Investigational regenerative medicine for non-traumatic osteonecrosis of the femoral head: a survey of registered clinical trials.

INTRODUCTION: Osteonecrosis of the femoral head (ONFH) is a refractory disease requiring joint replacement in young patients. Regenerative therapies have been developed. AREAS COVERED: This study surveyed clinical trials on regenerative medicine for ONFH. We extracted clinical trials on non-traumatic ONFH from the websites of five publicly available major registries (EuropeanUnion Clinical Trials Register ([EU-CTR],ClinicalTrials.gov, Chinese ClinicalTrial Registry [ChiCTR], University Hospital Medical InformationNetwork - Clinical Trial Registry [UMIN-CTR] and Australian New Zealand Clinical Trials Registry [ANZCTR]).The trials were classified into six categories based on purpose: surgical treatment, non-drug conservative treatment, conservative drug treatment, therapeutic strategy, diagnosis and pathogenesis, and regenerative therapy.) We extracted 169 clinical trials on ONFH. Of these, 37 were on regenerative medicine, including 29 on cell therapy. Surgical treatment was the most common treatment, followed by regenerative therapy.There were 9 clinical trials registered in the EU-CTR, with 5 on regenerative medicine; 79 trials registered on ClinicalTrials.gov, with 24 on regenerativemedicine; 54 trials registered in the ChiCTR, with 6 on regenerative medicine. EXPERT OPINION: The focus of the joint-preserving surgery has shifted to regenerative therapy based on using cell therapy in early-stage ONFH. The global standardisation of regenerative therapy is still ongoing.

Anterior Position of the Femoral Condyle During Mid-Flexion Worsens Knee Activity After Cruciate-Retaining Total Knee Arthroplasty.

BACKGROUND: The effects of kinematics on patient-reported outcome measures (PROMs) after cruciate-retaining (CR) total knee arthroplasty (TKA) remain unclear. This study investigated the effects of kinematic patterns after CR-TKA on PROMs. METHODS: We examined 35 knees (27 patients) undergoing primary CR-TKA. Knee kinematics and 2011 Knee Society Score were evaluated at a mean follow-up of 72.4 (± 28.2) months. Knee kinematics was analyzed using fluoroscopy, and the femoral antero-posterior position relative to the tibial component was assessed separately for medial and lateral compartments during a squat. The correlations between kinematics and PROMs were evaluated. RESULTS: The average amount of posterior femoral translation from full extension to maximum flexion was 0.2 (± 2.6) mm for the medial femoral condyle and 4.1 (± 2.9) mm for the lateral condyle. Medial pivot motion was observed in 24 knees (68.6%) with a low rate (14.3%) of paradoxical anterior translation. The anterior position of the medial femoral condyle at 60° had a negative impact on discretionary activities (ρ = -0.37; P = .039), and at maximum flexion, had a negative impact on total functional activities (ρ = -0.46; P = .005), advanced activities (ρ = -0.45; P = .006), and discretionary activities (ρ = -0.63; P < .001). Anterior position of the lateral femoral condyle at 30° had a negative impact on total functional activities (ρ = -0.48; P = .005), walking and standing (ρ = -0.56; P < .001), and advanced activities (ρ = -0.49; P = .004), and at 60° had a negative impact on walking and standing (ρ = -0.45; P = .010). CONCLUSIONS: The anterior positions of the medial and lateral femoral condyles at mid-flexion and maximum flexion had negative impacts on PROMs. Soft tissue conditions should be carefully managed to achieve medial knee joint stability, which can improve PROMs.

Comparison of knee kinematics and ligament forces in single and multi-radius cruciate-retaining total knee arthroplasty: A computer simulation study.

