WWP2 confers risk to osteoarthritis by affecting cartilage matrix deposition via hypoxia associated genes.

OBJECTIVE: To explore the co-expression network of the osteoarthritis (OA) risk gene WWP2 in articular cartilage and study cartilage characteristics when mimicking the effect of OA risk allele rs1052429-A on WWP2 expression in a human 3D in vitro model of cartilage. METHOD: Co-expression behavior of WWP2 with genes expressed in lesioned OA articular cartilage (N = 35 samples) was explored. By applying lentiviral particle mediated WWP2 upregulation in 3D in vitro pellet cultures of human primary chondrocytes (N = 8 donors) the effects of upregulation on cartilage matrix deposition was evaluated. Finally, we transfected primary chondrocytes with miR-140 mimics to evaluate whether miR-140 and WWP2 are involved in similar pathways. RESULTS: Upon performing Spearman correlations in lesioned OA cartilage, 98 highly correlating genes (|ρ| > 0.7) were identified. Among these genes, we identified GJA1, GDF10, STC2, WDR1, and WNK4. Subsequent upregulation of WWP2 on 3D chondrocyte pellet cultures resulted in a decreased expression of COL2A1 and ACAN and an increase in EPAS1 expression. Additionally, we observed a decreased expression of GDF10, STC2, and GJA1. Proteomics analysis identified 42 proteins being differentially expressed with WWP2 upregulation, which were enriched for ubiquitin conjugating enzyme activity. Finally, upregulation of miR-140 in 2D chondrocytes resulted in significant upregulation of WWP2 and WDR1. CONCLUSIONS: Mimicking the effect of OA risk allele rs1052429-A on WWP2 expression initiates detrimental processes in the cartilage shown by a response in hypoxia associated genes EPAS1, GDF10, and GJA1 and a decrease in anabolic markers, COL2A1 and ACAN.

Comorbidity and risk of infection among patients with hip fracture: a Danish population-based cohort study.

Impact of comorbidity on infection risk among hip fracture patients is unclear. We found high incidence of infection. Comorbidity was an important risk factor for infection up to 1 year after surgery. Results indicates a need for additional investment in pre- and postoperative programs that assist patients with high comorbidity. PURPOSE: Comorbidity level and incidence of infection have increased among older patients with hip fracture. The impact of comorbidity on infection risk is unclear. We conducted a cohort study examining the absolute and relative risks of infection in relation to comorbidity level among hip fracture patients. METHODS: Utilizing Danish population-based medical registries, we identified 92,600 patients aged ≥ 65 years undergoing hip fracture surgery between 2004 and 2018. Comorbidity was categorized by Charlson comorbidity index scores (CCI): none (CCI = 0), moderate (CCI = 1-2), or severe (CCI ≥ 3). Primary outcome was any hospital-treated infection. Secondary outcomes were hospital-treated pneumonia, urinary tract infection, sepsis, reoperation due to surgical-site infection (SSI), and a composite of any hospital- or community-treated infection. We calculated cumulative incidence and hazard ratios (aHRs) adjusted for age, sex, and surgery year, including 95% confidence intervals (CIs). RESULTS: Prevalence of moderate and severe comorbidity was 40% and 19%, respectively. Incidence of any hospital-treated infection increased with comorbidity level within 0-30 days (none 13% vs. severe 20%) and 0-365 days (none 22% vs. 37% severe). Patients with moderate and severe comorbidity, compared to no comorbidity, had aHRs of 1.3 (CI: 1.3-1.4) and 1.6 (CI: 1.5-1.7) within 0-30 days, and 1.4 (CI: 1.4-1.5) and 1.9 (CI: 1.9-2.0) within 0-365, respectively. Highest incidence was observed for any hospital- or community-treated infection (severe 72%) within 0-365 days. Highest aHR was observed for sepsis within 0-365 days (severe vs. none: 2.7 (CI: 2.4-2.9)). CONCLUSION: Comorbidity is an important risk factor for infection up to 1 year after hip fracture surgery.

Elbow flexion contractures in neonatal brachial plexus palsy: A one-year comparison of dynamic orthosis and serial casting.

