Aims. The diagnosis of periprosthetic joint infection (PJI) continues to present a significant clinical challenge. New biomarkers have been proposed to support clinical decision-making; among them, synovial fluid alpha-defensin has gained interest. Current research methodology suggests reference methods are needed to establish solid evidence for use of the test. This prospective study aims to evaluate the diagnostic accuracy of high-performance liquid chromatography coupled with the mass spectrometry (LC-MS) method to detect alpha-defensin in synovial fluid. Methods. Between October 2017 and September 2019, we collected synovial fluid samples from patients scheduled to undergo revision surgery for painful total knee arthroplasty (TKA). The International Consensus Meeting criteria were used to classify 33 PJIs and 92 aseptic joints. LC-MS assay was performed to measure alpha-defensin in synovial fluid of all included patients. Sensitivity, specificity, positive predictive value, negative predictive value, and the area under the receiver operating characteristic curve (AUC) were calculated to define the test diagnostic accuracy. Results. The AUC was 0.99 (95% confidence interval (CI) 0.98 to 1.00). Receiver operating characteristic (ROC) analysis showed that the optimal cut-off value of synovial fluid alpha-defensin was 1.0 μg/l. The sensitivity of alpha-defensin was 100% (95% CI 96 to 100), the specificity was 97% (95% CI 90 to 98), the positive predictive value was 89.2% (95% CI 82 to 94), and negative predictive value was 100% (95% CI 96 to 100). ROC analysis demonstrated an AUC of 0.99 (95% CI 0.98 to 1.0). Conclusion. The present study confirms the utility of alpha-defensin in the synovial fluid in patients with painful TKA to select cases of PJI. Since LC-MS is still a time-consuming technology and is available in highly specialized laboratories, further translational research studies are needed to take this evidence into routine procedures and promote a new diagnostic approach. Cite this article: Bone Joint J 2022;104-B(9):1047–1051

Aims. Current guidelines consider analyses of joint aspirates, including leucocyte cell count (LC) and polymorphonuclear percentage (PMN%) as a diagnostic mainstay of periprosthetic joint infection (PJI). It is unclear if these parameters are subject to a certain degree of variability over time. Therefore, the aim of this study was to evaluate the variation of LC and PMN% in patients with aseptic revision total knee arthroplasty (TKA). Methods. We conducted a prospective, double-centre study of 40 patients with 40 knee joints. Patients underwent joint aspiration at two different time points with a maximum period of 120 days in between these interventions and without any events such as other joint aspirations or surgeries. The main indications for TKA revision surgery were aseptic implant loosening (n = 24) and joint instability (n = 11). Results. Overall, 80 synovial fluid samples of 40 patients were analyzed. The average time period between the joint aspirations was 50 days (SD 32). There was a significantly higher percentage change in LC when compared to PMN% (44.1% (SD 28.6%) vs 27.3% (SD 23.7%); p = 0.003). When applying standard definition criteria, LC counts were found to skip back and forth between the two time points with exceeding the thresholds in up to 20% of cases, which was significantly more compared to PMN% for the European Bone and Joint Infection Society (EBJIS) criteria (p = 0.001), as well as for Musculoskeletal Infection Society (MSIS) (p = 0.029). Conclusion. LC and PMN% are subject to considerable variation. According to its higher interindividual variance, LC evaluation might contribute to false-positive or false-negative results in PJI assessment. Single LC testing prior to TKA revision surgery seems to be insufficient to exclude PJI. On the basis of the obtained results, PMN% analyses overrule LC measurements with regard to a conclusive diagnostic algorithm. Cite this article: Bone Jt Open 2021;2(8):566–572

