Tolerability of N-chlorotaurine in comparison with routinely used antiseptics: an in vitro study on chondrocytes.

BACKGROUND: Currently, povidone-iodine (PVP-I) and hydrogen peroxide (H2O2) are frequently used antiseptics in joint infections, but the cytotoxic effects of these solutions are already reported. N-chlorotaurine (NCT) shows a broad-spectrum bactericidal activity and is well tolerated in various tissues, but its effect on human chondrocytes is unknown. The purpose of this study was to assess the cytotoxic effect of NCT, PVP-I, and H2O2 on human chondrocytes compared to a control group in an in vitro setting to get first indications if NCT might be a promising antiseptic in the treatment of septic joint infections for the future. MATERIAL AND METHODS: Chondrocytes extracted from human cartilage were incubated with various concentrations of NCT, PVP-I, and H2O2 for 5 and 30 min respectively. EZ4U cell viability kit was used according to the manufacturer's recommendations determining cell viability. To assess cell viability based on their nuclear morphology, cells were stained with acridine-orange and identified under the fluorescence microscope. RESULTS: EZ4U kit showed after 5 and 30 min of incubation a significant decrease in cell viability at NCT 1%, NCT 0.1%, PVP-I, and H2O2, but not for NCT 0.001% and NCT 0.01%. Acridine-orange staining likewise presented a significant decrease in vital cells for all tested solutions except NCT 0.001% and NCT 0.01% after 5 and 30 min of incubation. CONCLUSION: Our results demonstrate that NCT is well tolerated by chondrocytes in vitro at the tested lower NCT concentrations 0.01% and 0.001% in contrast to the higher NCT concentrations 1% and 0.1%, PVP-I (1.1%), and H2O2 (3%), for which a significant decrease in cell viability was detected. Considering that the in vivo tolerability is usually significantly higher, our findings could be an indication that cartilage tissue in vivo would tolerate the already clinically used 1% NCT solution. In combination with the broad-spectrum bactericidal activity, NCT may be a promising antiseptic for the treatment of septic joint infections.

Biomechanical evaluation of the proximal chevron osteotomy in comparison to the Lapidus arthrodesis for the correction of hallux valgus deformities.

PURPOSE: The proximal chevron osteotomy and the modified Lapidus arthrodesis are both procedures utilized for deformity correction in patients with severe symptomatic hallux valgus. The aim of the current study was to compare their biomechanical stability when using locking plate fixation. METHODS: Twelve matched pairs of human anatomical lower leg specimens underwent on one side a proximal chevron osteotomy with a medial locking plate and on the other side a modified Lapidus arthrodesis with a plantar locking plate utilizing an interfragmentary compression screw. All specimens underwent bone mineral density (BMD) assessment and were tested in a servohydraulic load frame which applied a load on the centre of the metatarsal head over 1000 loading cycles with subsequently ultimate load testing. Displacement of the proximal and distal bone segment, ultimate load, and bending stiffness were analyzed. RESULTS: Mean displacement of both procedures showed no statistically significant difference throughout all the loading cycles (0.213 ≤ p ≤ 0.834). The mean ultimate load of the proximal chevron osteotomy was 227.9 N (± 232.4) and of the modified Lapidus arthrodesis 162.9 N (± 74.6) (p = 0.754). The proximal chevron osteotomy (38.2 N/mm (± 24.9)) had a significantly higher bending stiffness compared to the modified Lapidus arthrodesis (17.3 N/mm (± 9.9)) (p = 0.009). There was no correlation between BMD and displacement in all loading cycles, ultimate load, and bending stiffness of either procedure (p > 0.05). CONCLUSION: Although the bending stiffness of the chevron osteotomy was higher, there was no statistically significant difference between the surgical techniques in mean displacement and ultimate load. The BMD did not influence the overall stability of either reconstruction. Locking plate fixation increases the clinical value of the modified Lapidus arthrodesis by outweighing most of the biomechanical disadvantages in comparison to the proximal chevron osteotomy.

Antimicrobial potential and osteoblastic cell growth on electrochemically modified titanium surfaces with nanotubes and selenium or silver incorporation.