BACKGROUND: The single-radius design in total knee arthroplasty has been designed to develop a more fixed flexion-extension axis without mid-flexion instability compared with the multi-radius design. It remains unclear whether differences between the multi-radius and single-radius designs can affect kinematics and collateral ligament forces. This study aimed to simulate knee kinematics and kinetics between single-radius and multi-radius models using a musculoskeletal computer model. METHODS: The single-radius and multi-radius femoral components were virtually implanted in a computer simulation using the same tibial insert. The effects of implant design on kinematics and medial collateral ligament forces during squatting and gait activities were analyzed. RESULTS: During squatting, the multi-radius model exhibited paradoxical anterior translation on both the medial and lateral flexion facet center where peak anterior translation was 2.4 mm for medial flexion facet center and 2.2 mm for the lateral flexion facet center, while the peak anterior translation of the single-radius model was less than 1 mm at early flexion. A rapid decrease in medial collateral ligament tension was observed in the early flexion phase in the multi-radius model, which occurred simultaneously with paradoxical anterior translation, whereas the relatively constant medial collateral ligament tension was observed in the single-radius model. During gait activity, the single-radius model exhibited a more posterior position than the multi-radius model. CONCLUSION: These suggest that abrupt changes in the medial collateral ligament force influence anterior sliding of the femur, and that the single-radius design is a reasonable choice for prevention of mid-flexion instability.

Improved genetic prediction of the risk of knee osteoarthritis using the risk factor-based polygenic score.

BACKGROUND: Polygenic risk score (PRS) analysis is used to predict disease risk. Although PRS has been shown to have great potential in improving clinical care, PRS accuracy assessment has been mainly focused on European ancestry. This study aimed to develop an accurate genetic risk score for knee osteoarthritis (OA) using a multi-population PRS and leveraging a multi-trait PRS in the Japanese population. METHODS: We calculated PRS using PRS-CS-auto, derived from genome-wide association study (GWAS) summary statistics for knee OA in the Japanese population (same ancestry) and multi-population. We further identified risk factor traits for which PRS could predict knee OA and subsequently developed an integrated PRS based on multi-trait analysis of GWAS (MTAG), including genetically correlated risk traits. PRS performance was evaluated in participants of the Nagahama cohort study who underwent radiographic evaluation of the knees (n = 3,279). PRSs were incorporated into knee OA integrated risk models along with clinical risk factors. RESULTS: A total of 2,852 genotyped individuals were included in the PRS analysis. The PRS based on Japanese knee OA GWAS was not associated with knee OA (p = 0.228). In contrast, PRS based on multi-population knee OA GWAS showed a significant association with knee OA (p = 6.7 × 10-5, odds ratio (OR) per standard deviation = 1.19), whereas PRS based on MTAG of multi-population knee OA, along with risk factor traits such as body mass index GWAS, displayed an even stronger association with knee OA (p = 5.4 × 10-7, OR = 1.24). Incorporating this PRS into traditional risk factors improved the predictive ability of knee OA (area under the curve, 74.4% to 74.7%; p = 0.029). CONCLUSIONS: This study showed that multi-trait PRS based on MTAG, combined with traditional risk factors, and using large sample size multi-population GWAS, significantly improved predictive accuracy for knee OA in the Japanese population, even when the sample size of GWAS of the same ancestry was small. To the best of our knowledge, this is the first study to show a statistically significant association between the PRS and knee OA in a non-European population. TRIAL REGISTRATION: No. C278.

Excessive flexed position of the femoral component causes abnormal kinematics and joint contact/ ligament forces in total knee arthroplasty.

Poor clinical outcomes are reported in excessive flexion of the femoral component in total knee arthroplasty (TKA), but their mechanisms have not yet been elucidated. This study aimed to investigate the biomechanical effect of flexion of the femoral component. Cruciate-substituting (CS) and posterior-stabilised (PS) TKA were reproduced in a computer simulation. The femoral component was then flexed from 0° to 10° with anterior reference, keeping the implant size and the extension gap. Knee kinematics, joint contact, and ligament forces were evaluated in deep-knee-bend activity. When the femoral component was flexed 10° in CS TKA, paradoxical anterior translation of the medial compartment was observed at mid-flexion. The PS implant was best stabilised with a 4° flexion model in mid-flexion range. The medial compartment contact force and the medial collateral ligament (MCL) force increased with the flexion of the implant. There were no remarkable changes in the patellofemoral contact force or quadriceps in either implant. In conclusions, excessive flexion of the femoral component yielded abnormal kinematics and contact/ligament forces. Avoiding excessive flexion and maintaining mild flexion of the femoral component would provide better kinematics and biomechanical effects in CS and PS TKA.

