The impact of diabetes status on pain and physical function following total joint arthroplasty for hip and knee osteoarthritis: variation by sex and body mass index.

Few studies have examined diabetes impact on total joint arthroplasty (TJA) outcomes, with variable findings. We investigated the association between diabetes and post-TJA physical function and pain, examining whether diabetes impact differs by sex and BMI. Patient sample completed questionnaires within 3 months prior to hip or knee TJA for osteoarthritis (OA) and 1-year post-surgery. Surgical 'non-response' was defined as < 30% improvement in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and physical function at 1-year. Two adjusted logistic regression models were estimated: (1) excluding, (2) including an interaction between diabetes, sex and BMI. The sample (626 hip, 754 knee) was 54.9% female, had mean BMI of 30.1, 13.0% reported diabetes. In adjusted models excluding an interaction, diabetes was not associated with non-response. However, a significant 3-way interaction (physical function: p = 0.003; pain: p = 0.006) between diabetes, sex, and BMI was found and was associated with non-response: non-response probability increased with increasing BMI in men with diabetes, but decreased with increasing BMI in women in diabetes. Findings suggest uncertainty in diabetes impact may be due to differential impacts by sex and BMI. A simple consideration of diabetes as present vs. absent may not be sufficient, with implications for the large TJA population.

Total Hip Arthroplasty Versus Education and Exercise: A Propensity-Matched Analysis of 266 Patients Who Have Hip Osteoarthritis.

BACKGROUND: Total hip arthroplasty (THA) for osteoarthritis (OA) is a major health system cost. Education and exercise (Edu+Ex) programs may reduce the number of THAs needed, but supporting data is limited. This study aimed to estimate the treatment effect of THA versus Edu+Ex on pain, function, and quality of life outcomes 3- and 12-months after treatment initiation for hip OA. METHODS: Patients who had hip OA who underwent THA or an Edu+Ex program were included in this propensity-matched study. In 778 patients (Edu+Ex n = 303; THA n = 475), propensity scores were based on pre-treatment characteristics, and patients were matched on a 1:1 ratio. Between-group treatment effects (pain, function, and quality of life) were estimated as the mean difference in change from pre-treatment to 3- and 12-month follow-up using linear mixed models. RESULTS: The matched sample consisted of 266 patients (Edu+Ex n = 133; THA n = 133) that were balanced on all pre-treatment characteristics except opioid use. At 12-month follow-up, THA resulted in significantly greater improvements in pain (mean difference [MD] 35.4; 95% CI [confidence interval] 31.4 to 39.4), function (MD 30.5; 95% CI 26.3 to 34.7), and quality of life (MD 33.6; 95% CI 28.8 to 38.4). Between 17 and 30% of patients receiving Edu+Ex experienced a surgical threshold for clinically meaningful improvement in outcomes, compared to 84 and 90% of THA patients. CONCLUSIONS: A THA provides greater improvements in pain, function, and quality of life. A significant proportion of Edu+Ex patients had clinically meaningful improvements, suggesting Edu+Ex may result in THA deferral in some patients, but confirmatory trials are needed.

The impact of diabetes on physical and mental health status and patient satisfaction after total hip and knee arthroplasty.

OBJECTIVE: To assess the impact of diabetes on physical and mental health status, as well as patient satisfaction, one-year following knee and hip total joint arthroplasty (TJA) for osteoarthritis (OA). METHODS: Participants were 626 hip and 754 knee TJA patients. Pre-surgery data were collected on socio-demographics and health status. The 12-item Short Form Health Survey (SF-12) was collected pre- and one year post-surgery, and physical (PCS) and mental component (MCS) summary scores computed. One-year patient satisfaction was also recorded. Four regression models tested the effect of diabetes on: 1) PCS change score; 2) MCS change score; 3) achieving minimal clinically important improvement (MCII) on PCS; and 4) patient satisfaction ('Somewhat or Very Satisfied' vs. 'Somewhat or Very Dissatisfied'). An interaction between surgical joint and diabetes was tested in each model. RESULTS: Self-reported diabetes prevalence was 13.0% (95% CI: 11.2%-14.7%) and was more common in knee 16.1% (95% CI: 13.4%-18.7%) than hip 9.3% (95% CI: 7.0%-11.5%) patients. In adjusted analyses, change scores were 2.3 units less on the PCS for those with diabetes compared to those without (p = 0.005). Patients with diabetes were about half as likely to achieve MCII as patients without diabetes (p = 0.004). Diabetes was not significantly associated with satisfaction or changes in MCS scores. Diabetes effects did not differ by surgical joint. CONCLUSIONS: Findings support that diabetes has a negative impact on improvements in physical health after TJA. Considering the growing prevalence of OA and diabetes in the population, our findings support the importance of perioperative screening and management of diabetes in patients undergoing TJA.

Total Knee Arthroplasty Versus Education and Exercise for Knee Osteoarthritis: A Propensity-Matched Analysis.