Titanium nanotube surfaces containing silver, zinc, and copper have shown antimicrobial effects without decreasing osteoblastic cell growth. In this in-vitro study we present first results on the biological evaluation of surface modifications by incorporating selenium and silver compounds into titanium-dioxide (TiO2) nanotubes by electrochemical deposition. TiO2-nanotubes (TNT) and Phosphate-doped TNT (pTNT) were grown on the surface of Ti6Al4V discs by anodization. Hydroxyapatite (HA), selenium (Se) and silver (Ag) compounds were incorporated by electrochemical deposition. Colony forming units of Staphylococcus epidermidis (DSM 3269) were significantly decreased in SepTNT (0.97 ± 0.18 × 106 CFU/mL), SepTNT-HA (1.2 ± 0.39 × 106 CFU/mL), AgpTNT (1.36 ± 0.42 × 106 CFU/mL) and Ag2SepTNT (0.999 ± 0.12 × 106 CFU/mL) compared to the non-modified control (2.2 ± 0.21 × 106 CFU/mL). Bacterial adhesion was calculated by measuring the covered area after fluorescence staining. Adhesion was lower in SepTNT (37.93 ± 12%; P = 0.004), pTNT (47.3 ± 6.3%, P = 0.04), AgpTNT (24.9 ± 1.8%; P < 0.001) and Ag2SepTNT (14.9 ± 4.9%; P < 0.001) compared to the non-modified control (73.7 ± 11%). Biofilm formation and the growth of osteoblastic cells (MG-63) was observed by using Crystal Violet staining. Biofilm formation was reduced in SepTNT (22 ± 3%, P = 0.02) and Ag2SepTNT discs (23 ± 11%, P = 0.02) compared to the non-modified control (54 ± 8%). In comparison with the non-modified control the modified SepTNT-HA and pTNT surfaces showed a significant higher covered area with osteoblastic MG-63-cells. Scanning electron microscope (SEM) images confirmed findings regarding bacterial and osteoblastic cell growth. These findings show a potential synergistic effect by combining selenium and silver with titanium nanotubes.

Establishment of a human three-dimensional chip-based chondro-synovial coculture joint model for reciprocal cross talk studies in arthritis research.

Rheumatoid arthritis is characterised by a progressive, intermittent inflammation at the synovial membrane, which ultimately leads to the destruction of the synovial joint. The synovial membrane as the joint capsule's inner layer is lined with fibroblast-like synoviocytes that are the key player supporting persistent arthritis leading to bone erosion and cartilage destruction. While microfluidic models that model molecular aspects of bone erosion between bone-derived cells and synoviocytes have been established, RA's synovial-chondral axis has not yet been realised using a microfluidic 3D model based on human patient in vitro cultures. Consequently, we established a chip-based three-dimensional tissue coculture model that simulates the reciprocal cross talk between individual synovial and chondral organoids. When co-cultivated with synovial organoids, we could demonstrate that chondral organoids induce a higher degree of cartilage physiology and architecture and show differential cytokine response compared to their respective monocultures highlighting the importance of reciprocal tissue-level cross talk in the modelling of arthritic diseases.

Inferior performance of established and novel serum inflammatory markers in diagnosing periprosthetic joint infections.