Reduced angiogenesis and delayed endochondral ossification in CD163-/- mice highlights a role of M2 macrophages during bone fracture repair.

While recent studies showed that macrophages are critical for bone fracture healing, and lack of M2 macrophages have been implicated in models of delayed union, functional roles for specific M2 receptors have yet to be defined. Moreover, the M2 scavenger receptor CD163 has been identified as a target to inhibit sepsis following implant-associated osteomyelitis, but potential adverse effects on bone healing during blockage therapy have yet to be explored. Thus, we investigated fracture healing in C57BL/6 versus CD163-/- mice using a well-established closed, stabilized, mid-diaphyseal femur fracture model. While gross fracture healing in CD163-/- mice was similar to that of C57BL/6, plain radiographs revealed persistent fracture gaps in the mutant mice on Day 14, which resolved by Day 21. Consistently, 3D vascular micro-CT demonstrated delayed union on Day 21, with reduced bone volume (74%, 61%, and 49%) and vasculature (40%, 40%, and 18%) compared to C57BL/6 on Days 10, 14, and 21 postfracture, respectively (p < 0.01). Histology confirmed large amounts of persistent cartilage in CD163-/- versus C57BL/6 fracture callus on Days 7 and 10 that resolves over time, and immunohistochemistry demonstrated deficiencies in CD206+ M2 macrophages. Torsion testing of the fractures confirmed the delayed early union in CD163-/- femurs, which display decreased yield torque on Day 21, and a decreased rigidity with a commensurate increase in rotation at yield on Day 28 (p < 0.01). Collectively, these results demonstrate that CD163 is required for normal angiogenesis, callus formation, and bone remodeling during fracture healing, and raise potential concerns about CD163 blockade therapy.

Biomechanical Comparison of Kinematic and Mechanical Knee Alignment Techniques in a Computer Simulation Medial Pivot Total Knee Arthroplasty Model.

Several concepts may be used to restore normal knee kinematics after total knee arthroplasty. One is a kinematically aligned (KA) technique, which restores the native joint line and limb alignment, and the other is the use of a medial pivot knee (MPK) design, with a ball and socket joint in the medial compartment. This study aimed to compare motions, contact forces, and contact stress between mechanically aligned (MA) and KA (medial tilt 3° [KA3] and 5° [KA5]) models in MPK. An MPK design was virtually implanted with MA, KA3, and KA5 in a validated musculoskeletal computer model of a healthy knee, and the simulation of motion and contact forces was implemented. Anteroposterior (AP) positions, mediolateral positions, external rotation angles of the femoral component relative to the tibial insert, and tibiofemoral contact forces were evaluated at different knee flexion angles. Contact stresses on the tibial insert were calculated using finite element analysis. The AP position at the medial compartment was consistent for all models. From 0° to 120°, the femoral component in KA models showed larger posterior movement at the lateral compartment (0.3, 6.8, and 17.7 mm in MA, KA3, and KA5 models, respectively) and larger external rotation (4.2°, 12.0°, and 16.8° in the MA, KA3, and KA5 models, respectively) relative to the tibial component. Concerning the mediolateral position of the femoral component, the KA5 model was positioned more medially. The contact forces at the lateral compartment of all models were larger than those at the medial compartment at >60° of knee flexion. The peak contact stresses on the tibiofemoral joint at 90° and 120° of knee flexion were higher in the KA models. However, the peak contact stresses of the KA models at every flexion angle were <20 MPa. The KA technique in MPK can successfully achieve near-normal knee kinematics; however, there may be a concern for higher contact stresses on the tibial insert.

Static Mediolateral Tilt of the Joint Line after Total Knee Arthroplasty Does Not Reflect Dynamic Tilt during a Stair Ascent Activity.