OBJECTIVE: Elbow flexion contractures are common complications of neonatal brachial plexus palsy, but evidence on how to treat these contractures is weak. This study compared the treatment of elbow flexion contractures using a dynamic orthosis or serial circular casting. METHODS: A randomized controlled trial was conducted with one-year follow-up. Children with an elbow flexion contracture of ≥30° were treated with either a night-worn dynamic orthosis for one year or serial casting for four weeks followed by night splinting. For pragmatic reasons, some participants were included in an open part of this study, this group was also analyzed separately. Degree of contracture and goal attainment scaling was evaluated at baseline and after 8, 20 and 54 weeks. RESULTS: 55 patients were analyzed in this trial, 32 of whom were randomized to treatment. At one-year follow-up of the randomized group, both dynamic splinting (median -8.5°, interquartile range [IQR] -13.5, -5) and serial casting (median -11.0°, IQR -16, -5) resulted in significant reduction of contracture (P < 0.001). The reduction was significantly greater with serial casting in the first 20 weeks, but not at one-year follow-up (P = 0.683). In the entire cohort, the individual functional goals had been reached in 24 out of 32 cases (80%) of dynamic splinting and 18 out of 23 cases (82%) of serial casting, respectively. CONCLUSION: The dynamic night orthosis is comparable to serial casting for treating elbow flexion contractures in children with brachial plexus birth injury. We recommend selecting one of these treatment modalities in close consultation with parents and patients.

Administration of an adeno-associated viral vector expressing interferon-ß in patients with inflammatory hand arthritis, results of a phase I/II study.

OBJECTIVE: Inflammatory hand arthritis (IHA) results in impaired function. Local gene therapy with ART-I02, a recombinant adeno-associated virus (AAV) serotype 5 vector expressing interferon (IFN)-ß, under the transcriptional control of nuclear factor κ-B responsive promoter, was preclinically shown to have favorable effects. This study aimed to investigate the safety and tolerability of local gene therapy with ART-I02 in patients with IHA. METHODS: In this first-in-human, dose-escalating, cohort study, 12 IHA patients were to receive a single intra-articular (IA) injection of ART-I02 ranging 0.3 × 1012-1.2 × 1013 genome copies in an affected hand joint. Adverse events (AEs), routine safety laboratory and the clinical course of disease were periodically evaluated. Baseline- and follow-up contrast enhanced magnetic resonance images (MRIs), shedding of viral vectors in bodily fluids, and AAV5 and IFN-ß immune responses were evaluated. A data review committee provided safety recommendations. RESULTS: Four patients were enrolled. Long-lasting local AEs were observed in 3 patients upon IA injection of ART-I02. The AEs were moderate in severity and could be treated conservative. Given the duration of the AEs and their possible or probable relation to ART-I02, no additional patients were enrolled. No systemic treatment emergent AEs were observed. The MRIs reflected the AEs by (peri)arthritis. No T-cell response against AAV5 or IFN-ß, nor IFN-ß antibodies could be detected. Neutralizing antibody titers against AAV5 raised post-dose. CONCLUSION: Single IA doses of 0.6 × 1012 or 1.2 × 1012 ART-I02 vector genomes were administered without systemic side effects or serious AEs. However, local tolerability was insufficient for continuation. TRIAL REGISTRATION: NCT02727764.

Acute pain after total hip and knee arthroplasty does not affect chronic pain during the first postoperative year: observational cohort study of 389 patients.

Chronic pain is frequently reported after total hip and knee arthroplasties (THA/TKA) in osteoarthritis (OA) patients. We investigated if severity of acute postoperative pain following THA/TKA in OA patients was associated with pain during the first postoperative year. From an observational study, OA patients scheduled for primary THA/TKA (June 2012-December 2017) were included from two hospitals in the Netherlands. Acute postoperative pain scores were collected within 72 h postoperatively and categorized as no/mild (NRS ≤ 4) or moderate/severe (NRS > 4). Pain was assessed preoperatively, 3, 6 and 12 months postoperatively using the HOOS/KOOS subscale pain. With Multilevel Mixed-effects-analyses, we estimated associations between acute and chronic pain until one year postoperative, adjusted for confounders and including an interaction term (Time*Acute pain). 193 THA and 196 TKA patients were included, 29% of THA and 51% of TKA patients reported moderate/severe pain acutely after surgery. In the THA group, the difference in pain at 3 months between the no/mild and moderate/severe groups, was approximately six points, in favor of the no/mild group (95% CI [-12.4 to 0.9]) this difference became smaller over time. In the TKA group we found similar differences, with approximately four points (95% CI [-9.6 to 1.3]) difference between the no/mild and moderate/severe group at 6 months, this difference attenuated at 12 months. No association between severity of acute postoperative pain and pain during the first postoperative year was found. These findings suggest that measures to limit acute postoperative pain will likely not impact development of chronic pain.

