Association of thyroid hormone with osteoarthritis: from mendelian randomization and RNA sequencing analysis.

BACKGROUND: The relationship between thyroid hormone (TH) levels in vivo and osteoarthritis (OA) remains inconclusive. This study aims to investigate the association between TH levels and OA, analyze the effect of triiodothyronine on hypertrophic chondrocyte differentiation and OA progression, and identify potential target genes of triiodothyronine in OA to evaluate its diagnostic value. METHODS: Two-sample mendelian randomization method was used to probe the causal links between hyperthyroidism and OA. Differentially expressed genes (DEGs) from two RNA-sequencing data in Gene Expression Omnibus (GSE199847 and GSE114007) and enrichment analysis of DEGs (166 commonly upregulated genes and 71 commonly downregulated genes of GSE199847 and GSE114007) was performed to analyze the effect of triiodothyronine (T3) on hypertrophic chondrocyte differentiation and OA. C28/I2 cells treated with T3 and reverse transcription and quantitative real-time polymerase chain reaction were used to validate T3 targeted genes. The diagnostic performance of target genes was assessed by the receiver operating characteristic (ROC) curve and area under the curve (AUC). RESULTS: There was a positive causal association between hyperthyroidism and OA (IVW result, OR = 1.330, 95% CI 1.136-1.557, P = 0.0004). Weighted median and Weighted mode analysis also demonstrated that hyperthyroidism had a positive causal association with OA (p < 0.05, OR > 1). Bioinformatics analysis indicated T3 can partially induce the emergence of late hypertrophic chondrocyte and promote OA through extracellular matrix organization, blood vessel development, skeletal system development and ossification. Post-T3 treatment, MAFB, C1QTNF1, COL3A1 and ANGPTL2 were significantly elevated in C28/I2 cells. ROC curves in GSE114007 showed that AUC of all above genes were ≥ 0.7. CONCLUSIONS: This study identified that hyperthyroidism has a positive causal association with OA by MR analysis. T3 induced hypertrophic chondrocytes promote OA progression by upregulating genes such as MAFB, C1QTNF1, COL3A1 and ANGPTL2, which can also serve as OA diagnosis.

Association of peripheral inflammatory indicators with osteoarthritis risk.

Objectives: Numerous studies have established the role of inflammation in osteoarthritis (OA) progression, yet limited research explores the association between systemic inflammatory indicators and pre-diagnosis OA risk. This study aimed to investigate the association between peripheral inflammatory indicators and the risk of OA using data from the UK Biobank. Methods: The study analyzed data from 417,507 participants in the UK Biobank, including neutrophil count, lymphocyte count, monocyte count, platelet count, and C-reactive protein meter. Additionally, derived ratios such as NLR(neutrophils-lymphocytes ratio), PLR(Platelets-lymphocytes ratio), SII(systemic immune-inflammation index), and LMR (lymphocytes-monocytes ratio) were examined. Cox proportional hazards models and restricted cubic spline models were used to assess both linear and nonlinear associations. Results: Over a mean follow-up period of 12.7 years, a total of 49,509 OA events were identified. The findings revealed that CRP (HR:1.06, 95%CI:1.05-1.07), NLR (HR:1.02, 95%CI:1.01-1.03), PLR (HR:1.02, 95%CI:1.01-1.03), and SII (HR:1.03, 95%CI:1.01-1.04) were associated with an increased risk of OA, while LMR (HR:0.97, 95%CI:0.96-0.99) showed a significant negative correlation with OA risk. Subgroup analyses further emphasized that these associations were significant across most of the population. Although neutrophils, lymphocytes, monocytes, and platelets showed a nominal association with the risk of OA, the results were unreliable, especially for specific joint OA. Conclusion: The study provides evidence of a significant association between elevated peripheral inflammatory indicators and OA risk. These findings underscore the importance of low-grade chronic inflammation in OA development. The potential clinical utility of these indicators as early predictors of OA is suggested, warranting further exploration.