The correlation between static and dynamic mediolateral (ML) tilts of the joint line in the coronal plane remains unknown after total knee arthroplasty (TKA). The purpose was to evaluate the ML tilt as measured by two-dimensional to three-dimensional registration during stair ascent in TKA patients, and to examine the correlation between the dynamic ML tilt and radiographic measurements of static indices. Thirty-two knees that underwent TKA using the mechanical alignment method were included. Continuous sagittal fluoroscopy was taken from before initial contact (IC) until after the toe-off (TO) phase during the stair ascent. The ML tilt of the tibial component relative to the ground was analyzed in terms of dynamic alignment using image-matching techniques, whereas static alignment was measured using standing long-leg radiographs. The correlation between static and dynamic ML tilts was evaluated. In the fluoroscopic analysis, the joint line was neutral (0.0 degree, standard deviation [SD] = 3.4 degrees) around IC phases, then was tilted valgus (5.5° valgus, SD = 2.6 degrees) in the mid-stance (MS) phase. After the TO phase, the joint line became almost neutral (0.4 degrees valgus, SD = 3.1 degrees). The dynamic ML tilt was significantly more varus during the IC phase and significantly more valgus in MS and TO phases than the static ML tilt (1.4 degrees valgus, SD = 2.0 degrees). No correlation was found between static and dynamic ML tilts in weight-bearing phases. During stair ascent, the static tilt had no correlation with the dynamic tilt in weight-bearing phases despite being in the same range. Static lower limb alignment does not reflect coronal alignment during motion. Further research should be conducted to determine whether the horizontal dynamic ML tilt can improve long-term durability and clinical outcomes after TKA.

Hinge fractures reaching the tibial plateau can be caused by forcible opening of insufficient posterior osteotomy during open-wedge high tibial osteotomy.

PURPOSE: The purpose of this study was to use the finite element method (FEM) to reproduce fracture lines that reach the lateral tibial plateau during open-wedge high tibial osteotomy (OWHTO) in patients with Type III lateral hinge fracture (LHF). It was hypothesized that the FEM could clarify biomechanical causes of Type III LHF, enabling prevention of adverse complications. METHODS: This study used the nonlinear FEM to analyze the data of eight knees in eight patients (two males and six females) with Type III LHF among 82 patients who underwent OWHTO, as well as the data of eight individuals with no LHF. To predict the onset of Type III LHF, simulation models were also developed in which posterior osteotomy sufficiency varied from 50% to perfect, the latter defined as osteotomy reaching the hinge point. RESULTS: Real-life instances of Type III LHF caused by insufficient posterior osteotomy were reproduced in all patient-specific FEM models, and these models accurately predicted fracture types and locations. During opening of the osteotomy gap, the fracture line reached the lateral tibial plateau, and extended vertically from the end of the insufficient posterior osteotomy, avoiding the rigid proximal tibiofibular joint. In contrast, sufficient posterior osteotomy resulted in a lack of LHF. Posterior osteotomy extension ≥ 70% of the width of the osteotomy plane was the cut-off value to prevent Type III LHF. CONCLUSION: Forced opening of insufficient posterior osteotomy was found to be a biomechanical cause of Type III LHF that extended perpendicularly to the lateral tibial plateau, avoiding the proximal tibiofibular joint. The clinical significance of this study is that sufficient posterior osteotomy during OWHTO, defined as at least 70% of the width of the osteotomy plane, can prevent Type III LHF.

Physical and financial impacts caused by the COVID-19 pandemic exacerbate knee pain: A longitudinal study of a large-scale general population.

OBJECTIVES: This study aimed to evaluate the changes in knee pain, a dominant cause of physical disability, following the coronavirus disease (COVID-19) pandemic, and to identify factors affecting the changes in knee pain. METHODS: We analysed the pre- and post-COVID-19 longitudinal data set of the Nagahama Study. Knee pain was assessed using the Knee Society Score (KSS). The estimated KSS from the age and sex using regression model in the pre- and post-COVID-19 data set was compared. Factors including the activity score, educational level, and various impacts of COVID-19 were analysed for correlation analyses with changes in KSS. RESULTS: Data collected from 6409 participants showed statistically significant differences in KSS, pre- (mean = 22.0; SD = 4.4) and post-COVID-19 (mean = 19.5; SD = 6.4). Low activity score (p = .008), low educational level (p < .001), and undesirable financial impact (p = .030) were independently associated with knee pain exacerbation. CONCLUSION: The harmful effects of the COVID-19 pandemic on knee pain were suggested. People should be encouraged to engage in physical activities, such as walking, despite the state of emergency. Furthermore, social support for economically disadvantaged groups may improve healthcare access, preventing the acute exacerbations of knee pain.

