Krüppel-like factor 15 deficiency exacerbates osteoarthritis through reduced expression of peroxisome proliferator-activated receptor gamma signaling in mice.

OBJECTIVE: Krüppel-like zinc finger transcription factors (KLFs) play diverse roles in mammalian cell differentiation and development. In this study, we investigated the function of KLF15 in the progression of osteoarthritis (OA). METHODS: 0Destabilization of the medial meniscus (DMM) surgery was performed in 10-week-old male wild-type control (WT) mice and cartilage-specific KLF15 knockout (KO) mice. Histological analysis, immunohistochemistry, and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling staining were performed. Morphological changes were measured using microcomputed tomography. Six mice from each group were analyzed (total number of mice analyzed: 60). In vitro, immunofluorescence, quantitative reverse transcription-polymerase chain reaction, and western blot analyses were performed. RESULTS: KLF15 KO DMM mice exhibited significant cartilage degradation compared to WT mice. According to the Osteoarthritis Research Society International cartilage OA-histopathology scoring system, the mean sum score in KLF15 KO mice was significantly higher than that in WT mice at 8 weeks after surgery. Immunohistochemistry results revealed KLF15 KO mice exhibited reduced peroxisome proliferator-activated receptor gamma (PPARγ) expression, increased pIKKα/ß, a disintegrin-like and metalloproteinase with thrombospondin motifs (ADAMTS) 5, and Matrix metalloproteinases (MMP13) expression, and reduced Forkhead box O (FOXO1) and Light chain 3B (LC3B) expression. Inhibition of PPARγ phosphorylation accelerated the effects of interleukin (IL) 1ß-treatment in both KLF15 KO and WT chondrocytes, and activation of PPARγ expression canceled the IL1ß-induced catabolic effects. CONCLUSION: Our results indicated that the OA phenotype of KLF15 KO DMM mice was influenced by reduced PPARγ expression, including enhanced pIKKα/ß, ADAMTS5, and MMP13 expression, reduced autophagy, and increased apoptosis. KLF15 regulation may constitute a possible therapeutic strategy for the treating OA.

Temporal declines in bone mineral density and trabecular bone score during androgen deprivation therapy.

INTRODUCTION: The trabecular bone score (TBS) has emerged as a convenient measure for assessing the microstructure of trabecular bone in the second through fourth lumbar vertebrae (L2-4) and can be conducted concurrently with bone mineral density (BMD) assessment. This study was performed to evaluate changes in BMD and the TBS during ADT for prostate cancer. MATERIALS AND METHODS: Consecutive patients who had prostate cancer without bone metastases at Kobe University Hospital were studied from March 2020 to December 2021. BMD and TBS were measured every 6 months from the start of treatment using Hologic Horizon devices (Hologic, Inc., Marlborough, MA, USA). RESULTS: Thirty-four patients were followed for 2 years. Significant declines in BMD (-3.8% for femoral neck, -4.2% for total hip, and -6.1% for lumbar spine) and TBS (-16.6%) were noted after 2 years of ADT. Correlation analyses revealed a weak correlation between lumbar spine BMD and TBS at ADT initiation, but this correlation strengthened after 2 years. The multiple regression analysis results suggested that the rate of BMD loss may be slower in patients with a preserved pretreatment TBS. CONCLUSION: In patients without bone metastases undergoing ADT for prostate cancer, notable decreases were found in both BMD and TBS over a 2-year treatment period. Factors influencing the TBS decline remain unclear; however, patients with a lower pretreatment TBS exhibited a more rapid decline in BMD.

LIGHT regulated gene expression in rheumatoid synovial fibroblasts.

BACKGROUND: Synovial hyperplasia caused by rheumatoid arthritis (RA), an autoimmune inflammatory disease, leads to the destruction of the articular cartilage and bone. A member of the tumor necrosis factor superfamily, Lymphotoxin-related inducible ligand that competes for glycoprotein D binding to herpes virus entry mediator on T cells (LIGHT) has been shown to correlate with the pathogenesis of RA. METHODS: We used cDNA microarray analysis to compare the expression of genes in rheumatoid fibroblast-like synoviocytes with and without LIGHT stimulation. RESULTS: Significant changes in gene expression (P-values < 0.05 and fold change ≥ 2.0) were associated mainly with biological function categories of glycoprotein, glycosylation site as N-linked, plasma membrane part, integral to plasma membrane, intrinsic to plasma membrane, signal, plasma membrane, signal peptide, alternative splicing, and topological domain as extracellular. CONCLUSIONS: Our results indicate that LIGHT may regulate the expression in RA-FLS of genes which are important in the differentiation of several cell types and in cellular functions.