PURPOSE: Besides other diagnostic test methods, established serum inflammatory markers such as serum C-reactive protein or leukocyte count are widely used preoperatively to aid in diagnosing periprosthetic joint infections (PJI). Although low accuracies were reported, these parameters are easily accessible and routinely available. Novel biomarkers with promising results in diagnosing PJI (platelet count to mean platelet volume ratio) or other infectious conditions (percentage of neutrophils, neutrophils to lymphocytes ratio) were described. The purpose of this study was to investigate the diagnostic value of established and novel serum inflammatory biomarkers for the diagnosis of PJI so as to compare the results to find the serum inflammatory marker with the best performance. METHODS: In 177 patients with a previous total hip (n = 91) or knee (n = 86) arthroplasty and indicated revision surgery, the diagnostic value of the routinely available serum inflammatory markers C-reactive protein (CRP), white blood cell count (WBC), percentage of neutrophils (%N), neutrophils to lymphocytes ratio (NLR), fibrinogen and platelet count to mean platelet volume ratio (PC/mPV) were examined retrospectively via receiver operating characteristic curve analysis (AUC). The curves were compared using the z-test. RESULTS: Sensitivities of serum CRP, WBC, %N, NLR, fibrinogen and PC/mPV were calculated with 68%, 36%, 66%, 63%, 69% and 43%, respectively. Specificities were 87%, 89%, 67%, 73%, 89% and 81%, respectively. Serum CRP (0.78) and fibrinogen (0.79) showed significantly better AUCs compared with serum WBC (0.63), %N (0.67), NLR (0.68) and PC/mPV (0.62) (p < 0.0001). Patients with PJI caused by a low-virulent microorganism (median CRP: 17.6 mg/L) obtained lower CRP levels compared with infections caused by high-virulent microorganisms (median CRP: 49.2 mg/L; p = 0.044). The combination of CRP and fibrinogen showed a better sensitivity (77%) with similar specificity (83%) than one method alone but not at a significant level (CRP (p = 0.200); fibrinogen (p = 0.437)). CONCLUSION: Serum CRP and fibrinogen showed the best accuracies among these widely available serum inflammatory parameters. However, due to the insufficient performance, these biomarkers can only be recommended as suggestive criteria in diagnosing PJI. The preoperative workup should always be complemented by more specific tests such as synovial fluid analysis.

Monitoring tissue-level remodelling during inflammatory arthritis using a three-dimensional synovium-on-a-chip with non-invasive light scattering biosensing.

Rheumatoid arthritis is a chronic, systemic joint disease in which an autoimmune response translates into an inflammatory attack resulting in joint damage, disability and decreased quality of life. Despite recent introduction of therapeutic agents such as anti-TNFα, even the best current therapies fail to achieve disease remission in most arthritis patients. Therefore, research into the mechanisms governing the destructive inflammatory process in rheumatoid arthritis is of great importance and may reveal novel strategies for the therapeutic interventions. To gain deeper insight into its pathogensis, we have developed for the first time a three-dimensional synovium-on-a-chip system in order to monitor the onset and progression of inflammatory synovial tissue responses. In our study, patient-derived primary synovial organoids are cultivated on a single chip platform containing embedded organic-photodetector arrays for over a week in the absence and presence of tumor-necrosis-factor. Using a label-free and non-invasive optical light-scatter biosensing strategy inflammation-induced 3D tissue-level architectural changes were already detected after two days. We demonstrate that the integration of complex human synovial organ cultures in a lab-on-a-chip provides reproducible and reliable information on how systemic stress factors affect synovial tissue architectures.

IRF1 is critical for the TNF-driven interferon response in rheumatoid fibroblast-like synoviocytes : JAKinibs suppress the interferon response in RA-FLSs.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by persistent synovial inflammation. The major drivers of synovial inflammation are cytokines and chemokines. Among these molecules, TNF activates fibroblast-like synoviocytes (FLSs), which leads to the production of inflammatory mediators. Here, we show that TNF regulates the expression of the transcription factor interferon regulatory factor 1 (IRF1) in human FLSs as well as in a TNF transgenic arthritis mouse model. Transcriptomic analyses of IRF1-deficient, TNF-stimulated FLSs define the interferon (IFN) pathway as a major target of IRF1. IRF1 expression is associated with the expression of IFNß, which leads to the activation of the JAK-STAT pathway. Blocking the JAK-STAT pathway with the Janus kinase inhibitor (JAKinib) baricitinib or tofacitinib reduces the expression of IFN-regulated genes (IRGs) in TNF-activated FLSs. Therefore, we conclude that TNF induces a distinct inflammatory cascade, in which IRGs are key elements, in FLSs. The IFN-signature might be a promising biomarker for the efficient and personalized use of new treatment strategies for RA, such as JAKinibs.

Distal femoral reconstruction following failed total knee arthroplasty is accompanied with risk for complication and reduced joint function.