OBJECTIVE: We estimate the treatment effect of total knee arthroplasty (TKA) versus an education and exercise (Edu+Ex) program on pain, function, and quality of life outcomes 3 and 12 months after treatment initiation for knee osteoarthritis (OA). METHODS: Patients with knee OA who had undergone TKA were matched on a 1:1 ratio with participants in an Edu+Ex program based on a propensity score fitted to a range of pretreatment covariates. After matching, between-group differences in improvement (the treatment effect) in Knee Injury and Osteoarthritis Outcome Score 12-item version (0, worst to 100, best) pain, function, and quality of life from baseline to 3 and 12 months were estimated using linear mixed models, adjusting for unbalanced covariates, if any, after matching. RESULTS: The matched sample consisted of 522 patients (Edu+Ex, n = 261; TKA, n = 261) who were balanced on all pretreatment characteristics. At 12-month follow-up, TKA resulted in significantly greater improvements in pain (mean difference [MD] 22.8; 95% confidence interval [95% CI] 19.7-25.8), function (MD 21.2; 95% CI 17.7-24.4), and quality of life (MD 18.3; 15.0-21.6). Even so, at least one-third of patients receiving Edu+Ex had a clinically meaningful improvement in outcomes at 12 months compared with 75% of patients with TKA. CONCLUSION: TKA is associated with greater improvements in pain, function, and quality of life, but these findings also suggest that Edu+Ex may be a viable alternative to TKA in a meaningful proportion of patients, which may reduce overall TKA need. Confirmatory trials are needed.

High health care use prior to elective surgery for osteoarthritis is associated with poor postoperative outcomes: A Canadian population-based cohort study.

BACKGROUND: The characterization and influence of preoperative health care use on quality-of-care indicators (e.g., readmissions) has received limited attention in populations with musculoskeletal disorders. The purpose of this study was to characterize preoperative health care use and examine its effect on quality-of-care indicators among patients undergoing elective surgery for osteoarthritis. METHODS: Data on health care use for 124,750 patients with elective surgery for osteoarthritis in Ontario, Canada, from April 1, 2015 to March 31, 2018 were linked across health administrative databases. Using total health care use one-year previous to surgery, patients were grouped from low to very high users. We used Poisson regression models to estimate rate ratios, while examining the relationship between preoperative health care use and quality-of-care indicators (e.g., extended length of stay, complications, and 90-day hospital readmissions). We controlled for covariates (age, sex, neighborhood income, rural/urban residence, comorbidities, and surgical anatomical site). RESULTS: We found a statistically significant trend of increasing worse outcomes by health care use gradients that persisted after controlling for patient demographics and comorbidities. Findings were consistent across surgical anatomical sites. Moreover, very high users have relatively large numbers of visits to non-musculoskeletal specialists. CONCLUSIONS: Our findings highlight that information on patients' preoperative health care use, together with other risk factors (such as comorbidities), could help decision-making when benchmarking or reimbursing hospitals caring for complex patients undergoing surgery for osteoarthritis.

Time trends and patterns in opioid prescription use following orthopaedic surgery in Ontario, Canada, from 2004/2005 to 2017/2018: a population-based study.

OBJECTIVES: Increased use of opioids and their associated harms have raised concerns around prescription opioid use for pain management following surgery. We examined trends and patterns of opioid prescribing following elective orthopaedic surgery. DESIGN: Population-based study. SETTING: Ontario, Canada. PARTICIPANTS: Ontario residents aged 66+ years who had elective orthopaedic surgery from April 2004 to March 2018. PRIMARY AND SECONDARY OUTCOME MEASURES: Postoperative opioid use (short term: within 90 days of surgery, prolonged: within 180 days and chronic: within 1 year), specific opioids prescribed, average duration (days) and amount (morphine milligram equivalents) of the initial prescription by year of surgery. RESULTS: We included 464 460 elective orthopaedic surgeries in 2004/2005-2017/2018: 80% of patients used opioids within 1 year of surgery-25.1% were chronic users. There was an 8% increase in opioid use within 1 year of surgery, from 75.1% in 2004/2005 to 80.9% in 2017/2018: a 29% increase in short-term use and a decline in prolonged (9%) and chronic (22%) use. After 2014/2015, prescribed opioid amounts initially declined sharply, while the duration of the initial prescription increased substantially. Across categories of use, there was a steady decline in coprescription of benzodiazepines and opioids. CONCLUSIONS: Most patients filled opioid prescriptions after surgery, and many continued filling prescriptions after 3 months. During a period of general increase in awareness of opioid harms and dissemination of guidelines/policies aimed at opioid prescribing for chronic pain, we found changes in prescribing practices following elective orthopaedic surgery. Findings illustrate the potential impact of guidelines/policies on shaping prescription patterns in the surgical population, even in the absence of specific guidelines for surgical prescribing.

Hospital spending and length of stay attributable to perioperative adverse events for inpatient hip, knee, and spine surgery: a retrospective cohort study.