Three-dimensional printed calcium phosphate scaffolds emulate bone microstructure to promote bone regrowth and repair.

The interconnected structures in a 3D scaffold allows the movement of cells and nutrients. Therefore, this study aimed to investigate the in-vivo bioactivity of 3D-printed ß-tricalcium phosphate (ß-TCP) and hydroxyapatite (HAP) scaffolds that replicate biological bone. This study included 24-week-old male New Zealand white rabbits. A cylindrical bone defect with a diameter of 4.5 mm and a depth of 8 mm was created in the lateral aspect of the distal femur. A 3D-printed scaffold was implanted in the right femur (experimental side), whereas the left femur was kept free of implantation (control side). Micro-CT analysis and histological observations of the bone defect site were conducted at 4, 8, and 12 weeks postoperatively to track the bone repair progress. No evidence of new bone tissue formation was found in the medullary cavity of the bone defect on the control side. In contrast, on the experimental side, the 3D scaffold demonstrated sufficient bioactivity, leading to the growth of new bone tissue. Over time, new bone tissue gradually extended from the periphery toward the center, a phenomenon evident in both micro-CT images and biopsy staining. In the current study, we observed that the cells involved in bone metabolism adhered, spread, and proliferated on our newly designed 3D-printed scaffold with a bone microstructure. Therefore, it is suggested that this scaffold has sufficient bioactivity to induce new bone formation and could be expected to be a more useful artificial bone than the existing version.

Knee Osteotomy Decreases Joint Inflammation Based on Synovial Histology and Synovial Fluid Analysis.

PURPOSE: To examine the biological changes in the joints of patients with knee osteoarthritis (OA) before and after around-knee osteotomy (AKO), focusing on synovial fluid (SF) and synovial pathological changes. METHODS: Patients who underwent AKO for medial compartment knee OA between 2019 and 2021 were examined. SF and synovium were obtained at the time of AKO and plate removal after bone union (mean, 16.8 months [range: 11-38 months] postoperatively). SF volume and interleukin (IL)-6 concentrations in SF were assayed using enzyme-linked immunosorbent assay. Synovitis was assessed histologically using a semiquantitative scoring system. Macrophage infiltration was assessed by immunohistochemistry using a semiquantitative score for F4/80 expression. The M1/M2 ratio was calculated using percentage of cells positive for CD80 and CD163. The expression of proinflammatory cytokines was assessed by the percentage of IL-1ß- and IL-6-positive cells. The number of vascular endothelial growth factor-positive luminal structures was counted to assess angiogenesis. The change in each parameter was compared before and after AKO using the Wilcoxon matched-pairs signed-rank test. RESULTS: Twenty-four knees of 21 patients were included. SF volume and IL-6 concentration significantly decreased postoperatively (12.6 ± 2.1 mL vs 4.2 ± 0.6 mL; P < .0001 and 50.5 ± 8.6 pg/mL vs 20.7 ± 3.8 pg/mL; P = .0001, respectively). A significant reduction in synovitis score (P = .0001), macrophage infiltration (P < .0003), M1/M2 ratio (P < .0007), angiogenesis (P < .0001), and the percentage of IL-1ß- and IL-6-positive cells in the intima (P < .008 and P < .002, respectively) was found after AKO. CONCLUSIONS: SF volume and IL-6 concentrations in the SF decreased and inflammatory synovium pathology improved after AKO. In addition to biomechanical changes, the biological environment of the joint can be improved after AKO. LEVEL OF EVIDENCE: Level IV, retrospective therapeutic case series.