BACKGROUND: Substantial bone loss following failed total knee arthroplasty (TKA) represents a major challenge in revision arthroplasty, that can require distal femoral reconstruction (DFR). In this study, we aimed to assess the clinical outcome and the complication frequencies of individuals who underwent DFR with modular megaprostheses. Additionally, we aimed to compare functional outcome measures after DFR in these sophisticated cases to an age-matched control group of total knee prostheses to quantify the potential loss of function. METHODS: A retrospective chart review of 30 consecutive patients after DFR from 1997 to 2017 with a mean age of 74.38 years (± 10.1) was performed. Complications were classified according to the Henderson classification. Knee Society Score (KSS) was calculated and range of motion (ROM) was assessed. RESULTS: Thirteen (43.3%) patients had at least one complication requiring revision surgery. Revision-free survival was 74.8% at one year, 62.5% at three and 40.9% at 10 years post-op. Soft-tissue failure complications were found in three (10.0%) patients, aseptic loosening in four (13.3%) patients, structural failure in one (3.3%) patient and infection in eight (26.6%) patients. Of those with infection, five (16.6%) experienced ongoing prosthetic joint infection and three (10.0%) developed new infection after distal femur reconstruction. Patients with DFR achieved 69.3% of KSS pain score, 23.1% KSS function score and 76.2% of ROM compared to patients with primary TKA. CONCLUSIONS: DFR after failed TKA represents a treatment procedure with high risk for complication in this particular group. Despite the prospect of rapid postoperative mobilization, reduced functionality, range of motion and mobilization have to be considered when choosing this treatment option.

FOXO3 is involved in the tumor necrosis factor-driven inflammatory response in fibroblast-like synoviocytes.

Fibroblast-like synoviocytes (FLS) are major contributors to joint inflammation in rheumatoid arthritis (RA). Forkhead box O 3 (FOXO3) perturbations in immune cells are increasingly linked to RA pathogenesis. Here, we show that FOXO3 is distinctly inactivated/phosphorylated in the FLS of rheumatoid synovitis. In vitro, stimulation of FLS with tumor necrosis factor-alpha α (TNFα) induced a rapid and sustained inactivation of FOXO3. mRNA profiling revealed that the inactivation of FOXO3 is important for the sustained pro-inflammatory interferon response to TNFα (CXCL9, CXCL10, CXCL11, and TNFSF18). Mechanistically, our studies demonstrate that the inactivation of FOXO3 results from TNF-induced downregulation of phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1). Thus, we identified FOXO3 and its modulator PIK3IP1 as a critical regulatory circuit for the inflammatory response of the resident mesenchymal cells to TNFα and contribute insight into how the synovial tissue brings about chronic inflammation that is driven by TNFα.

A comparative study of intraoperative frozen section and alpha defensin lateral flow test in the diagnosis of periprosthetic joint infection.

Background and purpose - For decision-making (aseptic vs. septic), surgeons rely on intraoperatively available tests when a periprosthetic joint infection (PJI) cannot be confirmed or excluded preoperatively. We compared and evaluated the intraoperative performances of the frozen section and the alpha defensin lateral flow test in the diagnosis of PJI. Patients and methods - In this prospective study, consecutive patients with indicated revision surgery after arthroplasty were included. Patients were classified as having PJI using the MusculoSkeletal Infection criteria. The presence of alpha defensin was determined using the lateral flow test intraoperatively. During revision surgery, tissue samples were harvested for frozen and permanent section. Analysis of diagnostic accuracy was based on receiver-operating characteristics. Results - 101 patients (53 hips, 48 knees) were eligible for inclusion. Postoperatively, 29/101 patients were diagnosed with PJI, of which 8/29 cases were definitely classified as septic preoperatively. Of the remainder 21 septic cases, the intraoperative alpha defensin test and frozen section were positive in 13 and 17 patients, respectively. Sensitivities of the alpha defensin test and frozen section were 69% and 86%, respectively. The area under the curves of both tests showed a statistically significant difference (p = 0.006). Interpretation - The frozen section showed a significantly higher performance compared with the alpha defensin test and a near perfect concordance with the definitive histology, and therefore remains an appropriate intraoperative screening test in diagnosing PJI. Although the sensitivity of the alpha defensin test was lower compared with that of frozen section, this test is highly specific for confirming the diagnosis of PJI.

Multiplex PCR Unyvero i60 ITI application improves detection of low-virulent microorganisms in periprosthetic joint infections.