Association of coffee and tea consumption with osteoporosis risk: A prospective study from the UK biobank.

OBJECTIVE: The association of coffee and tea consumption with osteoporosis is highly controversial, and few studies have focused on the combined effects of the two beverages. This study aimed to investigate the independent and combined associations of coffee and tea consumption with osteoporosis risk. METHODS: A prospective cohort study involving 487,594 participants aged 38-73 years from the UK Biobank was conducted. Participants with reported coffee and tea consumption and without osteoporosis at baseline were included. Coffee and tea consumption were assessed via a touch-screen questionnaire at baseline. Newly diagnosed osteoporosis during the follow-up period, defined based on ICD-10 codes (M80-M82), was the primary outcome. Cox regression analyses were utilized to calculate hazard ratios (HRs) and 95 % confidence intervals (CIs). Dose-effect associations were assessed using restricted cubic spline analysis. RESULTS: During a median follow-up of 12.8 years, 15,211 cases of osteoporosis were identified. Compared to individuals without coffee or tea consumption, drinking coffee was associated with an HR of 0.93 (95 % CI: 0.89-0.96), and tea consumption with an HR of 0.86 (95 % CI: 0.83-0.90). Continuous trends were significant for both coffee and tea consumption, showing non-linear associations with osteoporosis incidence. Moderate consumption, such as 1-2 cups of coffee or 3-4 cups of tea per day, was associated with a lower incidence of osteoporosis, with HRs of 0.9 (95 % CI: 0.86-0.94) and 0.85 (95 % CI: 0.81-0.90), respectively. Additionally, combined coffee and tea consumption displayed a U-shaped association with osteoporosis risk, with the lowest risk observed in individuals who consumed 1-2 cups of both beverages daily, with an HR of 0.68 (95 % CI: 0.61-0.75). CONCLUSION: Our findings highlight the potential benefits of moderate coffee and tea consumption in reducing the risk of osteoporosis.

A machine learning-based model for "In-time" prediction of periprosthetic joint infection.

Background: Previous criteria had limited value in early diagnosis of periprosthetic joint infection (PJI). Here, we constructed a novel machine learning (ML)-derived, "in-time" diagnostic system for PJI and proved its validity. Methods: We filtered "in-time" diagnostic indicators reported in the literature based on our continuous retrospective cohort of PJI and aseptic prosthetic loosening patients. With the indicators, we developed a two-level ML model with six base learners including Elastic Net, Linear Support Vector Machine, Kernel Support Vector Machine, Extra Trees, Light Gradient Boosting Machine and Multilayer Perceptron), and one meta-learner, Ensemble Learning of Weighted Voting. The prediction performance of this model was compared with those of previous diagnostic criteria (International Consensus Meeting in 2018 (ICM 2018), etc.). Another prospective cohort was used for internal validation. Based on our ML model, a user-friendly web tool was developed for swift PJI diagnosis in clinical practice. Results: A total of 254 patients (199 for development and 55 for validation cohort) were included in this study with 38.2% of them diagnosed as PJI. We included 21 widely accessible features including imaging indicators (X-ray and CT) in the model. The sensitivity and accuracy of our ML model were significantly higher than ICM 2018 in development cohort (90.6% vs. 76.1%, P = 0.032; 94.5% vs. 86.7%, P = 0.020), which was supported by internal validation cohort (84.2% vs. 78.6%; 94.6% vs. 81.8%). Conclusions: Our novel ML-derived PJI "in-time" diagnostic system demonstrated significantly improved diagnostic potency for surgical decision-making compared with the commonly used criteria. Moreover, our web-based tool greatly assisted surgeons in distinguishing PJI patients comprehensively. Level of evidence: Diagnostic Level III.

Deconvolution of synovial myeloid cell subsets across pathotypes and role of COL3A1+ macrophages in rheumatoid arthritis remission.