Preoperative Increases in T2-Weighted Fat-Suppressed MRI Signal Intensities Associated with Advanced Tissue Degeneration and Mitochondrial Dysfunction in Rotator Cuff Tears.

PURPOSE: The purpose of this study was to investigate the relationship between magnetic resonance imaging (MRI) signal intensities and mitochondrial function in patients undergoing arthroscopic rotator cuff repair, assessed through histological and genetic profiling of tendon tissue. METHODS: This study, conducted between April 2022 and January 2023, included 20 patients undergoing rotator cuff repair for atraumatic/degenerative tears. Rotator cuff tendon edge samples were obtained during arthroscopic rotator cuff repair. Patients were classified based on signal intensity from preoperative T2-weighted fat suppressed MRI. Specifically, they were categorized as having either high or low signal intensity at the rotator cuff tendon edge, with the deltoid muscle serving as a reference. Comparative analyses specifically compared the histological features and genetic profiles of the tendon tissue at the rotator cuff tendon edge. Histological evaluation of harvested tendon specimens during arthroscopic rotator cuff repair employed the modified Bonar score. Real-time polymerase chain reaction was used to assess expression of various mitochondrial and apoptosis-related genes. The mitochondrial morphology of the rotator cuff torn site was examined using electron microscopy. RESULTS: The higher signal intensity group showed significantly higher modified Bonar scores (p=0.0068), decreased mitochondrial gene expression, increased TUNEL-positive cells (p=0.032), lower SOD activity (p=0.011), reduced ATP5A (p=0.031), and increased cleaved caspase-9 activity (p=0.026) when compared to the lower signal intensity group. Electron microscopy revealed fewer mitochondrial cristae in the higher signal intensity group. CONCLUSION: Our results suggest correlations between high MRI signal intensities and the presence of degeneration, mitochondrial dysfunction, and increased apoptosis in rotator cuff tissues. This underscores the utility of MRI signal intensity as an indicator of tissue condition. CLINICAL RELEVANCE: Building on the established premise that elevated preoperative MRI signal intensities may indicate higher rates of postoperative rotator cuff re-tears, the current study substantiates these findings from a mitochondrial function perspective.

Intraoperative lateral laxity greater than 4° is associated with inferior functional improvement in posterior-stabilised total knee arthroplasty.

PURPOSE: The study aimed to determine the impact of intraoperative lateral laxity at extension on clinical and functional outcomes 1 year after posterior-stabilised total knee arthroplasty (PS-TKA). METHODS: In total, 91 varus-type osteoarthritic knees that underwent PS-TKA using the medial preservation gap technique were included. After the femoral trial component placement and patellofemoral joint reduction, the soft-tissue balance was assessed using an offset-type tensor with a 40-lb joint-distraction force. Patients were divided into the following three groups according to the intraoperative lateral laxity at extension (i.e., varus ligament balance) using the mean ± 1 standard deviation: Groups A, ≤0°; B, 0-4°; and C, >4°. The 2011 Knee Society Score (KSS) and 3-m timed up-and-go test (TUG) time 1-year postoperatively, and their improvements were compared among the groups. RESULTS: While significant improvements were observed in all subscales of the 2011 KSS and TUG post-TKA (p < 0.05), the improvement of functional activities and TUG time were significantly lower in Group C than in Group B (p < 0.05). However, no significant differences were observed in symptom improvement, patient satisfaction or patient expectation scores among the groups. CONCLUSION: An excessive lateral laxity (varus angle) >4° at extension was associated with lower improvement in functional ability 1-year postoperatively. Therefore, excessive intraoperative lateral laxity should be avoided in PS-TKA. LEVEL OF EVIDENCE: Level IV.

Re-tear after arthroscopic rotator cuff tear surgery: risk analysis using machine learning.