PURPOSE: The aim of this study was to evaluate the pre-operative performance of an automated multiplex PCR (mPCR) system in patients with suspected periprosthetic joint infection (PJI). METHODS: Under sterile conditions, synovial fluid samples from patients with a suspected PJI were collected pre-operatively. One hundred eighty microliter of the aspirate was used for analysis in the mPCR. The remaining joint fluid was sent for microbiological analysis. PJI was diagnosed by using the Musculoskeletal Infection Society (MSIS) criteria. Total percentage agreement and Cohen's kappa coefficient were calculated to measure overall agreement. RESULTS: Overall, 90 patients with a suspected PJI were included. Using MSIS criteria, 38 (42%) patients were classified as septic. Total percent agreement between mPCR and synovial fluid culture was 86% with a Cohen's kappa of 0.68. The mPCR and synovial fluid culture showed sensitivities of 71% and 84%, respectively. Combined evaluation provided an even higher sensitivity of 92%. While Cutibacterium spp. were detected five times by mPCR, it could only be cultured once. A higher detection rate of CoNS by mPCR (n = 7) compared to conventional culture (n = 5) was also demonstrated. In comparison to synovial fluid culture, the mPCR missed Staphylococcus aureus five times. CONCLUSION: With a moderate agreement between synovial fluid mPCR and culture, the mPCR system could be a useful adjunct in diagnosing a PJI pre-operatively. Due to faster availability of results and a higher detection rate of low-virulent microorganisms, it can complement conventional culture.

Zirconium Nitride Coating Reduced Staphylococcus epidermidis Biofilm Formation on Orthopaedic Implant Surfaces: An In Vitro Study.

BACKGROUND: One of the most commonly identified pathogens responsible for orthopaedic implant infection is Staphylococcus epidermidis, which can form biofilms on surfaces. Currently, orthopaedic implants made of various surface materials are available, each with features influencing osseointegration, biocompatibility, and adherence of bacteria to the surface, which is the first step in biofilm formation. The aim of this experimental study was to investigate the effect of a high tribologic-resistant 2.5-µm zirconium nitride top coat on an antiallergic multilayer ceramic-covered cobalt-chromium-molybdenum surface on the formation of S. epidermidis biofilm compared with other commonly used smooth and rough orthopaedic implant surface materials. QUESTIONS/PURPOSES: (1) When evaluating the surfaces of a cobalt-chromium-molybdenum (CoCrMo) alloy with a zirconium (Zr) nitride coating, a CoCrMo alloy without a coating, titanium alloy, a titanium alloy with a corundum-blasted rough surface, and stainless steel with a corundum-blasted rough surface, does a Zr coating reduce the number of colony-forming units of S. epidermidis in an in vitro setting? (2) Is there quantitatively less biofilm surface area on Zr-coated surfaces than on the other surfaces tested in this in vitro model? METHODS: To determine bacterial adhesion, five different experimental implant surface discs were incubated separately with one of 31 different S. epidermidis strains each and subsequently sonicated. Twenty test strains were obtained from orthopaedic patients undergoing emergency hip prosthesis surgeries or revision of implant infection and 10 further strains were obtained from the skin of healthy individuals. Additionally, one reference strain, S. epidermidis DSM 3269, was tested. After serial dilutions, the number of bacteria was counted and expressed as colony-forming units (CFUs)/mL. For biofilm detection, discs were stained with 0.1% Safranin-O for 15 minutes, photographed, and analyzed with computer imaging software. RESULTS: The lowest bacterial count was found in the CoCrMo + Zr surface disc (6.6 x 10 CFU/mL ± 4.6 x 10 SD) followed by the CoCrMo surface (1.1 x 10 CFU/mL ± 1.9 x 10 SD), the titanium surface (1.36 x 10 CFU/mL ± 1.8 x 10 SD), the rough stainless steel surface (2.65 x 10 CFU/mL ± 3.8 x 10 SD), and the rough titanium surface (2.1 x 10 CFU/mL ± 3.0 x 10 SD). The mean CFU count was lower for CoCrMo + Zr discs compared with the rough stainless steel surface (mean difference: 2.0 x 10, p = 0.021), the rough titanium alloy surface (mean difference: 1.4 x 10, p = 0.002), and the smooth titanium surface (mean difference: 7.0 x 10, p = 0.016). The results of biofilm formation quantification show that the mean covered area of the surface of the CoCrMo + Zr discs was 19% (± 16 SD), which was lower than CoCrMo surfaces (35% ± 23 SD), titanium alloy surface (46% ± 20 SD), rough titanium alloy surface (66% ± 23 SD), and rough stainless steel surface (58% ± 18 SD). CONCLUSIONS: These results demonstrate that a multilayer, ceramic-covered, CoCrMo surface with a 2.5-µm zirconium nitride top coat showed less S. epidermidis biofilm formation compared with other surface materials used for orthopaedic implants. CLINICAL RELEVANCE: CoCrMo with a 2.5-µm zirconium nitride top coat seems to be a promising surface modification technology able to reduce bacterial attachment on the surface of an implant and, hence, may further prevent implant infection with S. epidermidis biofilm formation.