Background: Monocyte/macrophage (Mo/Mp) is a critical cell population involved in immune modulation of rheumatoid synovitis (RA) across different pathotypes. This study aims to investigate the contribution of Mo/Mp clusters to RA activity, and the biological function of particular subtypes in RA remission. Methods: We integrated single-cell RNA sequencing datasets from 4 published and 1 in-house studies using Liger selected by comparison. We estimated the abundance of Mo/Mp subtypes in bulk RNA-seq data from the 81 patients of the Pathobiology of Early Arthritis Cohort (PEAC) using deconvolution analysis. Correlations between Mo/Mp subtypes and RA clinical metrics were assessed. A particular cell type was identified using multicolor immunofluorescence and flow cytometry in vivo and successfully induced from a cell line in vitro. Potential immune modulation function of it was performed using immunohistochemical staining, adhesion assay, and RT-qPCR. Results: We identified 8 Mo/Mp clusters. As a particular subtype among them, COL3A1+ Mp (CD68+, COL3A1+, ACTA2-) enriched in myeloid pathotype and negatively correlated with RA severity metrics in all pathotypes. Flow cytometry and multicolor immunofluorescence evidenced the enrichment and M2-like phenotype of COL3A1+ Mp in the myeloid pathotype. Further assays suggested that COL3A1+ Mp potentially attenuates RA severity via expressing anti-inflammatory cytokines, enhancing Mp adhesion, and forming a physical barrier at the synovial lining. Conclusion: This study reported unexplored associations between different pathologies and myeloid cell subtypes. We also identified a fibroblast-and-M2-like cluster named COL3A1+ Mp, which potentially contributes to synovial immune homeostasis. Targeting the development of COL3A1+ Mp may hold promise for inducing RA remission.

Metabolic syndrome increases osteoarthritis risk: findings from the UK Biobank prospective cohort study.

OBJECTIVE: The association between Metabolic Syndrome (MetS), its components, and the risk of osteoarthritis (OA) has been a topic of conflicting evidence in different studies. The aim of this present study is to investigate the association between MetS, its components, and the risk of OA using data from the UK Biobank. METHODS: A prospective cohort study was conducted in the UK Biobank to assess the risk of osteoarthritis (OA) related to MetS. MetS was defined according to the criteria set by the International Diabetes Federation (IDF). Additionally, lifestyle factors, medications, and the inflammatory marker C-reactive protein (CRP) were included in the model. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI). The cumulative risk of OA was analyzed using Kaplan-Meier curves and log-rank tests. To explore potential nonlinear associations between MetS components and OA risk, a restricted cubic splines (RCS) model was employed. In addition, the polygenic risk score (PRS) of OA was calculated to characterize individual genetic risk. RESULTS: A total of 45,581 cases of OA were identified among 370,311 participants, with a median follow-up time of 12.48 years. The study found that individuals with MetS had a 15% higher risk of developing OA (HR = 1.15, 95%CI:1.12-1.19). Additionally, central obesity was associated with a 58% increased risk of OA (HR = 1.58, 95%CI:1.5-1.66), while hyperglycemia was linked to a 13% higher risk (HR = 1.13, 95%CI:1.1-1.15). Dyslipidemia, specifically in triglycerides (HR = 1.07, 95%CI:1.05-1.09) and high-density lipoprotein (HR = 1.05, 95%CI:1.02-1.07), was also found to be slightly associated with OA risk. When stratified by PRS, those in the high PRS group had a significantly higher risk of OA compared to those with a low PRS, whereas no interaction was found between MetS and PRS on OA risks. Furthermore, the presence of MetS significantly increased the risk of OA by up to 35% in individuals with elevated CRP levels (HR = 1.35, 95% CI:1.3-1.4). CONCLUSION: MetS and its components have been found to be associated with an increased risk of OA, particularly in individuals with elevated levels of CRP. These findings highlight the significance of managing MetS as a preventive and intervention measure for OA.

Application of the New Irrigation Protocol to Reduce Recurrence Rate in the Management Of Periprosthetic Joint Infection.

