Inhibition of Methicillin-resistant Staphylococcus aureus-induced cytokines mRNA production in human bone marrow derived mesenchymal stem cells by 1,25-dihydroxyvitamin D3

Background Methicillin-resistant Staphylococcus aureus (MRSA) is the predominant cause of bone infection. Toll like receptors (TLRs) are an important segments of host response to infection and are expressed by a variety of cells including human mesenchymal stem cells (hMSCs). The active form of Vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) has potent immunoregulatory properties, but the mechanism remains poorly understood. The genomic action of 1,25(OH)2D3 is mediated by vitamin D receptor (VDR), hormone-regulated transcription factor. VDR interacts with co-activators and co-repressors are associated with chromatin histone modifications and transcriptional regulation. The aim of our study is to explore MRSA-induced TLRs-mediated pro-inflammatory cytokines expression in hMSCs. Further, we hypothesized that 1,25(OH)2D3 inhibits MRSA-induced cytokines synthesis in hMSCs via inhibition of NF-кB transcription factor. Finally, we explored the regulatory role of 1,25(OH)2D3 in MRSA-mediated global epigenetic histone H3 mark, such as, trimethylated histone H3 lysine 9 (H3K9me3), which is linked to gene silencing. Results Quantitative PCR data revealed that MRSA-infection predominantly induced expression of TLRs 1, 2, 6, NR4A2, and inflammatory cytokines IL-8, IL-6, TNFα in hMSCs. MRSA-mediated TLR ligands reduced osteoblast differentiation and increased hMSCs proliferation, indicating the disrupted multipotency function of hMSCs. Pretreatment of 1,25(OH)2D3 followed by MRSA co-culture inhibited nuclear translocation of NF-кB-p65, reduced expression of NR4A2 and pro-inflammatory cytokines IL-8, IL-6, and TNFα in hMSCs. Further, NF-κB-p65, VDR, and NR4A2 were present in the same nuclear protein complex, indicating that VDR is an active part of the nuclear protein complexes for transcriptional regulation. Finally, 1,25(OH)2D3 activated VDR, restores the global level of H3K9me3, to repress MRSA-stimulated inflammatory cytokine IL-8 expression. Pretreatment of 5-dAZA, DNA methylatransferases (Dnmts) inhibitor, dramatically re-expresses 1,25(OH)2D3-MRSA-mediated silenced IL-8 gene. Conclusions This data indicates that TLR 1, 2, and 6 can be used as markers for localized S. aureus bone infection. 1,25(OH)2D3-VDR may exhibits its anti-inflammatory properties in MRSA-stimulated infection by inhibiting nuclear translocation of NF-kB-p65 and transcripts of IL-8, IL-6, TNFα, and NR4A2 in hMSCs. Finally, 1,25(OH)2D3-activated VDR, acting as an epigenetic regulator, inhibits synthesis of cytokines in MRSA-stimulated infection by restoring the global level of H3K9me3, a histone H3 mark for gene silencing

Midterm Follow Up For Knee Replacement: How Well Do We Follow Our Patients?

The lost to follow up rate specifically for five year post surgical UKAs is significantly higher for this population subset than the most recent published average as seen in a meta analysis review (Callahan et al. 1995). Follow up visits allow for proper assessment of complications such as wear and osteolysis which need early intervention to improve long-term outcomes and reduce the overall cost of care (Bhandari et al. 2012). Eleven patients, 27.5% of those that were lost to follow up, were without a correct or working phone number, which presents a significant barrier to care. Maintaining updated patient contact information and educating patients about the importance of intermittent follow up may aid in compliance. Further research is required to better characterize patients with poor follow up rates so that systematic surveillance methods can be developed to improve the quality of care

Retrospective Review of Intra-Articular Hip Steroid Injections and Their Association with Rapidly-Progressive Osteoarthritis

Based on strict inclusion criteria, 109 patients were eligible for analysis in this study. Of these patients, 23 developed RPOA—representing an incidence of 21%. The characteristics of patients who went on to develop RPOA in this study were: worse initial Kellgren-Lawrence grade and older age. Future studies of larger sample size that also include outcomes of patients who did not receive intra-articular injections will be needed to establish a causal relationship between these injections and RPOA

Implementation of patient-reported outcome measures in U.S. Total joint replacement registries: rationale, status, and plans