Comparison of Plantar Pressure Distribution and Functional Outcome after Scarf and Austin Osteotomy.

OBJECTIVE: To investigate the changes of plantar pressure distribution in patients who underwent either Austin or Scarf osteotomy and underwent a postoperative rehabilitation program. METHODS: Between September 2006 and December 2007, 50 participants who suffered from mild to moderate hallux valgus deformity were prospectively included in this study. An Austin osteotomy (Austin group) was performed in 25 patients and a Scarf osteotomy (Scarf group) in 25 patients. Indication for the Scarf or Austin technique was made according to the consensus of the Austrian society of foot and ankle surgery. Plantar pressure analysis was performed at 4 weeks, 8 weeks, and 6 months postoperatively. Furthermore, range of motion and the American Orthopaedic Foot and Ankle Society (AOFAS) questionnaire were evaluated. RESULTS: In the big toe and first metatarsal head region in groups, maximum force, peak pressure, and force-time integral increased significantly from 4 weeks to 6 months postoperatively (P ≤ 0.001). The mean AOFAS score increased from 60.7 preoperatively to 93.1 6 months after Austin surgery and from 56.7 preoperatively to 94.4 6 months after Scarf surgery. The Austin group had a mean range of motion (ROM) of 68.5° that increased to a mean ROM of 75.5° 6 months postoperatively, while the Scarf group had a mean ROM of 67.8° that increased to a mean ROM of 68.2° 6 months postoperatively. CONCLUSION: Despite different surgical techniques and the degree of deformity, there were no differences in plantar pressure parameters and functional outcomes between both groups.

Efficacy of different revision procedures for infected megaprostheses in musculoskeletal tumour surgery of the lower limb.

PURPOSE: The incidence of recurrent infections in patients following one or two stage revision for infected megaprostheses after resection of bone tumours was investigated. The difference between retaining at least one well fixed stem and a complete removal of the megaprosthesis during a two stage revision was also analysed. METHODS: 627 patients who experienced a replacement of a musculoskeletal tumour by megaprostheses were recorded. An infection occurred in 83 of 621 patients available for follow-up. 61 patients underwent one stage revision, and 16 patients two stage revision for the first revision surgery. In the entire study period, two stage revision was performed 32 times (first, second, and third revision). RESULTS: The cumulative incidence analysis showed a reinfection probability after one stage revision of 18% at one year, 30% at two years, 39% at five years, 46% at ten years, and 56% at 15 years. After two stage revision, a reinfection probability of 28% at two years, and 48% at five years was calculated. Cumulative incidence curves did not differ significantly (Gray's test; p = 0.51) between one and two stage revision (with and without complete removal of the stems). In two stage revision (n = 32), a statistically significant difference in infection rates between patients treated with complete removal of the megaprosthesis (n = 18) including anchorage stems and patients with at least one retained stem (n = 14) was shown (Fisher's exact test, p = 0.029). CONCLUSION: Two stage revisions with complete removal of the megaprosthesis showed the best results among limb salvage procedures for the treatment of infected megaprosthesis.

mTOR Senses Environmental Cues to Shape the Fibroblast-like Synoviocyte Response to Inflammation.