OBJECTIVE: Irrigation is a conventional treatment for acute and chronic periprosthetic joint infections (PJI). However, there has been no unified standard for irrigation during surgery for PJI in the past, and the efficacy is uncertain. The purpose of this study is to create a new irrigation protocol to enhance the infection control rate and reduce the postoperative recurrence rate of PJI patients. METHODS: We conducted a single-institution retrospective review with a total of 56 patients who underwent revision total hip or knee arthroplasties due to PJI from January 2011 to January 2022. Conventional irrigation (CI) was used in 32 cases, and standard operating procedure of irrigation (SOPI) was used in 24. The CI protocol carries out an empirical irrigation after debridement, which is quite random. Our SOPI protocol clearly stipulates the soaking concentration and time of hydrogen peroxide and povidone-iodine. The irrigation is carried out three times, and tissue samples are taken from multiple parts before and after irrigation, which are sent for microbial culture. The important statistical indicators were the rate of positive microbiological culture and postoperative recurrence rate with an average follow-up of 24 average months. RESULTS: The drainage volume was lower in the SOPI group than in the CI group on postoperative day 3 (p < 0.01) and 7 (p = 0.016). In addition, the percentage of positive microbiological cultures after the third irrigation was less than that before (p < 0.01) and after (p < 0.01) the first irrigation. The most common causative organism was Staphylococcus aureus, which was detected in 25.0% and 12.5% of the SOPI and CI groups, respectively. The failure rate at the final follow-up was 8.3% and 31.3% (p = 0.039) for the SOPI and CI groups, respectively. CONCLUSION: Compared with the traditional CI method, SOPI standardized the soaking time of hydrogen peroxide and povidone-iodine, increased the frequency of and irrigation, and proved that microorganisms were almost completely removed through the microbial culture of multiple tissues. SOPI has the potential to become a standardized irrigation process worthy of promotion, effectively reducing the postoperative recurrence rate of PJI patients.

Integrative group psychotherapy for patients with somatic symptom disorder: A randomized controlled trial.

The study aimed to determine whether specific integrative group psychotherapy (IGPT), based on CBT, combined with techniques of psychodynamic therapy and mindful body and emotional awareness is more effective than non-specific supportive group psychotherapy (SGPT) and treatment as usual (TAU) alone. A total of 120 SSD patients were randomly assigned to IGPT, SGPT or TAU groups. Both IGPT and SGPT showed significantly lower SSD-12 scores at the 4, 8, and 12-week follow-ups compared to TAU. No significant differences were observed between IGPT and SGPT at any follow-up point. These findings highlight the potential benefits of group psychotherapy in SSD treatment.

Identification of potential diagnostic biomarkers for tenosynovial giant cell tumour by integrating microarray and single-cell RNA sequencing data.

PURPOSE: Tenosynovial giant cell tumour (TGCT) is a benign hyperplastic and inflammatory disease of the joint synovium or tendon sheaths, which may be misdiagnosed due to its atypical symptoms and imaging features. We aimed to identify biomarkers with high sensitivity and specificity to aid in diagnosing TGCT. METHODS: Two scRNA-seq datasets (GSE210750 and GSE152805) and two microarray datasets (GSE3698 and GSE175626) were downloaded from the Gene Expression Omnibus (GEO) database. By integrating the scRNA-seq datasets, we discovered that the osteoclasts are abundant in TGCT in contrast to the control. The single-sample gene set enrichment analysis (ssGSEA) further validated this discovery. Differentially expressed genes (DEGs) of the GSE3698 dataset were screened and the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of DEGs were conducted. Osteoclast-specific up-regulated genes (OCSURGs) were identified by intersecting the osteoclast marker genes in the scRNA-seq and the up-regulated DEGs in the microarray and by the least absolute shrinkage and selection operator (LASSO) regression algorithm. The expression levels of OCSURGs were validated by an external dataset GSE175626. Then, single gene GSEA, protein-protein interaction (PPI) network, and gene-drug network of OCSURGs were performed. RESULT: 22 seurat clusters were acquired and annotated into 10 cell types based on the scRNA-seq data. TGCT had a larger population of osteoclasts compared to the control. A total of 159 osteoclast marker genes and 104 DEGs (including 61 up-regulated genes and 43 down-regulated genes) were screened from the scRNA-seq analysis and the microarray analysis. Three OCSURGs (MMP9, SPP1, and TYROBP) were finally identified. The AUC of the ROC curve in the training and testing datasets suggested a favourable diagnostic capability. The PPI network results illustrated the protein-protein interaction of each OCSURG. Drugs that potentially target the OCSURGs were predicted by the DGIdb database. CONCLUSION: MMP9, SPP1, and TYROBP were identified as osteoclast-specific up-regulated genes of the tenosynovial giant cell tumour via bioinformatic analysis, which had a reasonable diagnostic efficiency and served as potential drug targets.