BACKGROUND: Postoperative rotator cuff retear after arthroscopic rotator cuff repair (ARCR) is still a major problem. Various risk factors such as age, gender, and tear size have been reported. Recently, magnetic resonance imaging-based stump classification was reported as an index of rotator cuff fragility. Although stump type 3 is reported to have a high retear rate, there are few reports on the risk of postoperative retear based on this classification. Machine learning (ML), an artificial intelligence technique, allows for more flexible predictive models than conventional statistical methods and has been applied to predict clinical outcomes. In this study, we used ML to predict postoperative retear risk after ARCR. METHODS: The retrospective case-control study included 353 patients who underwent surgical treatment for complete rotator cuff tear using the suture-bridge technique. Patients who initially presented with retears and traumatic tears were excluded. In study participants, after the initial tear repair, rotator cuff retears were diagnosed by magnetic resonance imaging; Sugaya classification types IV and V were defined as re-tears. Age, gender, stump classification, tear size, Goutallier classification, presence of diabetes, and hyperlipidemia were used for ML parameters to predict the risk of retear. Using Python's Scikit-learn as an ML library, five different AI models (logistic regression, random forest, AdaBoost, CatBoost, LightGBM) were trained on the existing data, and the prediction models were applied to the test dataset. The performance of these ML models was measured by the area under the receiver operating characteristic curve. Additionally, key features affecting retear were evaluated. RESULTS: The area under the receiver operating characteristic curve for logistic regression was 0.78, random forest 0.82, AdaBoost 0.78, CatBoost 0.83, and LightGBM 0.87, respectively for each model. LightGBM showed the highest score. The important factors for model prediction were age, stump classification, and tear size. CONCLUSIONS: The ML classifier model predicted retears after ARCR with high accuracy, and the AI model showed that the most important characteristics affecting retears were age and imaging findings, including stump classification. This model may be able to predict postoperative rotator cuff retears based on clinical features.

Estimation of Shoulder Joint Rotation Angle Using Tablet Device and Pose Estimation Artificial Intelligence Model.

Traditionally, angle measurements have been performed using a goniometer, but the complex motion of shoulder movement has made these measurements intricate. The angle of rotation of the shoulder is particularly difficult to measure from an upright position because of the complicated base and moving axes. In this study, we attempted to estimate the shoulder joint internal/external rotation angle using the combination of pose estimation artificial intelligence (AI) and a machine learning model. Videos of the right shoulder of 10 healthy volunteers (10 males, mean age 37.7 years, mean height 168.3 cm, mean weight 72.7 kg, mean BMI 25.6) were recorded and processed into 10,608 images. Parameters were created using the coordinates measured from the posture estimation AI, and these were used to train the machine learning model. The measured values from the smartphone's angle device were used as the true values to create a machine learning model. When measuring the parameters at each angle, we compared the performance of the machine learning model using both linear regression and Light GBM. When the pose estimation AI was trained using linear regression, a correlation coefficient of 0.971 was achieved, with a mean absolute error (MAE) of 5.778. When trained with Light GBM, the correlation coefficient was 0.999 and the MAE was 0.945. This method enables the estimation of internal and external rotation angles from a direct-facing position. This approach is considered to be valuable for analyzing motor movements during sports and rehabilitation.

Predicting postoperative coronal alignment after fixed-bearing unicompartmental knee arthroplasty using a new morphological assessment method: the arithmetic hip-knee-ankle angle.

PURPOSE: Only a few reports have been published so far on factors that predict postoperative coronal alignment after unicompartmental knee arthroplasty (UKA). The purpose of this study is to clarify the relationship between the arithmetic hip-knee-ankle angle (aHKA) and postoperative coronal alignment after medial fixed-bearing UKA. METHODS: One hundred and one consecutive patients (125 knees) who underwent medial fixed-bearing UKA were assessed. Pre- and postoperative coronal HKA angles, lateral distal femoral angle (LDFA), medial proximal tibial angle (MPTA), and the thickness of the tibial and femoral bone cut were measured. aHKA was calculated as 180° - LDFA + MPTA. Correlations between postoperative HKA angle and aHKA, LDFA, and MPTA were investigated by single regression analysis. After the patients were divided into three groups according to the postoperative HKA angle, i.e., HKA angle > 180°, 175° < HKA angle ≤ 180°, and HKA angle ≤ 175°, aHKA, LDFA, MPTA, preoperative HKA angle, and the thickness of the distal femoral as well as tibial bone cut were compared among the three groups. RESULTS: aHKA and MPTA were positively correlated with postoperative HKA angle, while no correlation was found between postoperative HKA angle and LDFA. Among the three groups classified by postoperative HKA angle, significant differences were found in aHKA, MPTA, and preoperative HKA angle, while no significant difference was found in LDFA and the amount of distal femoral and tibial osteotomies. CONCLUSIONS: aHKA was correlated with postoperative HKA angle after medial fixed-bearing UKA, which was probably due to the influence of MPTA.