Accumulating evidence suggests that metabolic master regulators, including mTOR, regulate adaptive and innate immune responses. Resident mesenchymal tissue components are increasingly recognized as key effector cells in inflammation. Whether mTOR also controls the inflammatory response in fibroblasts is insufficiently studied. Here, we show that TNF signaling co-opts the mTOR pathway to shift synovial fibroblast (FLS) inflammation toward an IFN response. mTOR pathway activation is associated with decreased NF-κB-mediated gene expression (e.g., PTGS2, IL-6, and IL-8) but increased STAT1-dependent gene expression (e.g., CXCL11 and TNFSF13B). We further demonstrate how metabolic inputs, such as amino acids, impinge on TNF-mTORC1 signaling to differentially regulate pro-inflammatory signaling circuits. Our results define a critical role for mTOR in the regulation of the pro-inflammatory response in FLSs and unfold its pathogenic involvement in TNF-driven diseases, such as rheumatoid arthritis (RA).

Failed Two-Stage Exchange: Factors Leading to Unachievable Endoprosthetic Reconstruction After Multiple Revision Surgeries.

BACKGROUND: Information about the outcome after failed 2-stage exchange is scarce. The aim of this study is to determine possible influencing factors leading to multiple revisions, resulting in a failed endoprosthetic joint reconstruction. METHODS: Medical records of patients (15 hip and 29 knee joints) who had undergone additional revision surgeries due to a failed 2-stage exchange were reviewed concerning infection parameters, number and type of procedure(s), current state of the revised joint, and whether failure of endoprosthetic reconstruction had occurred. RESULTS: Endoprosthetic reconstruction was achieved in 52.3% (n = 23) of the patients. About 36.4% (n = 16) of patients successfully reached the second stage of the initial 2-stage exchange. Half of the patients (n = 22) had to undergo spacer exchange in the initial interstage period. Five or more revision surgeries significantly increased the odds of failure of endoprosthetic reconstruction compared to patients with <5 revision surgeries (odds ratio 4.98, 95% confidence interval 1.34-18.4, P = .016). Patients with initial culture-negative revision surgery showed no significant differences in the odds of failure of endoprosthetic reconstruction (odds ratio 0.69, 95% confidence interval 0.20-2.43, P = .567). CONCLUSION: Patients undergoing re-revision surgery due to a failed 2-stage exchange are very likely to ultimately experience a failed endoprosthetic reconstruction. The identification of the underlying pathogen does not influence the likelihood of a better outcome in terms of a successful endoprosthetic reconstruction.

Targeted inhibition of Janus kinases abates interfon gamma-induced invasive behaviour of fibroblast-like synoviocytes.

Objectives: The aim was to explore the function of the T-cell cytokine IFNγ for mesenchymal tissue remodelling in RA and to determine whether IFNγ signalling controls the invasive potential of fibroblast-like synoviocytes (FLS). Methods: To assess architectural responses, FLS were cultured in three-dimensional micromasses. FLS motility was analysed in migration and invasion assays. Signalling events relevant to cellular motility were defined by western blots. Baricitinib and small interfering RNA pools were used to suppress Janus kinase (JAK) functions. Results: Histological analyses of micromasses revealed unique effects of IFNγ on FLS shape and tissue organization. This was consistent with accelerated migration upon IFNγ stimulation. Given that cell shape and cell motility are under the control of the focal adhesion kinase (FAK), we next analysed its activity. Indeed, IFNγ stimulation induced the phosphorylation of FAK-Y925, a phosphosite implicated in FAK-mediated cell migration. Small interfering RNA knockdown of JAK2, but not JAK1, substantially abrogated FAK activation by IFNγ. Correspondingly, IFNγ-induced FAK activation and invasion of FLS was abrogated by the JAK inhibitor, baricitinib. Conclusion: Our study contributes insight into the synovial response to IFNγ and reveals JAK2 as a potential therapeutic target for FLS-mediated joint destruction in arthritis, especially in RA.

Preoperative MRI is helpful but not sufficient to detect associated lesions in patients with chronic ankle instability.