Aims. Patients with flexion instability after total knee arthroplasty (TKA) often present with a recurrent effusion, which may be a haemarthrosis. While the radiographic factors contributing to flexion instability have been elucidated, the clinical diagnosis remains challenging. Our aim, in this study, was to determine the mean white cell count and differential profile in pre-operative aspirations of synovial fluid in a consecutive series of patients undergoing revision TKA for flexion instability. Patients and Methods. Between 2000 and 2010, 60 patients undergoing aseptic revision TKA for flexion instability were identified. The results of the pre-operative aspiration of synovial fluid were available for 53 patients (88%). These patients were 1:2 matched to 106 patients who underwent aseptic TKA for indications other than flexion instability. The mean age of the patients at revision TKA was 65 years (44 to 82) and 55% were women. The mean follow-up was 4.3 years (2 to 10.2). Results. In the flexion instability group, the median total cell count was 312 cells/µL (interquartile range (IQR) 104 to 624), with a mean distribution of 45% macrophages (2% to 90%), 30% lymphocytes (1% to 69%), 18% neutrophils (0% to 80%), 0.5% eosinophils (0% to 6%) and 7% other cells (0% to 42%; mainly synovial cells). There was no significant difference in the median total cell count (p = 0.14) or mean distribution of macrophages (p = 0.42), lymphocytes (p = 0.38), neutrophils (p = 0.19) and eosinophils (p = 0.89) between the flexion instability and control groups. There was a significant difference in the percentage of bloody serosanguineous aspirations which was 58% in the flexion instability group and 18% in the control group (odds ratio = 6.5; p = 0.0001). Conclusions. In the group of patients who underwent revision TKA for flexion instability, most had a mean cell count and differential similar to those who underwent revision for other aseptic indications. However, bloody serosanguineous aspirations were 6.5 times more common in those with flexion instability confirming that many of the recurrent effusions seen in this condition are haemarthroses. Cite this article: Bone Joint J 2017;99-B:1477–81

Aims. The anterior cruciate ligament (ACL) is known to have a poor wound healing capacity, whereas other ligaments outside of the knee joint capsule such as the medial collateral ligament (MCL) apparently heal more easily. Plasmin has been identified as a major component in the synovial fluid that varies among patients. The aim of this study was to test whether plasmin, a component of synovial fluid, could be a main factor responsible for the poor wound healing capacity of the ACL. Methods. The effects of increasing concentrations of plasmin (0, 0.1, 1, 10, and 50 µg/ml) onto the wound closing speed (WCS) of primary ACL-derived ligamentocytes (ACL-LCs) were tested using wound scratch assay and time-lapse phase-contrast microscopy. Additionally, relative expression changes (quantitative PCR (qPCR)) of major LC-relevant genes and catabolic genes were investigated. The positive controls were 10% fetal calf serum (FCS) and platelet-derived growth factor (PDGF). Results. WCS did not differ significantly among no plasmin versus each of the tested concentrations (six donors). The positive controls with PDGF and with FCS differed significantly from the negative controls. However, we found a trend demonstrating that higher plasmin concentrations up-regulate the expression of matrix metalloproteinase 13 (MMP13), 3 (MMP3), and tenomodulin (TNMD). Conclusion. The clinical relevance of this study is the possibility that it is not solely the plasmin, but also additional factors in the synovial fluid of the knee, that may be responsible for the poor healing capacity of the ACL. Cite this article: Bone Joint Res 2020;9(9):543–553

Aims. Adenosine, lidocaine, and Mg. 2+. (ALM) therapy exerts differential immuno-inflammatory responses in males and females early after anterior cruciate ligament (ACL) reconstruction (ACLR). Our aim was to investigate sex-specific effects of ALM therapy on joint tissue repair and recovery 28 days after surgery. Methods. Male (n = 21) and female (n = 21) adult Sprague-Dawley rats were randomly divided into ALM or Saline control treatment groups. Three days after ACL rupture, animals underwent ACLR. An ALM or saline intravenous infusion was commenced prior to skin incision, and continued for one hour. An intra-articular bolus of ALM or saline was also administered prior to skin closure. Animals were monitored to 28 days, and joint function, pain, inflammatory markers, histopathology, and tissue repair markers were assessed. Results. Despite comparable knee function, ALM-treated males had reduced systemic inflammation, synovial fluid angiogenic and pro-inflammatory mediators, synovitis, and fat pad fibrotic changes, compared to controls. Within the ACL graft, ALM-treated males had increased expression of tissue repair markers, decreased inflammation, increased collagen organization, and improved graft-bone healing. In contrast to males, females had no evidence of persistent systemic inflammation. Compared to controls, ALM-treated females had improved knee extension, gait biomechanics, and elevated synovial macrophage inflammatory protein-1 alpha (MIP-1α). Within the ACL graft, ALM-treated females had decreased inflammation, increased collagen organization, and improved graft-bone healing. In articular cartilage of ALM-treated animals, matrix metalloproteinase (MMP)-13 expression was blunted in males, while in females repair markers were increased. Conclusion. At 28 days, ALM therapy reduces inflammation, augments tissue repair patterns, and improves joint function in a sex-specific manner. The study supports transition to human safety trials. Cite this article: Bone Joint Res 2024;13(6):279–293