A tailored intervention does not reduce low value MRI's and arthroscopies in degenerative knee disease when the secular time trend is taken into account: a difference-in-difference analysis.

PURPOSE: To evaluate the effectiveness of a tailored intervention to reduce low value MRIs and arthroscopies among patients ≥ 50 years with degenerative knee disease in 13 Dutch orthopaedic centers (intervention group) compared with all other Dutch orthopaedic centers (control group). METHODS: All patients with degenerative knee disease ≥ 50 years admitted to Dutch orthopaedic centers from January 2016 to December 2018 were included. The tailored intervention included participation of clinical champions, education on the Dutch Choosing Wisely recommendation for MRI's and arthroscopies in degenerative knee disease, training of orthopaedic surgeons to manage patient expectations, performance feedback, and provision of a patient brochure. A difference-in-difference analysis was used to compare the time trend before (admitted January 2016-June 2017) and after introduction of the intervention (July 2017-December 2018) between intervention and control hospitals. Primary outcome was the monthly percentage of patients receiving a MRI or knee arthroscopy, weighted by type of hospital. RESULTS: 136,446 patients were included, of whom 32,163 were treated in the intervention hospitals. The weighted percentage of patients receiving a MRI on average declined by 0.15% per month (ß = - 0.15, P < 0.001) and by 0.19% per month for arthroscopy (ß = - 0.19, P < 0.001). However, these changes over time did not differ between intervention and control hospitals, neither for MRI (ß = - 0.74, P = 0.228) nor arthroscopy (ß = 0.13, P = 0.688). CONCLUSIONS: The extent to which patients ≥ 50 years with degenerative knee disease received a MRI or arthroscopy declined significantly over time, but could not be attributed to the tailored intervention. This secular downward time trend may reflect anoverall focus of reducing low value care in The Netherlands. LEVEL OF EVIDENCE: III.

Performing a knee arthroscopy among patients with degenerative knee disease: one-third is potentially low value care.

PURPOSE: The purpose of this study was to assess in which proportion of patients with degenerative knee disease aged 50+ in whom a knee arthroscopy is performed, no valid surgical indication is reported in medical records, and to explore possible explanatory factors. METHODS: A retrospective study was conducted using administrative data from January to December 2016 in 13 orthopedic centers in the Netherlands. Medical records were selected from a random sample of 538 patients aged 50+ with degenerative knee disease in whom arthroscopy was performed, and reviewed on reported indications for the performed knee arthroscopy. Valid surgical indications were predefined based on clinical national guidelines and expert opinion (e.g., truly locked knee). A knee arthroscopy without a reported valid indication was considered potentially low value care. Multivariate logistic regression analysis was performed to assess whether age, diagnosis ("Arthrosis" versus "Meniscal lesion"), and type of care trajectory (initial or follow-up) were associated with performing a potentially low value knee arthroscopy. RESULTS: Of 26,991 patients with degenerative knee disease, 2556 (9.5%) underwent an arthroscopy in one of the participating orthopedic centers. Of 538 patients in whom an arthroscopy was performed, 65.1% had a valid indication reported in the medical record and 34.9% without a reported valid indication. From the patients without a valid indication, a joint patient-provider decision or patient request was reported as the main reason. Neither age [OR 1.013 (95% CI 0.984-1.043)], diagnosis [OR 0.998 (95% CI 0.886-1.124)] or type of care trajectory [OR 0.989 (95% CI 0.948-1.032)] were significantly associated with performing a potentially low value knee arthroscopy. CONCLUSIONS: In a random sample of knee arthroscopies performed in 13 orthopedic centers in 2016, 65% had valid indications reported in the medical records but 35% were performed without a reported valid indication and, therefore, potentially low value care. Patient and/or surgeons preference may play a large role in the decision to perform an arthroscopy without a valid indication. Therefore, interventions should be developed to increase adherence to clinical guidelines by surgeons that target invalid indications for a knee arthroscopy to improve care. LEVEL OF EVIDENCE: IV.