BACKGROUND: In the U.S. and abroad, the use of patient-reported outcome measures to evaluate the impact of total joint replacement surgery on patient quality of life is increasingly common. Analyses of patient-reported outcomes have documented substantial pain relief and functional gain among the vast majority of patients managed with total joint replacement. In addition, postoperative patient-reported outcomes are useful to identify persistent pain and suboptimal outcomes in the minority of patients who have them. The leaders of five U.S. total joint replacement registries report the rationale, current status, and vision for the use of patient-reported outcome measures in U.S. total joint replacement registries. METHODS: Surgeon leaders of the Function and Outcomes Research for Comparative Effectiveness in Total Joint Replacement registry, American Joint Replacement Registry, California Joint Replacement Registry, Michigan Arthroplasty Registry Collaborative Quality Initiative, and Virginia Joint Registry report the rationale supporting the adoption of patient-reported outcome measures, factors associated with the selection and successful implementation of patient-reported outcome measures, and barriers to complete and valid data. RESULTS: U.S. registries are at varied stages of implementation of preoperative surveys and postoperative total joint replacement outcome measures. Surgeon leaders report unified rationales for adopting patient-reported outcome measures: to capture data on pain relief and functional gain following total joint replacement as well as to identify suboptimal implant performance. Key considerations in the selection of a patient-reported outcome measure include its ability to measure both joint pain and physical function while limiting any burden on patients and surgeons related to its use. Complete patient-reported outcomes data will be associated with varied modes of survey completion, including options for home-based completion, to ensure consistent timing and data capture. CONCLUSIONS: The current stage of implementation of patient-reported outcome measures varies widely among U.S. registries. Nonetheless, evidence from the Function and Outcomes Research for Comparative Effectiveness in Total Joint Replacement registry supports the feasibility of successful implementation of patient-reported outcome measures with careful attention to the selection of the outcome measure, mode and timing of postoperative administration, and minimization of any burden on the patient and surgeon

Deep learning-based algorithm for assessment of knee osteoarthritis severity in radiographs matches performance of radiologists

A fully-automated deep learning algorithm matched performance of radiologists in assessment of knee osteoarthritis severity in radiographs using the Kellgren-Lawrence grading system. To develop an automated deep learning-based algorithm that jointly uses Posterior-Anterior (PA) and Lateral (LAT) views of knee radiographs to assess knee osteoarthritis severity according to the Kellgren-Lawrence grading system. We used a dataset of 9739 exams from 2802 patients from Multicenter Osteoarthritis Study (MOST). The dataset was divided into a training set of 2040 patients, a validation set of 259 patients and a test set of 503 patients. A novel deep learning-based method was utilized for assessment of knee OA in two steps: (1) localization of knee joints in the images, (2) classification according to the KL grading system. Our method used both PA and LAT views as the input to the model. The scores generated by the algorithm were compared to the grades provided in the MOST dataset for the entire test set as well as grades provided by 5 radiologists at our institution for a subset of the test set. The model obtained a multi-class accuracy of 71.90% on the entire test set when compared to the ratings provided in the MOST dataset. The quadratic weighted Kappa coefficient for this set was 0.9066. The average quadratic weighted Kappa between all pairs of radiologists from our institution who took a part of study was 0.748. The average quadratic-weighted Kappa between the algorithm and the radiologists at our institution was 0.769. The proposed model performed demonstrated equivalency of KL classification to MSK radiologists, but clearly superior reproducibility. Our model also agreed with radiologists at our institution to the same extent as the radiologists with each other. The algorithm could be used to provide reproducible assessment of knee osteoarthritis severity

Automated Grading of Radiographic Knee Osteoarthritis Severity Combined with Joint Space Narrowing

The assessment of knee osteoarthritis (KOA) severity on knee X-rays is a central criteria for the use of total knee arthroplasty. However, this assessment suffers from imprecise standards and a remarkably high inter-reader variability. An algorithmic, automated assessment of KOA severity could improve overall outcomes of knee replacement procedures by increasing the appropriateness of its use. We propose a novel deep learning-based five-step algorithm to automatically grade KOA from posterior-anterior (PA) views of radiographs: (1) image preprocessing (2) localization of knees joints in the image using the YOLO v3-Tiny model, (3) initial assessment of the severity of osteoarthritis using a convolutional neural network-based classifier, (4) segmentation of the joints and calculation of the joint space narrowing (JSN), and (5), a combination of the JSN and the initial assessment to determine a final Kellgren-Lawrence (KL) score. Furthermore, by displaying the segmentation masks used to make the assessment, our algorithm demonstrates a higher degree of transparency compared to typical "black box" deep learning classifiers. We perform a comprehensive evaluation using two public datasets and one dataset from our institution, and show that our algorithm reaches state-of-the art performance. Moreover, we also collected ratings from multiple radiologists at our institution and showed that our algorithm performs at the radiologist level. The software has been made publicly available at https://github.com/MaciejMazurowski/osteoarthritis-classification

Effect of Sustained Gene Delivery of Platelet‐Derived Growth Factor or Its Antagonist (PDGF‐1308) on Tissue‐Engineered Cementum