Aims. The diagnosis of periprosthetic joint infection (PJI) can be challenging as the symptoms are similar to other conditions, and the markers used for diagnosis have limited sensitivity and specificity. Recent research has suggested using blood cell ratios, such as platelet-to-volume ratio (PVR) and platelet-to-lymphocyte ratio (PLR), to improve diagnostic accuracy. The aim of the study was to further validate the effectiveness of PVR and PLR in diagnosing PJI. Methods. A retrospective review was conducted to assess the accuracy of different marker combinations for diagnosing chronic PJI. A total of 573 patients were included in the study, of which 124 knees and 122 hips had a diagnosis of chronic PJI. Complete blood count and synovial fluid analysis were collected. Recently published blood cell ratio cut-off points were applied to receiver operating characteristic curves for all markers and combinations. The area under the curve (AUC), sensitivity, specificity, and positive and negative predictive values were calculated. Results. The results of the analysis showed that the combination of ESR, CRP, synovial white blood cell count (Syn. WBC), and polymorphonuclear neutrophil percentage (PMN%) with PVR had the highest AUC of 0.99 for knees, with sensitivity of 97.73% and specificity of 100%. Similarly, for hips, this combination had an AUC of 0.98, sensitivity of 96.15%, and specificity of 100.00%. Conclusion. This study supports the use of PVR calculated from readily available complete blood counts, combined with established markers, to improve the accuracy in diagnosing chronic PJI in both total hip and knee arthroplasties. Cite this article: Bone Jt Open 2023;4(11):881–888

Aims. Vitamin E-infused highly cross-linked polyethylene (E1) has recently been introduced in total knee arthroplasty (TKA). An in vitro wear simulator study showed that E1 reduced polyethylene wear. However there is no published information regarding in vivo wear. Previous reports suggest that newly introduced materials which reduce in vitro polyethylene wear do not necessarily reduce in vivo polyethylene wear. To assist in the evaluation of the newly introduced material before widespread use, we established an in vivo polyethylene wear particle analysis for TKA. The aim of this study was to compare in vivo polyethylene wear particle generation between E1 and conventional polyethylene (ArCom) in TKA. Methods. A total of 34 knees undergoing TKA (17 each with ArCom or E1) were investigated. Except for the polyethylene insert material, the prostheses used for both groups were identical. Synovial fluid was obtained at a mean of 3.4 years (SD 1.3) postoperatively. The in vivo polyethylene wear particles were isolated from the synovial fluid using a previously validated method and examined by scanning electron microscopy. Results. The total number of polyethylene wear particles obtained from the knees with E1 (mean 6.9, SD 4.0 × 10. 7. counts/knee) was greater than that obtained from those with ArCom (mean 2.2, SD 2.6 × 10. 7. counts/knee) (p = 0.001). The particle size (equivalent circle of diameter) from the knees with E1 was smaller (mean 0.5 μm, SD 0.1) than that of knees with ArCom (mean 1.5, SD 0.3 μm) (p = 0.001). The aspect ratio of particles from the knees with E1 (mean 1.3, SD 0.1) was smaller than that with ArCom (mean 1.4, SD 0.1) (p < 0.001 ). Conclusion. This is the first report of in vivo wear particle analysis of E1. E1 polyethylene did not reduce the number of in vivo polyethylene wear particles compared with ArCom in early clinical stage. Further careful follow-up of newly introduced E1 for TKA should be carried out. Cite this article: Bone Joint J 2020;102-B(11):1527–1534