Characterization of dynamic changes in Matrix Gla Protein (MGP) gene expression as function of genetic risk alleles, osteoarthritis relevant stimuli, and the vitamin K inhibitor warfarin.

OBJECTIVE: We here aimed to characterize changes of Matrix Gla Protein (MGP) expression in relation to its recently identified OA risk allele rs1800801-T in OA cartilage, subchondral bone and human ex vivo osteochondral explants subjected to OA related stimuli. Given that MGP function depends on vitamin K bioavailability, we studied the effect of frequently prescribed vitamin K antagonist warfarin. METHODS: Differential (allelic) mRNA expression of MGP was analyzed using RNA-sequencing data of human OA cartilage and subchondral bone. Human osteochondral explants were used to study exposures to interleukin one beta (IL-1ß; inflammation), triiodothyronine (T3; Hypertrophy), warfarin, or 65% mechanical stress (65%MS) as function of rs1800801 genotypes. RESULTS: We confirmed that the MGP risk allele rs1800801-T was associated with lower expression and that MGP was significantly upregulated in lesioned as compared to preserved OA tissues, mainly in risk allele carriers, in both cartilage and subchondral bone. Moreover, MGP expression was downregulated in response to OA like triggers in cartilage and subchondral bone and this effect might be reduced in carriers of the rs1800801-T risk allele. Finally, warfarin treatment in cartilage increased COL10A1 and reduced SOX9 and MMP3 expression and in subchondral bone reduced COL1A1 and POSTN expression. DISCUSSION & CONCLUSIONS: Our data highlights that the genetic risk allele lowers MGP expression and upon OA relevant triggers may hamper adequate dynamic changes in MGP expression, mainly in cartilage. The determined direct negative effect of warfarin on human explant cultures functionally underscores the previously found association between vitamin K deficiency and OA.

No differences in cost-effectiveness and short-term functional outcomes between cemented and uncemented total knee arthroplasty.

BACKGROUND: There is an ongoing debate regarding optimal fixation of total knee arthroplasty (TKA), however cost has not been addressed as profoundly. Therefore, the current study primarily aimed to compare costs and cost-effectiveness 1 year after cemented or uncemented TKA. A secondary objective was to compare short-term functional outcomes between both groups. METHODS: A posthoc prospective observational multicenter cohort study of 60 cemented and 50 uncemented Low Contact Stress (LCS) knee systems. Outcome was evaluated using the EuroQol5D-3 L (EQ5D) index, in order to calculate quality adjusted life years (QALYs). Total costs were calculated considering direct costs within the hospital setting (inpatient cost) as well as direct and indirect costs outside the hospital. Cost-effectiveness (total costs per QALY), Oxford Knee Score (OKS) and Numeric Rating Scale (NRS) were compared between cemented and uncemented cases at 1 year after surgery. HealthBASKET project, a micro-costing approach, represents the Dutch costs and situation and was used to calculate hospital stay. (In) direct costs outside the healthcare (medical cost and productivity cost) were determined using two validated questionnaires. RESULTS: Median costs per QALY were similar between cemented and uncemented TKA patients (€16,269 and €17,727 respectively; p = 0.50). Median OKS (44 and 42; p = 0.79), EQ5D (0.88 and 0.90; p = 0.82) and NRS for pain (1.0 and 1.0; p = 0.48) and satisfaction (9.0 and 9.0; p = 0.15) were also comparable between both groups. CONCLUSION: For this type of knee implant (LCS), inpatient hospital costs and costs after hospitalization were comparable between groups.

Preferences and beliefs of Dutch orthopaedic surgeons and patients reduce the implementation of "Choosing Wisely" recommendations in degenerative knee disease.