Systemic chronic diseases coexist with and affect locomotive syndrome: The Nagahama Study.

OBJECTIVES: The concept of locomotive syndrome was proposed to highlight older adults who require nursing care services due to the malfunctioning of their locomotive organs. With the coming of a super-ageing society, there is a growing need to understand the relation between systemic chronic diseases and locomotive syndrome. METHODS: We analysed the second-visit dataset of the Nagahama Study. The association analysis was performed to identify the chronic diseases that were risk factors associated with the occurrence and the progression of locomotive syndrome in both the cross-sectional and longitudinal studies. RESULTS: Hypertension, stroke, coronary heart disease, rheumatoid arthritis, chronic renal failure, osteoporosis, anaemia, and gastroesophageal reflux disease were independently correlated with locomotive syndrome through the deterioration of body pain, social activity, and cognitive function in the cross-sectional study. Multiple chronic diseases had additive effects and significantly increased the risk of locomotive syndrome. In the longitudinal study, osteoporosis and kidney disease were significantly correlated with the worsening of the total GLFS-25 score. CONCLUSIONS: Locomotive syndrome coexisted with various systemic chronic diseases, especially cardiovascular diseases. Osteoporosis and kidney disease were significantly correlated with the progression of locomotive dysfunction. The management of various chronic diseases may be useful to prevent locomotive syndrome and vice versa.

Larger bone marrow lesion volume before medial open-wedge high tibial osteotomy correlates with better improvement of clinical scores in patients with knee osteoarthritis.

PURPOSE: This study evaluated the clinical outcomes of medial open-wedge high tibial osteotomy (MOWHTO) and bone marrow lesion (BML) scores and volumes. The hypotheses were that quantitative BML volume is more associated with clinical outcomes of MOWHTO than qualitative BML evaluations, and pre-operative BML volume is associated with the improvement of clinical outcomes. METHODS: Patients who underwent MOWHTO were retrospectively enrolled. The Knee Injury and Osteoarthritis Outcome Score (KOOS) was recorded before the initial surgery and at plate removal surgery. Using pre-operative short-time inversion recovery magnetic resonance imaging, BMLs were evaluated using three qualitative scores, reflecting the maximum length, proportion, and intensity of BML. For quantification, BMLs of the femur and tibia were separately defined as lesions with a threshold greater than the mean signal intensity plus two standard deviations, using the corresponding lateral condyles as controls. The association between the KOOS scales and BML scores/volume was evaluated using Spearman's correlation coefficient. Multivariate linear regression analyses for post-operative KOOS scales were performed using the tibial BML volume as one of the four independent variables. RESULTS: The final analysis included 40 MOWHTO cases. Two qualitative BML scores correlated only with pre-operative KOOS sports. Femoral and tibial BML volumes were correlated with post-operative KOOS QOL (ρ = 0.40, p = 0.01) and sports (ρ = 0.36, p = 0.02), respectively. Tibial BML volume was significantly correlated with all five delta KOOS scales (ρ = 0.39-0.51, p = 0.01-0.001), however, femoral BML volume was only correlated with delta KOOS QOL (ρ = 0.41, p = 0.01). In multivariate analyses, tibial BML volume was a significant positive predictor for every post-operative KOOS scale, while post-operative % mechanical axis was also a positive significant variable, except post-operative KOOS pain. CONCLUSION: Tibial BML volume was positively correlated with one post-operative KOOS scale and all delta KOOS scales. A larger pre-operative tibial BML and appropriate alignment correction were associated with a better post-operative KOOS scales. Pre-operative large BML had no negative influence on post-operative clinical outcomes; hence, surgeons need not hesitate to perform MOWHTO in patients with large BMLs in the medial condyles. LEVEL OF EVIDENCE: Retrospective case series, Level IV.

Opening-Wedge High Tibial Osteotomy With High Hinge Position Risks Lateral Hinge Fracture in Men With Posterolateral Tibial Condyle Protrusion.