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141209/1/jper0429.pd

Do Fixed or Mobile Bearing Implants Have Better Survivorship in Medial Unicompartmental Knee Arthroplasty? A Study From the Australian Orthopaedic Association National Joint Replacement Registry

BACKGROUND: During the last 5 years, there has been an increase in the use of unicompartmental knee arthroplasty (UKA) to treat knee osteoarthritis in Australia, and these account for almost 6% of annual knee replacement procedures. However, there is debate as to whether a fixed bearing or a mobile bearing design is best for decreasing revision for loosening and disease progression as well as improving survivorship. Small sample sizes and possible confounding in the studies on the topic may have masked differences between fixed and mobile bearing designs. QUESTIONS/PURPOSES: Using data from the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR), we selected the four contemporary designs of medial compartment UKA: mobile bearing, fixed modular, all-polyethylene, and fixed molded metal-backed used for the treatment of osteoarthritis to ask: (1) How do the different designs of unicompartmental knees compare with survivorship as measured by cumulative percentage revision (CPR)? (2) Is there a difference in the revision rate between designs as a function of patient sex or age? (3) Do the reasons for revision differ, and what types of revision procedures are performed when these UKA are revised? METHODS: The AOANJRR longitudinally maintains data on all primary and revision joint arthroplasties, with nearly 100% capture. The study population included all UKA procedures undertaken for osteoarthritis between September 1999 and December 2018. Of 56,628 unicompartmental knees recorded during the study period, 50,380 medial UKA procedures undertaken for osteoarthritis were included in the analysis after exclusion of procedures with unknown bearing types (31 of 56,628), lateral or patellofemoral compartment UKA procedures (5657 of 56,628), and those performed for a primary diagnosis other than osteoarthritis (560 of 56,628). There were 50,380 UKA procedures available for analysis. The study group consisted of 40% (20,208 of 50,380) mobile bearing UKA, 35% (17,822 of 50,380) fixed modular UKA, 23% (11,461 of 50,380) all-polyethylene UKA, and 2% (889 of 50,380) fixed molded metal-backed UKA. There were similar sex proportions and age distributions for each bearing group. The overall mean age of patients was 65 ± 9.4 years, and 55% (27,496 of 50,380) of patients were males. The outcome measure was the CPR, which was defined using Kaplan-Meier estimates of survivorship to describe the time to the first revision. Hazard ratios from Cox proportional hazards models, adjusted for sex and age, were performed to compare the revision rates among groups. The cohort was stratified into age groups of younger than 65 years and 65 years and older to compare revision rates as a function of age. Differences among bearing groups for the major causes and modes of revision were assessed using hazard ratios. RESULTS: At 15 years, fixed modular UKA had a CPR of 16% (95% CI 15% to 17%). In comparison, the CPR was 23% (95% CI 22% to 24%) for mobile bearing UKA, 26% (95% CI 24% to 27%) for all-polyethylene UKA, and 20% (95% CI 16% to 24%) for fixed molded metal-backed UKA. The lower revision rate for fixed modular UKA was seen through the entire period compared with mobile bearing UKA (hazard ratio 1.5 [95% CI 1.4 to 1.6]; p < 0.001) and fixed molded metal-backed UKA (HR 1.3 [95% CI 1.1 to 1.6]; p = 0.003), but it varied with time compared with all-polyethylene UKA. The findings were consistent when stratified by sex or age. Although all-polyethylene UKA had the highest revision rate overall and for patients younger than 65 years, for patients aged 65 years and older, there was no difference between all-polyethylene and mobile bearing UKA. When compared with fixed modular UKA, a higher revision risk for loosening was shown in both mobile bearing UKA (HR 1.7 [95% CI 1.5 to 1.9]; p < 0.001) and all-polyethylene UKA (HR 2.4 [95% CI 2.1 to 2.7]; p < 0.001). The revision risk for disease progression was higher for all-polyethylene UKA at all time points (HR 1.4 [95% CI 1.3 to 1.6]; p < 0.001) and for mobile bearing UKA after 8 years when each were compared with fixed modular UKA (8 to 12 years: HR 1.4 [95% CI 1.2 to 1.7]; p < 0.001; 12 or more years: HR 1.9 [95% CI 1.5 to 2.3]; p < 0.001). The risk of revision to TKA was higher for mobile bearing UKA compared with fixed modular UKA (HR 1.4 [95% CI 1.3 to 1.5]; p < 0.001). CONCLUSION: If UKA is to be considered for the treatment of isolated medial compartment osteoarthritis, the fixed modular UKA bearing has the best survivorship of the current UKA designs. LEVEL OF EVIDENCE: Level III, therapeutic study