PURPOSE: The purpose of this study was to assess which factors were associated with the implementation of "Choosing Wisely" recommendations to refrain from routine MRI and arthroscopy use in degenerative knee disease. METHODS: Cross-sectional surveys were sent to 123 patients (response rate 95%) and 413 orthopaedic surgeons (response rate 62%) fulfilling the inclusion criteria. Univariate and multivariate logistic regression analyses were used to identify factors associated with implementation of "Choosing Wisely" recommendations. RESULTS: Factors reducing implementation of the MRI recommendation among patients included explanation of added value by an orthopaedic surgeon [OR 0.18 (95% CI 0.07-0.47)] and patient preference for MRI [OR 0.27 (95% CI 0.08-0.92)]. Factors reducing implementation among orthopaedic surgeons were higher valuation of own MRI experience than existing evidence [OR 0.41 (95% CI 0.19-0.88)] and higher estimated patients' knowledge to participate in shared decision-making [OR 0.38 (95% CI 0.17-0.88)]. Factors reducing implementation of the arthroscopy recommendation among patients were orthopaedic surgeons' preferences for an arthroscopy [OR 0.03 (95% CI 0.00-0.22)] and positive experiences with arthroscopy of friends/family [OR 0.03 (95% CI 0.00-0.39)]. Factors reducing implementation among orthopaedic surgeons were higher valuation of own arthroscopy experience than existing evidence [OR 0.17 (95% CI 0.07-0.46)] and belief in the added value [OR 0.28 (95% CI 0.10-0.81)]. CONCLUSIONS: Implementation of "Choosing Wisely" recommendations in degenerative knee disease can be improved by strategies to change clinician beliefs about the added value of MRIs and arthroscopies, and by patient-directed strategies addressing patient preferences and underlying beliefs for added value of MRI and arthroscopies resulting from experiences of people in their environment. LEVEL OF EVIDENCE: IV.

Pseudotumor in metal-on-metal hip arthroplasty: a comparison study of three grading systems with MRI.

OBJECTIVE: Pseudotumors, a well-known complication of metal-on-metal total hip arthroplasty (MoM THA), are well identified on metal artifact-reducing sequences magnetic resonance imaging (MARS-MRI). Several MRI grading systems are described in the orthopedic literature, but their validity is unknown in large clinical studies. Our study was undertaken to describe the classification of pseudotumors in a preselected cohort divided into high- and low-risk patients, using three pseudotumor grading systems applied on MARS-MRI, and to determine the interobserver reliability of the grading systems. PATIENTS AND METHODS: A retrospective study was performed on 377 consecutive patients (240 MRI scans) treated with an M2a-38 and Taperloc stem combination (Biomet, Warsaw, IN, USA). Patients were divided into a high-risk and a low-risk group based on previous published risk factors. Two observers determined the presence of pseudotumors using three different pseudotumor grading systems for classifying MARS-MRI results. RESULTS: The prevalence of pseudotumors as determined with MARS-MRI was 59% in our high-risk group, 0% in the low-risk group and 43% in the control group. Serum cobalt values were increased in the high-risk group. The kappa values of the Anderson, Hauptfleisch and Matthies grading system scores were 0.43, 0.44, and 0.49 respectively. CONCLUSIONS: High-risk patients are at a high risk for pseudotumor development. No pseudotumor development was found in low-risk patients. Interobserver reliability scored best with the Matthies system, but all three grading systems showed only a moderate agreement.

Patients who underwent total hip or knee arthroplasty are more physically active than the general Dutch population.

Total hip arthroplasty (THA) and total knee arthroplasty (TKA) bring relief of pain and functional disability to patients with end-stage osteoarthritis, and however, the literature on their impact on patients' level of physical activity (PA) is scarce. Cross-sectional study in patients who underwent THA/TKA surgery in the preceding 6-22 months and a random sample of persons aged >40 years from the Dutch general population, participating in a national survey. PA in minutes per week (min/week) and adherence to the Dutch recommendation for PA (NNGB yes/no) were measured by the short questionnaire to assess health-enhancing PA. Multivariable linear (total min/week) and logistic regression analyses (meeting recommendations PA), adjusting for confounders, were performed for THA and TKA separately. In total, 258 THA [62.3% female, aged 69.4 (9.1)] and 221 TKA [65.7% female, aged 69.5 (8.9)] patients and 4373 persons from the Dutch general population [51.4% female, aged 58.9 (11.6)] were included. The presence of THA was associated after adjusting for age, sex, BMI education and musculoskeletal comorbidities, with more total min/week spent on PA (THA 13.8% increase, 95% CI 1.6-27.6%), whilst both TJA groups were associated with adhering to NNGB (THA: OR 1.79, 95% CI 1.26-2.56; TKA: OR 1.73, 95% CI 1.20-2.51). As this study used questionnaires to compare the PA of THA/TKA patients to the general population, some recall and selection bias might have been induced. After surgery, overall, TJA patients are more likely to adhere NNGB than a representative sample of persons >40 years from the Dutch general population.

Evolution of synovitis in osteoarthritic knees and its association with clinical features.