Aims. In patients with a “dry” aspiration during the investigation of prosthetic joint infection (PJI), saline lavage is commonly used to obtain a sample for analysis. The aim of this study was to investigate prospectively the impact of saline lavage on synovial fluid analysis in revision arthroplasty. Methods. Patients undergoing revision hip (THA) or knee arthroplasty (TKA) for any septic or aseptic indication were enrolled. Intraoperatively, prior to arthrotomy, the maximum amount of fluid possible was aspirated to simulate a dry tap (pre-lavage) followed by the injection with 20 ml of normal saline and re-aspiration (post-lavage). Pre- and post-lavage synovial white blood cell (WBC) count, percent polymorphonuclear cells (%PMN), and cultures were compared. Results. A total of 78 patients had data available for analysis; 17 underwent revision THA and 61 underwent revision TKA. A total of 16 patients met modified Musculoskeletal Infection Society (MSIS) criteria for PJI. Pre- and post-lavage %PMNs were similar in septic patients (87% vs 85%) and aseptic patients (35% vs 39%). Pre- and post-lavage synovial fluid WBC count were far more disparate in septic (53,553 vs 8,275 WBCs) and aseptic (1,103 vs 268 WBCs) cohorts. At a cutoff of 80% PMN, the post-lavage aspirate had a sensitivity of 75% and specificity of 95%. At a cutoff of 3,000 WBCs, the post-lavage aspirate had a sensitivity of 63% and specificity of 98%. As the post-lavage synovial WBC count increased, the difference between pre- and post-lavage %PMN decreased (mean difference of 5% PMN in WBC < 3,000 vs mean difference 2% PMN in WBC > 3,000, p = 0.013). Of ten positive pre-lavage fluid cultures, only six remained positive post-lavage. Conclusion. While saline lavage aspiration significantly lowered the synovial WBC count, the %PMN remained similar, particularly at WBC counts of > 3,000. These findings suggest that in patients with a dry-tap, the %PMN of a saline lavage aspiration has reasonable sensitivity (75%) for the detection of PJI. Cite this article: Bone Joint J 2020;102-B(6 Supple A):138–144

Aims. It remains difficult to diagnose early postoperative periprosthetic joint infection (PJI) following total knee arthroplasty (TKA). We aimed to validate the optimal cutoff values of ESR, CRP, and synovial fluid analysis for detecting early postoperative PJI in a large series of primary TKAs. Methods. We retrospectively identified 27,066 primary TKAs performed between 2000 and 2019. Within 12 weeks, 169 patients (170 TKAs) had an aspiration. The patients were divided into two groups: those evaluated ≤ six weeks, or between six and 12 weeks postoperatively. The 2011 Musculoskeletal Infection Society (MSIS) criteria for PJI diagnosis in 22 TKAs. The mean follow-up was five years (two months to 17 years). The results were compared using medians and Mann-Whitney U tests and thresholds were analyzed using receiver operator characteristic curves. Results. Within six weeks, the median CRP (101 mg/l vs 35 mg/l; p = 0.011), synovial WBCs (58,295 cells/μl vs 2,121 cells/μl; p ≤ 0.001), percentage of synovial neutrophils (91% vs 71% (p < 0.001), and absolute synovial neutrophil count (ANC) (50,748 cells/μl vs 1,386 cells/μl (p < 0.001) were significantly higher in infected TKAs. Between six and 12 weeks, the median CRP (85 mg/l vs 5 mg/l (p < 0.001)), ESR (33 mm/hr vs 14 mm/hr (p = 0.015)), synovial WBCs (62,247 cells/μl vs 620 cells/μl (p < 0.001)), percentage of synovial neutrophils (93% vs 54% (p < 0.001)), and ANC (55,911 cells/μl vs 326 cells/μl (p < 0.001)) were also significantly higher in infected TKAs. Optimal thresholds at ≤ six weeks were: CRP ≥ 82 mg/l (sensitivity 70%, specificity 77%), synovial WBCs ≥ 8,676 cells/μl (83%, 90%), percentage of synovial neutrophils ≥ 88% (67%, 78%), and ANC ≥ 8,346 cells/μl (83%, 91%). Between six and 12 weeks, thresholds were: CRP ≥ 34 mg/l (90%, 93%), synovial WBCs ≥ 1,983 cells/μl (80%, 85%), percentage of synovial neutrophils ≥ 76% (80%, 81%), and ANC ≥ 1,684 cells/μl (80%, 87%). Conclusion. Early PJI after TKA should be suspected within six weeks if the CRP is ≥ 82 mg/l, synovial WBCs are ≥ 8,676 cells/μl, the percentage of synovial neutrophils is ≥ 88%, and/or the ANC is ≥ 8,346 cells/μl. Between six and 12 weeks, thresholds include a CRP of ≥ 34 mg/l, synovial WBC of ≥ 1,983 cells/μl, a percentage of synovial neutrophils of ≥ 76%, and/or an ANC of ≥ 1,684 cells/μl. Cite this article: Bone Joint J 2021;103-B(6 Supple A):177–184