PURPOSE: The primary aim of this study was to evaluate the 3-dimensional morphology of the proximal tibia around the osteotomy plane in open-wedge high tibial osteotomy, focusing on the posterolateral (PL) and posteromedial (PM) tibial condyles, and to clarify the changes in morphologic parameters due to differences in patient characteristics and hinge position. The secondary aim was to examine whether morphologic features were associated with insufficient osteotomy, which increases the risk of lateral hinge fracture (LHF). METHODS: The PL and PM anteroposterior distance, asymmetry ratio, and discrepancy between PL and PM distances along the tibial osteotomy plane were measured. We investigated changes in the parameters due to differences in patient characteristics and hinge position. Osteotomy configurations and LHFs were evaluated using postoperative computed tomography scans. RESULTS: The 3-dimensional preoperative plans of 117 knees (male, 41 knees; female, 76 knees) were evaluated. PL distances were larger than PM distances in almost all cases. The average asymmetry ratio was 1.35, and the standard deviation was 0.22. Higher hinge position was associated with a larger asymmetry ratio and discrepancy (P < .001). The asymmetry ratio and discrepancy were independently positively correlated with male sex (P = .002 and P = .001, respectively) and gentle posterior tibial slope (P < .001 and P < .001, respectively). Osteotomies with type III LHFs showed lower osteotomy sufficiency than osteotomies without LHFs (P < .001). CONCLUSIONS: PL tibial condyle protrusion was more pronounced in male patients and those with a high hinge position, and may result in insufficient PL osteotomy, which is a risk factor for type III LHF during open-wedge high tibial osteotomy. The optimal hinge position was located approximately 15 mm and 20 mm distal to the lateral tibial plateau in female and male patients, respectively. LEVEL OF EVIDENCE: IV: retrospective case series.

How does asymmetric tibial insert affect tibiofemoral kinematics and contact stresses in total knee Arthroplasty?

BACKGROUND: Asymmetric tibial insert design is expected to restore normal knee kinematics better than symmetric design. A tri-condylar implant has asymmetric and symmetric tibial inserts with a ball-and-socket joint to replace the post-cam mechanism. The purpose of this study was to compare the knee kinematics of the two designs and to measure tibiofemoral contact stresses, including that of the ball-and-socket joint. METHODS: Using a computer simulation, the anteroposterior position and axial rotation of the femoral component were simulated during a weight-bearing deep knee bend for six validated models. Contact forces were simultaneously simulated in the medial, lateral, and ball-and-socket compartments. The relative position and the magnitude and direction of each contact force were applied to aforce/displacement control knee simulator. The contact stresses were measured individually using a pressure sensor. RESULTS: The asymmetric tibial insert demonstrated a more posterior position of the femoral component in the lateral compartment during the entire range of motion and greater external rotation of the femoral component, compared to the symmetrical tibial insert. The mean peak contact stress of the medial and lateral compartments was < 9 Mpa, with no significant differences between the two designs except at 0°. The contact stress of the ball-and-socket joint was < 5 MPa. CONCLUSIONS: Asymmetry of the tibial insert shows significant kinematic difference and has little influence on the peak contact stress, which is considerably lower than the yield strength of polyethylene. The asymmetric tibial insert can lead to clinical benefits owing to its kinematic and kinetic properties.

Systemic IL-27 administration prevents abscess formation and osteolysis via local neutrophil recruitment and activation.

Interleukin-27 is a pleiotropic cytokine whose functions during bacterial infections remain controversial, and its role in patients with S. aureus osteomyelitis is unknown. To address this knowledge gap, we completed a clinical study and observed elevated serum IL-27 levels (20-fold higher, P < 0.05) in patients compared with healthy controls. Remarkably, IL-27 serum levels were 60-fold higher in patients immediately following septic death than in uninfected patients (P < 0.05), suggesting a pathogenic role of IL-27. To test this hypothesis, we evaluated S. aureus osteomyelitis in WT and IL-27Rα-/- mice with and without exogenous IL-27 induction by intramuscular injection of rAAV-IL-27p28 or rAAV-GFP, respectively. We found that IL-27 was induced at the surgical site within 1 day of S. aureus infection of bone and was expressed by M0, M1 and M2 macrophages and osteoblasts but not by osteoclasts. Unexpectedly, exogenous IL-27p28 (~2 ng·mL-1 in serum) delivery ameliorated soft tissue abscesses and peri-implant bone loss during infection, accompanied by enhanced local IL-27 expression, significant accumulation of RORγt+ neutrophils at the infection site, a decrease in RANK+ cells, and compromised osteoclast formation. These effects were not observed in IL-27Rα-/- mice compared with WT mice, suggesting that IL-27 is dispensable for immunity but mediates redundant immune and bone cell functions during infection. In vitro studies and bulk RNA-seq of infected tibiae showed that IL-27 increased nos1, nos2, il17a, il17f, and rorc expression but did not directly stimulate chemotaxis. Collectively, these results identify a novel phenomenon of IL-27 expression by osteoblasts immediately following S. aureus infection of bone and suggest a protective role of systemic IL-27 in osteomyelitis.