PURPOSE: The aim of this study was to determine the reliability and validity of preoperative magnetic resonance imaging (MRI) scans for the detection of additional pathologies in patients with chronic ankle instability (CAI) compared to arthroscopic findings. METHODS: Preoperative MRI images of 30 patients were evaluated regarding articular and periarticular comorbidities and compared to intraoperative findings. The reliability of MRI was determined by calculating specificity, sensitivity, as well as positive and negative predictive values. The accuracy of the classification of cartilage lesions by Outerbridge and Berndt and Harty rating scales was determined by calculating the area under the receiver operating curve (AUC). RESULTS: In total, 72 additional pathologies were found arthroscopically compared to 73 lesions gathered from MRI images. Sensitivity ranged from 89% for peroneal tendinopathy to 28% for additional ligamentous lesions. Specificity ranged from 100% for anterolateral impingement, loose bodies and peroneal tendinopathy to 38% for additional ligamentous lesions. For cartilage lesions, sensitivity was at 91% and specificity was at 55% for the Outerbridge grading scale. For the Berndt and Harty classification system, sensitivity was at 91% and specificity was at 28%. Correlation of additional pathologies ranged from weak (r s = 0.48; p = 0.02) to moderate results (r s = 0.67; p < 0.001). CONCLUSION: CAI is associated with a high incidence of additional pathologies. In some cases, MRI delivers insufficient results, which may lead to misinterpretation of present comorbidities. MRI is a helpful tool for preoperative evaluation, but arthroscopy remains gold standard in the diagnosis of associated lesions in patients with CAI. LEVEL OF EVIDENCE: III.

The influence of antibiotic-loaded cement spacers on the risk of reinfection after septic two-stage hip revision surgery.

PURPOSE: The aim of this study was the evaluation of possible outcome differences of patients undergoing two-stage hip exchange with antibiotic-loaded spacers, compared to patients without an interim spacer implantation. METHODS: We evaluated 46 patients undergoing two-stage hip revision surgery. Twenty-five patients received an interim ALS. Additional to a Kaplan-Meier survival analysis, a competing risk analysis was performed to estimate the cumulative incidence function for re-revisions due to infection accounting for death as a competing event. RESULTS: Nine patients (seven non-ALS vs. two ALS) had to undergo re-revision surgery due to reinfection of the hip joint. The non-ALS group showed a risk of re-revision of 19% (95% CI 5-38%) at 12 and 24 months and 30% (95% CI 12-51%) at 36 months. The group with ALS implantation displayed a 0% risk of re-revision surgery in the first 36 months. The Gray test revealed a significant difference in the cumulative incidence between both observed groups (p = 0.026). CONCLUSION: Our findings suggest that ALS implantation significantly reduces the risk of reinfection after two-stage hip revision surgery.

Surgical treatment of shoulder infections: a comparison between arthroscopy and arthrotomy.

BACKGROUND: Management of bacterial shoulder infections includes antibiotic therapy and surgical joint decompression. Arthroscopy and open arthrotomy are recommended treatment options. Whether 1 of the 2 surgical options is superior remains unclear. The present study aimed (1) to compare the reinfection rates after arthroscopy and open arthrotomy and (2) to identify risk factors of reinfection after surgical intervention. MATERIALS AND METHODS: The data of 59 consecutive patients were available for final analysis. All patients received arthroscopy or open arthrotomy at our institution between 2001 and 2015. The reinfection rates between the 2 distinct interventions were compared. We also evaluated the influence of potential confounders, such as age, sex, comorbidities, microbiological findings, duration of symptoms, osteoarthritis, Gächter score, and preoperative inflammatory parameters, on the recurrence of infections and compared the functional outcome between the 2 surgery groups. RESULTS: From 59 included patients, 38 (64.4%) underwent open arthrotomy, and 21 (35.6%) were treated arthroscopically. Reinfection was documented in 18 patients (30.5%). The reinfection rate was significantly higher in arthroscopically treated patients (11 [52.4%]) than in patients who underwent open arthrotomy (7 [18.4%]; P = .007). An infection with Staphylococcus aureus negatively influenced the treatment success (P = .034). CONCLUSION: According to our data, open arthrotomy is the more effective treatment method in septic arthritis of the shoulder, with lower reinfection rates and a comparable functional outcome. Furthermore, we could identify Staphylococcus aureus as an independent risk factor for the recurrence of infections.