Combined assessment of acetabular coverage and femoral head-neck shapes predicts osteoarthritis progression after periacetabular osteotomy.

INTRODUCTION: Postoperative osteoarthritis (OA) progression is a major determinant of failure after curved periacetabular osteotomy (CPO). A large postoperative combination angle, i.e., the combination of computed tomography-based anterior center edge and alpha angles, is associated with femoroacetabular impingement after CPO, but its association with postoperative OA progression is unclear. We aimed to identify the anatomical parameters that can lead to OA progression after CPO and the impact of the combination angle on the same. MATERIALS AND METHODS: We included 90 hips that were subjected to CPO at our center between March 2013 and March 2018. Seventeen hips showed OA progression with an increase in the Tönnis classification after surgery; 73 hips showed no progression. Radiographic anatomical parameters, including the lateral and anterior center edge angles, femoral and acetabular anteversion, and combination angle, and clinical outcomes, including modified Harris Hip Scores (mHHSs), postoperative anterior impingement, and range of motion, were compared between the two groups. Statistical significance was set at P < 0.05. RESULTS: Postoperative OA progression was significantly affected by preoperative OA evidence (P = 0.017), acetabular anteversion < 5.0° (P = 0.003), and a combination angle > 107.0° (P = 0.025). Patients with radiographic OA progression were associated with poor mHHSs (P = 0.017) and high frequencies of anterior impingement with a limited hip flexion and internal rotation angle. CONCLUSIONS: OA progression after CPO may be associated with preoperative evidence of OA and postoperative acetabular retroversion as well as a large combination angle. Surgeons should focus on the potential effects of preoperative OA grades, postoperative reduction in acetabular anteversion, and postoperative combination angle.

Accuracy of portable navigation during THA in patients with severe developmental dysplasia of hip.

INTRODUCTION: Correct cup placement in total hip arthroplasty (THA) for patients with developmental dysplasia of the hip (DDH) is considerably difficult. This study aimed to analyze the orientation accuracy of cup insertion during THA using a portable navigation system in patients with DDH. MATERIALS AND METHODS: In this retrospective cohort study, we analyzed data from 64 patients who underwent THA using infrared stereo camera-matching portable navigation. Patients underwent THA via the anterolateral approach in the lateral decubitus position. Navigation records for intraoperative cup angles, postoperative cup angles measured on computed tomography (CT) images, and cup angle measurement differences were measured and compared between patients with non-DDH/mild DDH and severe DDH. Furthermore, the predictive factors for outliers of accurate acetabular cup placement were analyzed. RESULTS: The average measurement absolute abduction differences (postoperative CT-navigation record) were 3.9 ± 3.5° (severe DDH) and 3.3 ± 2.6° (non-DDH/ mild DDH), and the anteversion differences were 4.7 ± 3.4° (severe DDH) and 2.3 ± 2.1° (non-DDH/ mild DDH). The anteversion difference was different between the two groups. Multivariate analysis showed that the navigation difference (absolute difference in anteversion between postoperative CT and navigation records of > 5°) was significantly associated with severe DDH (odds ratio [OR]: 3.3; p = 0.049, 95% confidence interval [CI]: 1.0-11.1) and posterior pelvic tilt (OR: 1.1; p = 0.042, 95% CI: 1.0-1.27). CONCLUSIONS: In patients with severe DDH, it is important to pay close attention during THA using portable navigation. However, the average difference was < 5º even in patients with severe DDH, and the accuracy may be acceptable in a clinical setting when the cost is considered.

The assessment of canal flare index and proximal femoral bone density can improve stem selection for peri-prosthetic bone maintenance after total hip arthroplasty.

