. The most common procedure was isolated implant removal (18.8%), and females were at highest risk (odds ratio [OR], 1.7; p = 0.002). The median time to implant removal was twelve months. A reoperation secondary to nonunion, deep infection, and malunion occurred in 2.6%, 2.6%, and 1.1% of the patients after a median of six, five, and fourteen months, respectively. Risk factors for clavicle nonunion included female sex (OR, 2.2; p = 0.04) and a high comorbidity score (OR, 2.8; p = 0.009). For surgeons, fewer years in practice was associated with a small risk of the patient developing an infection (OR, 1.1; p < 0.001). Sixteen pneumothoraces (1.2%) were identified; however, brachial plexus and subclavian vessel injuries were each found in five or fewer patients. Conclusions: Following clavicle ORIF, one in four patients underwent a reoperation. The most common procedure was implant removal, and although the rates of reoperations secondary to nonunion, malunion, and infection were low they were higher than previously reported. Pneumothoraces and neurovascular injuries were infrequent and should continue to be considered rare complications of clavicle ORIF. Level of Evidence: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Improvements in implant materials and designs have broadened surgical indications and improved the technical successes of joint arthroplasty surgery. Nevertheless, a small but notable proportion of patients remain dissatisfied despite technically successful surgery. Given reported associations between unfulfilled patient expectations and dissatisfaction, we performed a systematic review to investigate the current state of knowledge concerning potential associations between clinical status and patient expectations of joint arthroplasty procedures. A wide range of expectation assessment instruments was identified, some of which assessed probabilistic expectations and other value-based expectations. Consistent associations were identified between probabilistic expectations of surgery and better pre-operative disease-specific and general health status, as well as more desirable post-operative disease specific scores. In contrast, no consistent associations were identified between clinical status and value-based expectations. Fulfillment of expectations was consistently associated with superior disease-specific and general health absolute and change scores, irrespective of the expectations paradigm used.