OBJECTIVE: To investigate the course of synovitis on contrast-enhanced magnetic resonance images (CE-MRI) in osteoarthritic knees over 2 years, and its association with pain and cartilage deterioration. DESIGN: Consecutive patients (n = 39, mean age 61 years, 79% woman, median (range) body mass index (BMI) 29 (24-48) kg/mm2) with clinical osteoarthritis (OA) were included. Baseline and follow-up CE-MRI (3 T) were scored paired in chronological order for synovitis (semi-quantitatively at 11 sites (range 0-22)), cartilage deterioration and bone marrow lesions (BMLs) (semi-quantitatively according to Knee Osteoarthritis Scoring System (KOSS)). Changes in sum scores were calculated. Cartilage deterioration was defined as change of ≥2 above the smallest detectable change (SDC). Pain was assessed by standardized questionnaires. Analysis of covariance (ANCOVA) and linear regression models were used to investigate association between synovitis change and cartilage deterioration and between synovitis change or cartilage deterioration and change in pain. RESULTS: The total synovitis score did not change over 2 years (mean change 0.2 (standard deviation (SD) 3.2)), although changes in individual patients were observed. Cartilage deterioration was observed in 51% of patients. Synovitis change score was lower in patients without compared to patients with cartilage deterioration, taking BML change in account (mean difference -2.1 (-4.1 to -0.1)). Change in synovitis was not associated with change in pain, whereas cartilage deterioration was associated with change in Intermittent and Constant OsteoArthritis Pain (ICOAP) constant pain in adjusted models (unstandardised coefficient (B) (95% confidence interval (CI)) 2.8 (0.4-5.3)). CONCLUSIONS: In individual patients synovitis fluctuates during disease course. Synovitis change was not associated with change in pain. Increase in synovitis is associated with cartilage deterioration, suggesting a role for synovitis as a target for disease-modifying treatment.

Neo-cartilage engineered from primary chondrocytes is epigenetically similar to autologous cartilage, in contrast to using mesenchymal stem cells.

OBJECTIVES: To compare the epigenetic landscape of 3D cell models of human primary articular chondrocytes (hPACs) and human bone-marrow derived mesenchymal stem cells (hBMSCs) and their respective autologous articular cartilage. DESIGN: Using Illumina Infinium HumanMethylation450 BeadChip arrays, the DNA methylation landscape of the different cell sources and autologous cartilage was determined. Pathway enrichment was analyzed using DAVID. RESULTS: Principal Component Analysis (PCA) of methylation data revealed separate clustering of hBMSC samples. Between hBMSCs and autologous cartilage 86,881 cytosine-phosphate-guanine dinucleotides (CpGs) (20.2%), comprising 3,034 differentially methylated regions (DMRs; Δß > 0.1; with the same direction of effect), were significantly differentially methylated. In contrast, between hPACs and autologous cartilage only 5,706 CpGs (1.33%) were differentially methylated. Of interest was the finding of the transcriptionally active, hyper-methylation of a Cartilage Intermediate Layer Protein (CILP) annotated DMR (Δß = 0.16) in PAC-cartilage, corresponding to a profound decrease in CILP expression after in vitro culturing of hPACs as compared to autologous cartilage. CONCLUSIONS: In vitro engineered neo-cartilage tissue from primary chondrocytes, hPACs, exhibits a DNA methylation landscape that is almost identical (99% similarity) to autologous cartilage, in contrast to neo-cartilage engineered from bone marrow-derived mesenchymal stem cells (MSCs). Although hBMSCs are widely used for cartilage engineering purposes the effects of these vast differences on cartilage regeneration and long term consequences of implantation, are not known. The use of hBMSCs or hPACs for future cartilage tissue regeneration purposes should therefore be investigated in more depth in future endeavors to better understand the consequences of the differential methylome on neo-cartilage.

Characterization of synovial mast cells in knee osteoarthritis: association with clinical parameters.