Introduction. Mechanical or corrosive failure of total knee arthroplasties (TKAs) is difficult to diagnose with current laboratory and radiographic analyses. As such, the goal of this study was to determine the mean blood concentration of cobalt, chromium, and titanium in a series of revision TKAs with mechanical implant failure and evaluate whether they facilitated identification of the underlying TKA failure mechanism. Methods. Serum cobalt, chromium, and titanium levels and synovial fluid characteristics were evaluated in 12 patients (13 aseptic revision TKAs) who underwent revision TKA between 2000 and 2020 at a single academic institution for mechanical implant failure or corrosion. Seventy-five percent were re-revisions of previously revised TKAs. Mean time to revision was 6 years. Modular metallic junctions were present in 100%. Twenty-five percent did not have another in situ total joint arthroplasty, and the remaining patients did not have a metal-on-metal articulation that could lead to elevation in serum metal ion levels. Mean follow-up after the revision TKA was 8 months. Results. Mean serum cobalt, chromium, and titanium concentrations were 11 ng/mL, 6 ng/mL, and 3 ng/mL, respectively. Serum metal ion levels facilitated failure mechanism identification in 75%, which included modular junction failure (6 cases), constraint locking mechanism failure (3 cases), corrosion of modular metallic interfaces (2 cases), and implant fracture (1 case). Arthrocentesis was performed in 75%. Mean synovial fluid cell count was 950 cells/mcL. Monocytes were the predominant mean cell type (41%), followed by neutrophils (35%), and lymphocytes (22%). Conclusion. Serum metal ion assessment should be considered when the etiology of painful primary or revision TKAs, particularly those with modular metallic junctions, remains elusive after routine evaluation