BACKGROUND: The incremental hospital cost and length of stay (LOS) associated with adverse events (AEs) has not been well characterized for planned and unplanned inpatient spine, hip, and knee surgeries. METHODS: Retrospective cohort study of hip, knee, and spine surgeries at an academic hospital in 2011-2012. Adverse events were prospectively collected for 3,063 inpatient cases using the Orthopaedic Surgical AdVerse Event Severity (OrthoSAVES) reporting tool. Case costs were retrospectively obtained and inflated to equivalent 2021 CAD values. Propensity score methodology was used to assess the cost and LOS attributable to AEs, controlling for a variety of patient and procedure factors. RESULTS: The sample was 55% female and average age was 64; 79% of admissions were planned. 30% of cases had one or more AEs (82% had low-severity AEs at worst). The incremental cost and LOS attributable to AEs were $8,500 (95% confidence interval [CI]: 5100-11,800) and 4.7 days (95% CI: 3.4-5.9) per admission. This corresponded to a cumulative $7.8 M (14% of total cohort cost) and 4,290 bed-days (19% of cohort bed-days) attributable to AEs. Incremental estimates varied substantially by (1) admission type (planned: $4,700/2.4 days; unplanned: $20,700/11.5 days), (2) AE severity (low: $4,000/3.1 days; high: $29,500/11.9 days), and (3) anatomical region (spine: $19,800/9 days; hip: $4,900/3.8 days; knee: $1,900/1.5 days). Despite only 21% of admissions being unplanned, adverse events in these admissions cumulatively accounted for 59% of costs and 62% of bed-days attributable to AEs. CONCLUSIONS: This study comprehensively demonstrates the considerable cost and LOS attributable to AEs in orthopaedic and spine admissions. In particular, the incremental cost and LOS attributable to AEs per admission were almost five times as high among unplanned admissions compared to planned admissions. Mitigation strategies focused on unplanned surgeries may result in significant quality improvement and cost savings in the healthcare system.

Individual participant data meta-analysis of metabolomics on sustained knee pain in primary osteoarthritis patients.

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 < 2 × 10-5), were significantly associated with sustained knee pain. 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.

Identification of a differential metabolite-based signature in patients with late-stage knee osteoarthritis.

Objective: Multiple disease phenotypes have been identified in knee osteoarthritis (OA) patients based on anthropometric, sociodemographic and clinical factors; however, differential systemic metabolite-based signatures in OA patients are not well understood. We sought to identify differential plasma metabolome signatures in a cross-sectional sample of late-stage knee OA patients. Methods: Plasma from 214 (56.5% female; mean age â€‹= â€‹67.58 years) non-diabetic, non-obese (BMI <30 â€‹kg/m2, mean â€‹= â€‹26.25 â€‹kg/m2), radiographic KL 3/4 primary knee OA patients was analyzed by metabolomics. Patients with post-traumatic OA and rheumatoid arthritis were excluded. Hierarchical clustering was used to identify patient clusters based on metabolite levels. A refined metabolite signature differentiating patient clusters was determined based on ≥ 10% difference, significance by FDR-adjusted t-test (q-value < 0.05), and random forests importance score ≥1, and analyzed by AUROC. Bioinformatics analysis was used to identify genes linked to ≥2 annotated metabolites. Associated enriched pathways (q â€‹< â€‹0.05) were determined. Results: Two patient clusters were determined based on the levels of 151 metabolites identified. Metabolite signature refinement found 24 metabolites could accurately predict cluster classification within the sample (AUC â€‹= â€‹0.921). Fifty-six genes were linked to at least 2 â€‹KEGG annotated metabolites. Pathway analysis found 26/56 genes were linked to enriched pathways including tRNA acylation and B-vitamin metabolism. Conclusion: This study demonstrates systemic metabolites can classify a cross-sectional cohort of OA patients into distinct clusters. Links between metabolites, genes and pathways can help determine biological differences between OA patients, potentially improving precision medicine and decision-making.

Restricting Branched-Chain Amino Acids within a High-Fat Diet Prevents Obesity.

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.

Healthcare Utilization and Costs for Musculoskeletal Disorders in Ontario, Canada.

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.

Analgesic effect of perineural local anesthetics, steroids, and conventional medical management for trauma and compression-related peripheral neuropathic pain: a retrospective cohort study.

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.

MicroRNA-34a-5p Promotes Joint Destruction During Osteoarthritis.

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.

What Goes Bump in the Night: An Evaluation of Emergency Department Visits Following Total Joint Arthroplasty.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Healthcare utilization and costs for spinal conditions in Ontario, Canada - opportunities for funding high-value care: a retrospective cohort study.

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.

Sex-Modified Effects of Depression, Low Back Pain, and Comorbidities on Pain After Total Knee Arthroplasty for Osteoarthritis.

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.

Risk of Ankle Fusion or Arthroplasty After Operatively and Nonoperatively Treated Ankle Fractures: A Matched Cohort Population Study.

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.

Patterns of Depressive Symptoms Before and After Surgery for Osteoarthritis: A Descriptive Study.

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.

Bone Marrow Mesenchymal Stromal Cell Treatment in Patients with Osteoarthritis Results in Overall Improvement in Pain and Symptoms and Reduces Synovial Inflammation.

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.

Synovial fluid monocyte/macrophage subsets and their correlation to patient-reported outcomes in osteoarthritic patients: a cohort study.

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.