INTRODUCTION: Bone maintenance after total hip arthroplasty (THA) is important for implant success. This study aimed to investigate the relationship between patient characteristics and periprosthetic bone maintenance after THA for better implant selection. MATERIALS AND METHODS: This retrospective cohort study enrolled 112 consecutive patients who underwent THA using full hydroxyapatite (HA) compaction with short (n = 55) or short-tapered wedge (n = 61) stems. Periprosthetic bone mineral density (BMD) was compared between the two groups after propensity score matching, and the relationship between periprosthetic BMD changes and patient background was analyzed. RESULTS: Both groups showed similar periprosthetic BMD changes after adjusting for patient background using propensity score matching. Canal flare index > 3.7 in patients that underwent THA using tapered-wedge stem (odds ratio (OR), 3.2; 95% confidence interval (CI), 1.3-7.9, p = 0.013) and baseline zone 1 BMD > 0.65 in patients that received with short HA compaction stems (OR, 430.0; 95% CI 1.3-1420, p = 0.040) were associated with proximal periprosthetic bone maintenance after THA. CONCLUSION: Considering their predictive value, canal flare index and zone 1 BMD assessment might be useful strategies for implant selection during THA.

The medullary cavity morphology of the proximal femur influences the fixation pattern of the rectangular tapered short stem in total hip arthroplasty.

INTRODUCTION: This study aimed to evaluate differences in the pattern of fixation with a rectangular tapered short stem (Fitmore stem) due to proximal femoral medullary cavity morphology based on periprosthetic bone mineral density (BMD) and radiological findings. MATERIALS AND METHODS: We analyzed 105 consecutive patients (Dorr type A, 18; Dorr type B, 66; Dorr type C, 21) who underwent total hip arthroplasty using a Fitmore stem. Periprosthetic BMD was measured using dual-energy X-ray absorptiometry from 1 to 24 months postoperatively and radiological analysis was performed. Clinical outcomes were evaluated using the Harris hip score (HHS) and the University of California Los Angeles (UCLA) activity score preoperatively and 24 months postoperatively. RESULTS: At 24 months postoperatively, Dorr type C had significantly decreased BMD changes in Gruen zones 2, 6, and 7 compared to Dorr types A and B, and conversely, significantly increased BMD changes in zone 4 (p < 0.05). Dorr type C had significantly greater subsidence than the other types (p < 0.01) and significantly higher cortical hypertrophy in zone 3 (p < 0.01). Stress shielding was not significantly different between Dorr types. The preoperative and postoperative HHS and UCLA activity scores showed no significant differences between the Dorr types. CONCLUSIONS: In Dorr type C, BMD significantly decreased in the proximal femur with a rectangular tapered short stem, suggesting that the stem was fixed at the distal part. Careful observation of this prosthesis over time is needed in patients with Dorr type C.

Treatment of Osteoporosis in Men on Androgen Deprivation Therapy in Japan.

Background and Objectives: Androgen deprivation therapy (ADT) for prostate cancer has greatly improved treatment outcomes. As patient survival rates have increased, reports of decreased bone density and increased bone fractures as side effects of ADT have emerged. The prevalence of osteoporosis in Japanese men was 4.6%. The purpose of this study was to evaluate the effect of osteoporosis treatment in prostate cancer patients who underwent ADT in Japan. Materials and Methods: The subjects were 33 male patients who had undergone ADT for prostate cancer, who were noted to have decreased bone density. Mean age was 76.2 ± 7.7 years (64-87). Medications included vitamin D in one case, bisphosphonates (BP) in 27 cases, and denosumab in five cases. The evaluation method examined the rate of change in bone mineral density (BMD) before osteoporosis treatment and 1 year after. For comparison, a group without osteoporosis treatment intervention (n = 33) was selected, and matched for prostate cancer treatment and age. The rate of change in trabecular bone score (TBS) was also calculated. Results: The percentage changes in BMD before and 1 year after treatment were as follows: lumbar spine, 7.1 ± 5.8% in the treatment group versus -3.9 ± 4.1% in the no treatment group; femoral neck, 5.5 ± 6.2% in the treatment group versus -0.9 ± 3.9% in the no treatment group; total femur, 6.6 ± 6.4% in the treatment group versus the no treatment group which was -1.7 ± 3.2%. In all cases, there was a clear significant difference (p < 0.01). The percent change in TBS was further calculated in the same manner. There was no significant difference between the two groups: +1.7 ± 3.8% in the treated group versus +0.3 ± 4.1% in the untreated group. Conclusions: Osteoporosis treatment in Japanese patients with prostate cancer on ADT therapy was found to significantly increase BMD compared to the untreated group. BP and denosumab were found to be very effective in increasing BMD.