Introduction. Topical diclofenac has proven efficacy and safety in the management of osteoarthritic pain. Its therapeutic efficacy is dependent on its ability to deliver pharmacodynamically active concentrations to the underlying tissues in the affected joint. However, the disposition of topical diclofenac is not fully characterized, and no studies have been performed using diclofenac diethylamine 2.32% gel. Methods. This study investigated the penetration of topical diclofenac into knee synovial tissue and fluid and evaluated relative exposure in the knee versus plasma. In this phase 1, double-blind, placebo-controlled steady-state multicenter pharmacokinetic study, patients scheduled for arthroplasty to treat knee OA were randomly assigned 2:1 to 4 g diclofenac/placebo gel, applied to the affected knee every 12 hours for 7 days pre-surgery. Diclofenac concentrations were measured in synovial tissue, fluid, and plasma ≥12 hours after last application. Adverse events (AEs) were evaluated. Diclofenac concentrations were assayed by validated high-performance liquid chromatography and tandem mass spectrometry. Results. Samples were obtained from 45 (diclofenac n=29; placebo n=16) of 47 patients enrolled. Mean (SD) age was 71.2 (7.9) years with 52.2% women and mean (SD) BMI 30.7 (4.8) kg/m. 2. All diclofenac-treated participants had measurable diclofenac concentrations in synovial tissue (mean [95% CI]) 1.57 [1.12, 2.20] ng/g) and fluid 2.27 [1.87, 2.76] ng/mL ≥12 hours after the last dose. The mean (95% CI) ratio of diclofenac in synovial tissue:plasma was 0.32 (0.23, 0.45) and in synovial fluid:plasma was 0.46 (0.34, 0.54). AEs were similar for diclofenac (55.2%) and placebo (58.8%); none were treatment related. No correlation (r=−0.003) between BMI and synovial fluid concentration, and weak positive correlation (r=0.315) between BMI and synovial tissue concentration were observed. Conclusions. Topical diclofenac diethylamine 2.32% gel penetrated the knee and remained detectable at the end of the final 12-hour dosing cycle. BMI had no impact on diclofenac's penetration into the knee

Introduction. Diagnosing acute postoperative periprosthetic joint infections (PJIs) after primary total knee arthroplasties (TKAs) remains difficult. Published diagnostic thresholds for ESR, CRP, and synovial fluid analysis have not been replicated. We aimed to validate the optimal cutoffs for detecting acute postoperative PJIs in a large series of primary TKAs. Methods. We retrospectively identified 27,066 primary TKAs performed between 2000–2019. Within 12 weeks, 171 knees (170 patients) had a synovial fluid aspiration. Patients were divided into two groups: evaluation <6 weeks or 6–12 weeks. The 2011 MSIS criteria for PJI diagnosed infection in 22 knees. Mann-Whitney U tests compared medians; ROC analyses determined optimal thresholds. Mean follow-up was 5 years. Results. Within 6 weeks, CRP (101 mg/L vs. 35 mg/L; p=0.01), synovial WBCs (58,295 cells/μL vs. 2121 cells/μL; p=<0.001), and synovial neutrophils (91% vs. 71%; p<0.001) were significantly higher in infected TKAs. ESR did not differ between groups at <6 weeks. Between 6–12 weeks, CRP (85 mg/L vs. 6 mg/L; p<0.001), ESR (33 mm/h vs. 15 mm/h; p=0.02), synovial WBCs (62,247 cells/μL vs. 596 cells/μL; p<0.001), and synovial neutrophils (93% v. 54%; p<0.001) were significantly higher in infected TKAs. Optimal thresholds at <6 weeks were: CRP ≥81 mg/L (sensitivity 80%, specificity 77%), synovial WBCs ≥8515 cells/μL (sensitivity 92%, specificity 90%), and synovial neutrophils≥86% (sensitivity 92%, specificity 72%). Between 6–12 weeks, thresholds were: CRP ≥32 mg/L (sensitivity 100%, specificity 93%), synovial WBCs ≥7450 cells/μL (sensitivity 80%, specificity 98%), and synovial neutrophils ≥84% (sensitivity 80%, specificity 89%). Conclusion. Acute PJI after TKA should be suspected within 6 weeks if CRP is ≥81 mg/L, synovial WBCs are ≥8500 cells/μL, and/or synovial neutrophils≥86%. Between 6–12 weeks, concerning thresholds include a CRP ≥ 32 mg/L, synovial WBC ≥7450, and synovial neutrophils ≥ 84%