OBJECTIVE: To investigate the presence of mast cells in the osteoarthritic (OA) synovium and their association with clinical parameters in comparison with rheumatoid arthritis (RA) samples. METHOD: Synovial tissues of 56 symptomatic OA and 49 RA patients were obtained. Two to three paraffin slides were used to quantify inflammation using haematoxylin and eosin (H&E) staining (synovitis score 0-9), and numbers of mast cells (per 10 high-power fields) using double immunofluorescence for CD117 and tryptase. Average scores per patient were used for analysis. Knee radiographs of OA patients were scored according to the Kellgren and Lawrence (KL) system and pain was determined in OA patients at baseline by visual analogue scale (VAS). RESULTS: Median (range) of mast cells was significantly higher in OA samples 45 (1-168) compared to RA samples 4 (1-47) (P-value < 0.001), despite a lower median (range) synovitis score in OA (2.5 (0-6.0)) compared to 4.6 (0-8.0) in RA samples. The synovitis score was significantly correlated with the number of mast cells (in OA Spearman's rho (P-value) 0.3 (0.023) and RA 0.5 (P-value < 0.001)). Interestingly, we observed a trend towards an association between the number of mast cells and an increased KL-grade (P-value 0.05) in OA patients, independently of synovitis. No associations were found with self-reported pain. CONCLUSION: Prevalence of mast cells in OA synovial tissue is relatively high and associates with structural damage in OA patients, suggesting a role of mast cells in this disease.

Erythropoietin to reduce allogeneic red blood cell transfusion in patients undergoing total hip or knee arthroplasty.

BACKGROUND AND OBJECTIVES: To determine the value of erythropoietin in reducing allogeneic transfusions, it is important to assess the effects, safety and costs for individual indications. Previous studies neither compared the effects of erythropoietin between total hip and total knee arthroplasty, nor evaluated the safety or costs. We performed a meta-analysis to assess the effects of erythropoietin in total hip and knee arthroplasty separately. Safety and costs were evaluated as secondary outcomes. MATERIALS AND METHODS: A systematic literature search was performed to identify randomized controlled trials evaluating the effect of erythropoietin in total hip and knee arthroplasty until April 2014. Study data were extracted using standardized forms and pooled using a random-effects model. Strength of the evidence was evaluated using Cochrane's Collaboration's tool for risk of bias assessment. RESULTS: Seven studies were included (2439 patients). Erythropoietin significantly reduced exposure to allogeneic transfusion in both hip (RR 0·45; 95%CI 0·33-0·61) and knee (RR 0·38; 95%CI 0·27-0·53) arthroplasty, without differences between indications (P = 0·44). Mean number of transfused red blood cell units was significantly decreased in erythropoietin-treated patients (mean difference -0·57; 95%CI -0·86 to -0·29)(unable to split). No differences in thromboembolic or adverse events were found. Only one study evaluated costs, so that no pooled cost-effectiveness estimates could be given. CONCLUSION: Erythropoietin is effective in both hip and knee arthroplasty and can be considered as safe. However, the decision to use erythropoietin on a routine base should be balanced against its costs, which may be relatively high.

The reason why orthopaedic surgeons perform total knee replacement: results of a randomised study using case vignettes.

PURPOSE: End-stage knee osteoarthritis (OA) results in total knee arthroplasty (TKA) surgery. The decision to perform TKA is not well defined, resulting in variation of indications among orthopaedic surgeons. Non-operative treatment measures are often not extensively used. Aim of this study was to investigate factors influencing the decision to perform TKA by Dutch orthopaedic surgeons. METHODS: Three case vignettes, each case divided into two versions, being identical except for information on age (younger and older age), pain (mild and severe pain) or radiological OA (low and high grade) were developed. A questionnaire including these three case vignettes was sent to 599 Dutch orthopaedic surgeons, who were randomised to either one of the two versions. The orthopaedic surgeons were asked whether TKA would be the next step in treatment. Furthermore, from a list of patient factors they were asked how strong these factors would influence the decision to perform TKA. RESULTS: 54 % of the orthopaedic surgeons completed the questionnaire (n = 326). Orthopaedic surgeons indicated to perform TKA significantly more often at higher age (73.3 vs. 45.5 %, p < 0.001). In the presence of mild pain, orthopaedic surgeons were slightly more reluctant to perform a TKA compared to severe pain (57.0 vs. 64.0 %, n.s.). Mild radiological OA made surgeons more reluctant to perform TKA compared to severe OA (9.7 vs. 96.9 %, p < 0.001). CONCLUSION: Old age and severe radiological OA are variables which are considered to be important in the decision to perform a TKA. Pain symptoms of moderate or severe pain are unequivocal when considering a TKA. LEVEL OF EVIDENCE: Economic/decision analysis, Level III.