What effect does preoperative flexion contracture have on the component angles in unicompartmental knee arthroplasty?

PURPOSE: The indication for unicompartmental knee arthroplasty (UKA) has been extended to cases with some degree of preoperative knee flexion contracture recently. The purpose of this study was to clarify the effect of flexion contracture on component angles. MATERIALS AND METHODS: Thirty-five fixed-bearing UKAs using the spacer block technique with preoperative flexion contracture (Group FC) and 35 UKAs using the same technique without preoperative flexion contracture (Group NC) were included. Using radiographs, the coronal femoral component angle, coronal tibial component angle, sagittal femoral component angle, and sagittal tibial component angle were determined. Also, extension and flexion angles of the knee as well as coronal Hip-Knee-Ankle (HKA) angles in long-leg standing radiographs were measured. The data about the thickness of the selected insert were also collected. The above results were compared between the two groups. RESULTS: The femoral component tended to be placed in a more varus and flexed position in Group FC, while no significant difference was found about the tibial component angles. While there was no significant difference in pre- and postoperative knee flexion angles between the two groups, flexion contracture remained postoperatively in Group FC. Preoperative HKA angle was greater in Group FC while the difference was no longer significant postoperatively. Regarding the thickness of the selected insert, thicker inserts tended to be used in Group FC. CONCLUSIONS: In fixed-bearing UKA with the spacer block technique, the femoral component tended to be placed in a flexed and varus position in the knees with preoperative flexion contracture.

Elicitation of Inhibitory Effects for AGE-Induced Oxidative Stress in Rotator Cuff-Derived Cells by Apocynin.

Advanced glycation end-products (AGEs) play a critical supportive role during musculoskeletal disorders via glycosylation and oxidative stress. Though apocynin, identified as a potent and selective inhibitor of NADPH oxidase, has been reported to be involved in pathogen-induced reactive oxygen species (ROS), its role in age-related rotator cuff degeneration has not been well clarified. Therefore, this study aims to evaluate the in vitro effects of apocynin on human rotator cuff-derived cells. Twelve patients with rotator cuff tears (RCTs) participated in the study. Supraspinatus tendons from patients with RCTs were collected and cultured. After the preparation of RC-derived cells, they were divided into four groups (control group, control + apocynin group, AGEs group, AGEs + apocynin group), and gene marker expression, cell viability, and intracellular ROS production were evaluated. The gene expression of NOX, IL-6, and the receptor for AGEs (RAGE) was significantly decreased by apocynin. We also examined the effect of apocynin in vitro. The results showed that ROS induction and increasing apoptotic cells after treatment of AGEs were significantly decreased, and cell viability increased considerably. These results suggest that apocynin can effectively reduce AGE-induced oxidative stress by inhibiting NOX activation. Thus, apocynin is a potential prodrug in preventing degenerative changes of the rotor cuff.

Phase III clinical trial of autologous CD34 + cell transplantation to accelerate fracture nonunion repair.

BACKGROUND: We previously demonstrated that CD34 + cell transplantation in animals healed intractable fractures via osteogenesis and vasculogenesis; we also demonstrated the safety and efficacy of this cell therapy in an earlier phase I/II clinical trial conducted on seven patients with fracture nonunion. Herein, we present the results of a phase III clinical trial conducted to confirm the results of the previous phase studies using a larger cohort of patients. METHODS: CD34 + cells were mobilized via administration of granulocyte colony-stimulating factor, harvested using leukapheresis, and isolated using magnetic cell sorting. Autologous CD34 + cells were transplanted in 15 patients with tibia nonunion and 10 patients with femur nonunion, who were followed up for 52 weeks post transplantation. The main outcome was a reduction in time to heal the tibia in nonunion patients compared with that in historical control patients. We calculated the required number of patients as 15 based on the results of the phase I/II study. An independent data monitoring committee performed the radiographic assessments. Adverse events and medical device failures were recorded. RESULTS: All fractures healed during the study period. The time to radiological fracture healing was 2.8 times shorter in patients with CD34 + cell transplantation than in the historical control group (hazard ratio: 2.81 and 95% confidence interval 1.16-6.85); moreover, no safety concerns were observed. CONCLUSIONS: Our findings strongly suggest that autologous CD34 + cell transplantation is a novel treatment option for fracture nonunion. TRIAL REGISTRATION: UMIN-CTR, UMIN000022814. Registered on 22 June 2016.