Background. In the setting of a “dry” aspiration, saline lavage is commonly used to obtain a sample for analysis. The purpose of this study is to prospectively determine the impact of saline lavage on synovial fluid markers in revision arthroplasty. Methods. 79 patients undergoing revision hip (19) and knee (60) arthroplasty were enrolled. Intraoperatively, prior to arthrotomy, the maximum amount of fluid possible was aspirated to simulate a dry-tap (“pre-lavage”) followed by subsequent injection with 20 mL of normal saline and re-aspiration (“post-lavage”). Pre and post-lavage synovial white blood cell (WBC) count, percent polymorphonuclear cells (%PMN), and cultures were compared. Statistical analyses utilized the Wilcoxon signed-rank test. Results. Nine patients met modified MSIS criteria for prosthetic joint infection (PJI). Pre and post-lavage %PMN were similar in septic patients (90.1% vs. 88.2%, p=0.40 for septic). Pre and post-lavage WBC counts were different in both cohorts (69,432 vs. 6,547 WBCs, p=0.008 for septic; 1,850 vs. 449 WBCs for aseptic, p<0.001). Using a pre-lavage cutoff of >80% PMN, the post-lavage aspirate correctly identified 84.6% of true positives (sensitivity) and 98.5% of true negatives (specificity). Using a pre-lavage cutoff of >3000 WBCs, the post-lavage aspirate correctly identified only 38.1% of true positives (sensitivity). As the synovial fluid WBC count increased, the correlation between pre and post-lavage %PMN was stronger (mean difference of 7.0% PMN in WBC <3000 vs. mean difference −2.9% PMN in WBC >3000, p=0.002). Of seven positive pre-lavage fluid cultures, 4 remained positive post-lavage. Conclusion. While saline lavage aspiration significantly lowers the synovial WBC count, the %PMN is well maintained, particularly at WBC counts >3000. Our findings suggest that in the setting of a dry tap where saline lavage is required to obtain a sample, the %PMN has reasonable sensitivity and specificity for the detection of PJI. For figures, tables, or references, please contact authors directly

Introduction. Surgical management of PJI remains challenging with patients failing treatment despite the best efforts. An important question is whether these later failures reflect reinfection or the persistence of infection. Proponents of reinfection believe hosts are vulnerable to developing infection and new organisms emerge. The alternative hypothesis is that later failure is a result of an organism that was present in the joint but was not picked up by initial culture or was not a pathogen initially but became so under antibiotic pressure. This multicenter study explores the above dilemma. Utilizing next-generation sequencing (NGS), we hypothesize that failures after two stage exchange arthroplasty can be caused by an organism that was present at the time of initial surgery but not isolated by culture. Methods. This prospective study involving 15 institutions collected samples from 635 revision total hip (n=310) and knee (n=325) arthroplasties. Synovial fluid, tissue and swabs were obtained intraoperatively for NGS analysis. Patients were classified per 2018 Consensus definition of PJI. Treatment failure was defined as reoperation for infection that yielded positive cultures, during minimum 1-year follow-up. Concordance of the infecting pathogen cultured at failure with NGS analysis at initial revision was determined. Results. Among the total cohort, 203 revisions were considered infected and 432 were aseptic (based on ICM-criteria). Of the infected cases, 157 were NGS-positive and 46 NGS-negative. Twenty-nine ICM-positive patients (29/157;18.5%) failed by reoperation with an organism confirmed on culture. In 23 of these (23/29;79.3%), the organism at failure was present on NGS at initial revision. The remaining 6 cases detected discordant organisms between initial NGS and culture at failure. Of the 432 ICM-negative patients, NGS identified microbes in 48.1% (208/432) of “aseptic” revisions, and 17 of these failed. Thirteen of the 17 failures (76.5%) were due to an organism previously detected by NGS at initial revision. Conclusion. Our collaborative findings suggest that most failures (79.3%) by infection recurrence could be attributed to an organism previously detected by NGS at index revision surgery. For any figures or tables, please contact the authors directly

Aims

This study aimed to explore the biological and clinical importance of dysregulated key genes in osteoarthritis (OA) patients at the cartilage level to find potential biomarkers and targets for diagnosing and treating OA.

Aims

Fungal periprosthetic joint infections (PJIs) are rare, but their diagnosis and treatment are highly challenging. The purpose of this study was to investigate the clinical outcomes of patients with fungal PJIs treated with two-stage exchange knee arthroplasty combined with prolonged antifungal therapy.