Return to work after total hip and knee arthroplasty: results from a clinical study.

The aim of this study was to measure return to work and duration until return to work in patients undergoing total hip or knee arthroplasty (THA or TKA). This prospective study included patients under 65 years of age, undergoing THA or TKA, who provided information on their work status preoperatively (paid work yes/no and working hours) and 1 year thereafter (paid work yes/no, working hours and time until return to work). Seventy-one THA and 64 TKA patients had a paid job preoperatively. The employment rates 1 year postoperatively were 64/71 (90 %) after THA and 53/64 (83 %) after TKA. Of those who returned to work, 9/64 (14 %) of THA patients and 10/53 (19 %) of TKA patients worked less hours than preoperatively [mean decrease of 16 (SD 11.5) and 14 (SD 13.0) hours, respectively]. The mean time to return to work was 12.5 (SD 7.6) and 12.9 (SD 8.0) weeks in THA and TKA, respectively. The majority of working patients who underwent THA or TKA returned to work, after approximately 12 weeks. A considerable proportion of the patients returning to work worked less hours than preoperatively. More research into patients who do not return or decrease their working hours is needed.

The association between comorbidities and pain, physical function and quality of life following hip and knee arthroplasty.

The aim of the study was to examine the relationship between comorbidities and pain, physical function and health-related quality of life (HRQoL) after total hip arthroplasty (THA) and total knee arthroplasty (TKA). A cross-sectional retrospective survey was conducted including 19 specific comorbidities, administered in patients who underwent THA or TKA in the previous 7-22 months in one of 4 hospitals. Outcome measures included pain, physical functioning, and HRQoL. Of the 521 patients (281 THA and 240 TKA) included, 449 (86 %) had ≥1 comorbidities. The most frequently reported comorbidities (>15 %) were severe back pain; neck/shoulder pain; elbow, wrist or hand pain; hypertension; incontinence of urine; hearing impairment; vision impairment; and cancer. Only the prevalence of cancer was significantly different between THA (n = 38; 14 %) and TKA (n = 52; 22 %) (p = 0.01). The associations between a higher number of comorbidities and worse outcomes were stronger in THA than in TKA. In multivariate analyses including all comorbidities with a prevalence of >5 %, in THA dizziness in combination with falling and severe back pain, and in TKA dizziness in combination with falling, vision impairments, and elbow, wrist or hand pain was associated with worse outcomes in most of the analyses. A broad range of specific comorbidities needs to be taken into account with the interpretation of patients' health status after THA and TKA. More research including the ascertainment of comorbidities preoperatively is needed, but it is conceivable that in particular, the presence of dizziness with falling, pain in other joints, and vision impairments should be assessed and treated in order to decrease the chance of an unfavorable outcome.

Survey on the management of acute first-time anterior shoulder dislocation amongst Dutch public hospitals.

INTRODUCTION: The primary aim of this study was to record how orthopaedic surgeons are currently managing acute first-time anterior shoulder dislocation (AFASD) 8 years after introduction of the Dutch national guideline: "acute primary shoulder dislocation, diagnostics and treatment" in 2005. The second aim was to evaluate how these surgeons treat recurrent instability after AFASD. MATERIALS AND METHODS: An online questionnaire regarding the management of AFASD and recurrent shoulder instability was held amongst orthopaedic surgeons of all 98 Dutch hospitals. RESULTS: The overall response rate was 60%. Of the respondents, 75% had a local protocol for managing AFASD, of which 28% had made changes in their treatment protocol after the introduction of the national guideline. The current survey showed wide variety in the overall treatment policies for AFASD. Twenty-seven percent of the orthopaedic surgeons were currently unaware of the national guideline. The variability in treatment for AFASD was present throughout the whole treatment from which policy at the emergency department; when to operate for recurrent instability; type of surgical technique for stabilization and type of fixation of the labrum. As for the treatment of recurrent instability, the same variability was seen: 36% of the surgeons perform only arthroscopic procedures, 7% only open and 57% perform both open and arthroscopic procedures. CONCLUSIONS: Despite the introduction of the national guideline for the initial management of AFASD in 2005, still great variety among orthopaedic surgeons in the Netherlands was present. As for the surgical stabilization technique, the vast majority of the respondents are performing an arthroscopic shoulder stabilization procedure at the expense of the more traditional open procedure as a first treatment option for post-traumatic shoulder instability.