Differential Contribution of the Medial and the Lateral Side of the Joint to Symptoms in Knee Osteoarthritis: A Radiographic and Laboratory Analysis in the Nagahama Study.

OBJECTIVE: This cross-sectional study aimed to explore the differences of the medial and lateral sides of the knee joint and precise radiographic abnormalities in contribution to the knee pain and clinical outcomes. DESIGN: Participants 60 years or older who underwent radiographic evaluation were included. Knee radiography was assessed using grading systems of the Osteoarthritis Research Society International (OARSI) atlas. The Japanese Knee Osteoarthritis Measure (JKOM) was evaluated as clinical outcomes. Serum high-sensitivity C-reactive protein (hsCRP) was used to evaluate systemic inflammation. We divided the participants into normal, medial-, lateral-, and medial & lateral-OA types and compared their JKOM using an analysis of covariance. Furthermore, we analyzed the relationship between the knee pain and stiffness of JKOM and the grading of each radiographic feature using a multiple regression model. RESULTS: Lateral- and medial & lateral-OA groups had a significantly worse symptoms in the total and the pain score, especially in movement subscales, in JKOM score. Lateral-OA groups had higher hsCRP than medial-OA group. Multivariate analysis showed that medial joint space narrowing (JSN), and lateral femoral and tibial osteophytes significantly affected knee pain (adjusted odds ratios: 1.73, 1.28, and 1.55, respectively). The radiographic changes are associated with pain more in JSN in the medial side and osteophytes in the lateral side. CONCLUSION: Lateral- and medial & lateral-OA groups showed worth symptom. In addition, medial JSN and lateral osteophytes have potent effects on the knee pain.

Development of Bisphosphonate-Conjugated Antibiotics to Overcome Pharmacodynamic Limitations of Local Therapy: Initial Results with Carbamate Linked Sitafloxacin and Tedizolid.

The use of local antibiotics to treat bone infections has been questioned due to a lack of clinical efficacy and emerging information about Staphylococcus aureus colonization of the osteocyte-lacuno canalicular network (OLCN). Here we propose bisphosphonate-conjugated antibiotics (BCA) using a "target and release" approach to deliver antibiotics to bone infection sites. A fluorescent bisphosphonate probe was used to demonstrate bone surface labeling adjacent to bacteria in a S. aureus infected mouse tibiae model. Bisphosphonate and hydroxybisphosphonate conjugates of sitafloxacin and tedizolid (BCA) were synthesized using hydroxyphenyl and aminophenyl carbamate linkers, respectively. The conjugates were adequately stable in serum. Their cytolytic activity versus parent drug on MSSA and MRSA static biofilms grown on hydroxyapatite discs was established by scanning electron microscopy. Sitafloxacin O-phenyl carbamate BCA was effective in eradicating static biofilm: no colony formation units (CFU) were recovered following treatment with 800 mg/L of either the bisphosphonate or α-hydroxybisphosphonate conjugated drug (p < 0.001). In contrast, the less labile tedizolid N-phenyl carbamate linked BCA had limited efficacy against MSSA, and MRSA. CFU were recovered from all tedizolid BCA treatments. These results demonstrate the feasibility of BCA eradication of S. aureus biofilm on OLCN bone surfaces and support in vivo drug development of a sitafloxacin BCA.

Interleukin-27 and Its Diverse Effects on Bacterial Infections.