Aims

Metal particles detached from metal-on-metal hip prostheses (MoM-THA) have been shown to cause inflammation and destruction of tissues. To further explore this, we investigated the histopathology (aseptic lymphocyte-dominated vasculitis-associated lesions (ALVAL) score) and metal concentrations of the periprosthetic tissues obtained from patients who underwent revision knee arthroplasty. We also aimed to investigate whether accumulated metal debris was associated with ALVAL-type reactions in the synovium.

Aims

The purpose of this study is to determine an individual’s age-specific prevalence of total knee arthroplasty (TKA) after cruciate ligament surgery, and to identify clinical and genetic risk factors associated with undergoing TKA.

Aims

Knee osteoarthritis (OA) is characterized by a chronic inflammatory process involving multiple cytokine pathways, leading to articular cartilage degeneration. Intra-articular therapies using pharmaceutical or autologous anti-inflammatory factors offer potential non-surgical treatment options. Autologous protein solution (APS) is one such product that uses the patient’s blood to produce a concentrate of cells and anti-inflammatory cytokines. This study evaluated the effect of a specific APS intra-articular injection (nSTRIDE) on patient-reported outcome measures compared to saline in moderate knee OA.

Introduction. Next generation sequencing (NGS) has been shown to facilitate detection of microbes in a clinical sample, particularly in the setting of culture-negative periprosthetic joint infection (PJI). However, it is unknown whether every microbial DNA signal detected by NGS is clinically relevant. This multi-institutional study was conceived to 1) identify species detected by NGS that may predict PJI, then 2) build a predictive model for PJI in a developmental cohort; and 3) validate the predictive utility of the model in a separate multi-institutional cohort. Methods. This multicenter investigation involving 15 academic institutions prospectively collected samples from 194 revision total knee arthroplasties (TKA) and 184 revision hip arthroplasties (THA) between 2017–2019. Patients undergoing reimplantation or spacer exchange procedures were excluded. Synovial fluid, deep tissue and swabs were obtained at the time of surgery and shipped to MicrogenDx (Lubbock, TX) for NGS analysis. Deep tissue specimens were also sent to the institutional labs for culture. All patients were classified per the 2018 Consensus definition of PJI. Microbial DNA analysis of community similarities (ANCOM) was used to identify 17 candidate bacterial species out of 294 (W-value >50) for differentiating infected vs. noninfected cases. Logistic Regression with LASSO model selection and random forest algorithms were then used to build a model for predicting PJI. For this analysis, ICM classification was the response variable (gold standard) and the species identified through ANCOM were the predictor variables. Recruited cases were randomly split in half, with one half designated as the training set, and the other half as the validation set. Using the training set, a model for PJI diagnosis was generated. The optimal resulting model was then tested for prediction ability with the validation set. The entire model-building procedure and validation was iterated 1000 times. From the model set, distributions of overall assignment rate, specificity, sensitivity, positive predictive value (PPV) and negative predicative value (NPV) were assessed. Results. The overall predictive accuracy achieved in the model was 75.9% (Figure 1). There was a high accuracy in true-negative and false-negative classification of patients using this predictive model (Figure 2), which has previously been a criticism of NGS interpretation and reporting. Specificity was 97.1%, PPV was 75.0%, and NPV was 76.2%. On comparison of the distribution of abundances between ICM-positive and ICM-negative patients, Staphylococcus aureus was the strongest contributor (F=0.99) to the predictive power of the model (Figure 3). In contrast, Cutibacterium acnes was less predictive (F=0.309) and noted to be abundant across both infected and noninfected revision TJA samples. Discussion. This study is the first to utilize predictive modeling algorithms on a large prospective multicenter database in order to transform analytic NGS data into a clinically relevant diagnostic signal. Our collaborative findings suggest the microbial DNA signal identified on NGS may be an independent useful adjunct for the diagnosis of PJI, as well as help identify causative organisms. Further work applying artificial intelligence tools will improve accuracy, predictive power and clinical utility of high-throughput sequencing technology. For figures, tables, or references, please contact authors directly