Trends of disease activity in Japanese patients over 75 years with rheumatoid arthritis from 2014 to 2021- the ANSWER cohort study.

OBJECTIVES: To investigate if disease activity among elderly RA patients over 75 years has changed over time in the real-world clinical setting. METHODS: Data from an observational multicentre registry of RA patients in Japan were analyzed. The primary outcome was to evaluate the changes in the proportion of very elderly RA patients (over 75 years) who achieved remission and low disease activity, from 2014 to 2021. The secondary outcome was to identify factors associated with remission and low disease activity by comparing demographic and clinical characteristics among the patients who had a study visit within the study period, using multivariate logistic regression. RESULTS: A total of 32 161 patient visits were identified from 2014 to 2021. The proportion of patients over 75 years increased from 16.5% to 26.9%, with biologics and targeted-synthetic disease modifying anti-rheumatic drugs (b/tsDMARDs) usage increasing and glucocorticoids usage decreasing, while conventional-synthetic DMARDs usage remained relatively stable. The proportion of RA patients over 75 years achieving remission and low disease activity significantly increased from 62.2% to 78.2% (p for trend < 0.001). A negative factor associated with achieving remission and low disease activity was glucocorticoid usage, seropositivity, and history of previous b/tsDMARDs use while MTX usage was associated positively, independent of other predictors. CONCLUSIONS: In our cohort, disease activity among very elderly RA patients has improved over time. The study suggests the importance of using a treat-to-target approach in very elderly RA patients to improve clinical outcomes.

Real-world comparative study of the efficacy of Janus kinase inhibitors in patients with rheumatoid arthritis: the ANSWER cohort study.

OBJECTIVE: This multicentre, retrospective study compared the efficacy and safety of tofacitinib, baricitinib, peficitinib and upadacitinib in real-world clinical settings after minimizing selection bias and adjusting the confounding patient characteristics. METHOD: The 622 patients were selected from the ANSWER cohort database and treated with tofacitinib (TOF), baricitinib (BAR), peficitinib (PEF) or upadacitinib (UPA). The patient's background was matched using propensity score-based inverse probability of treatment weighting (IPTW) among four treatment groups. The values of Clinical Disease Activity Index (CDAI), C-reactive protein (CRP), and modified Health Assessment Questionnaire (mHAQ) after drug initiation and the remission or low disease activity (LDA) rates of CDAI at 6 months after drug initiation were compared among the four groups. Further, the predictive factor for TOF and BAR efficacy was analysed. RESULTS: The retention and discontinuation rates until 6 months after drug initiations were not significantly different among the four JAK inhibitors treatment groups. Mean CDAI value, CDAI remission rate, and CDAI-LDA rate at 6 months after drug initiation were not significantly different among treatment groups. Baseline CDAI (TOFA: OR 1.09, P < 0.001; BARI: OR 1.07, P < 0.001), baseline CRP (TOFA: OR 1.32, P = 0.049), baseline glucocorticoid dose (BARI: OR 1.18, 95% CI 1.01-1.38, P = 0.035), a number of previous biological or targeted synthetic disease-modifying antirheumatic drugs (biological/targeted synthetic DMARDs) (BARI: OR 1.36, P = 0.004) were predictive factors for resistance to CDAI-LDA achievement to JAK inhibitor treatment. CONCLUSION: The efficacy and safety of TOF, BAR, PEF and UPA were not significantly different for the treatment of patients with rheumatoid arthritis.