Innate and adaptive immune responses against pathogens are known to be carefully orchestrated by specific cytokines that initiate and down regulate immune cell functions from the initial infection through tissue repair and homeostasis. However, some cytokines, including interleukin-27, are expressed at multiple phases of the infection, such that their pro and anti-inflammatory functions have been difficult to interpret. As elucidation of specific cytokine functions throughout infection is central to our understanding of protective vs. susceptible immunity and return to homeostasis vs. prolonged inflammation leading to septic shock, here we review the literature on IL-27 signaling and the various functions of this heterodimeric ligand member of the IL-12 cytokine family. Canonically, IL-27 is produced by antigen-presenting cells, and is thought of as an immunostimulatory cytokine due to its capacity to induce Th1 differentiation. However, many studies have also identified various immunosuppressive effects of IL-27 signaling, including suppression of Th17 differentiation and induction of co-inhibitory receptors on T cells. Thus, the exact role of IL-27 in the context of infectious diseases remains a topic of debate and active research. Additionally, as recent interest has focused on clinical management of acute vs. chronic infections, and life-threatening "cytokine storm" from sepsis, we propose a hypothetical model to explain the biphasic role of IL-27 during the early and late phases of immune responses to reconcile its known pro and anti-inflammatory functions, which could be therapeutically regulated to improve patient outcomes of infection.

Association between quantitative lower limb arterial calcification and bilateral severe knee osteoarthritis.

OBJECTIVES: To investigate whether lower limb arterial calcification (LLAC) quantified using computed tomography (CT) was a risk factor for bilateral severe knee osteoarthritis (OA). METHODS: This cross-sectional study included patients who were scheduled for surgical treatment of primary varus knee OA. Knee OA was evaluated using the Kellgren-Lawrence (KL) classification, KL grades 3 and 4 were defined as severe OA. The LLAC score in the bilateral whole leg CT was quantitatively measured and categorized into low or high groups based on the median value. A modified Poisson regression model was used to examine the relationship between the categorized LLAC score and the presence of bilateral severe knee OA with adjustment for possible confounders. RESULTS: Of a total of 252 patients examined, multivariable modified Poisson regression analysis showed a significant association between higher LLAC score and the presence of bilateral severe knee OA (adjusted risk ratio = 1.28; 95% confidence interval [CI], 1.12-1.48; p < .001). A substantial interaction was observed between male sex and high LLAC (p for interaction = .03). CONCLUSION: LLAC was associated with bilateral severe knee OA, and the LLAC score may be a useful measurement to identify patients at risk of bilateral severe knee OA.

Distinct vasculotropic versus osteotropic features of S. agalactiae versus S. aureus implant-associated bone infection in mice.

Osteomyelitis is a devastating complication of orthopaedic surgery and commonly caused by Staphylococcus aureus (S. aureus) and Group B Streptococcus (GBS, S. agalactiae). Clinically, S. aureus osteomyelitis is associated with local inflammation, abscesses, aggressive osteolysis, and septic implant loosening. In contrast, S. agalactiae orthopaedic infections generally involve soft tissue, with acute life-threatening vascular spread. While preclinical models that recapitulate the clinical features of S. aureus bone infection have proven useful for research, no animal models of S. agalactiae osteomyelitis exist. Here, we compared the pathology caused by these bacteria in an established murine model of implant-associated osteomyelitis. In vitro scanning electron microscopy and CFU quantification confirmed similar implant inocula for both pathogens (~105 CFU/pin). Assessment of mice at 14 days post-infection demonstrated increased S. aureus virulence, as S. agalactiae infected mice had significantly greater body weight, and fewer CFU on the implant and in bone and adjacent soft tissue (p < 0.05). X-ray, µCT, and histologic analyses showed that S. agalactiae induced significantly less osteolysis and implant loosening, and fewer large TRAP+ osteoclasts than S. aureus without inducing intraosseous abscess formation. Most notably, transmission electron microscopy revealed that although both bacteria are capable of digesting cortical bone, S. agalactiae have a predilection for colonizing blood vessels embedded within cortical bone while S. aureus primarily colonizes the osteocyte lacuno-canalicular network. This study establishes the first quantitative animal model of S. agalactiae osteomyelitis, and demonstrates a vasculotropic mode of S. agalactiae infection, in contrast to the osteotropic behavior of S. aureus osteomyelitis.