Identification of anterior cruciate ligament fibroblasts and their contribution to knee osteoarthritis progression using single-cell analyses.

The mechanical properties of the anterior cruciate ligament (ACL) in the knee have been highlighted, but its role in the regulation of the joint microenvironment remains unclear, especially in the progression of Knee Osteoarthritis (KOA). Here, single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) data were integrated to reveal the transcriptional and epigenomic landscape of ACL in normal and OA states. We identified a novel subpopulation of fibroblasts in ACL, which provides new insights into the role of the ACL in knee homeostasis and disease. Degeneration of the ACL during OA mechanically alters the knee joint homeostasis and influences the microenvironment by regulating inflammatory- and osteogenic-related factors, thereby contributing to the progression of KOA. Additionally, the specific mechanism by which these Inflammation-associated Fibroblasts (IAFs) regulate KOA progression was uncovered, providing new foundation for the development of targeted treatments for KOA.

Macrophage-derived exosomes modulate wear particle-induced osteolysis via miR-3470b targeting TAB3/NF-κB signaling.

Aseptic prosthesis loosening (APL) is one of the most prevalent complications associated with arthroplasty. The main cause is the periprosthetic osteolysis induced by wear particles. However, the specific mechanisms of crosstalk between immune cells and osteoclasts/osteoblasts during osteolysis are unclear. In this study, we report the role and mechanism of macrophage-derived exosomes in wear particle-induced osteolysis. The results of exosomes up-taken experiments revealed that osteoblast and mature osteoclasts capture macrophage-derived exosomes (M-Exo). Next-generation sequencing and RT-qPCR on M-Exo revealed that exosomal microRNA miR-3470b was downregulated in wear particle-induced osteolysis. The results of analysis on Luciferase reporter assays/fluorescence in situ hybridization (FISH)/immunofluorescence (IF)/immunohistochemistry (IHC) and co-culture experiments demonstrated that wear particles induced osteoclast differentiation by increasing the expression of NFatc1 via M-Exo miR-3470b targeting TAB3/ NF-κB signaling. We also illustrate that engineered exosomes enriching miR-3470b facilitated to suppressed the osteolysis; the microenvironment enriching with miR-3470b could suppress wear particle-induced osteolysis via inhibition of TAB3/ NF-κB in vivo. In summary, our findings indicate that macrophage-derived exosomes transfer to osteoclasts to induce osteolysis in wear particle-induced APL. Engineering exosomes enriching with miR-3470b might be a novel strategy for the targeting treatment of bone resorption-related diseases.

Machine learning research based on diffusion tensor images to distinguish between anorexia nervosa and bulimia nervosa.

Background: Anorexia nervosa (AN) and bulimia nervosa (BN), two subtypes of eating disorders, often present diagnostic challenges due to their overlapping symptoms. Machine learning has proven its capacity to improve group classification without requiring researchers to specify variables. The study aimed to distinguish between AN and BN using machine learning models based on diffusion tensor images (DTI). Methods: This is a cross-sectional study, drug-naive females diagnosed with anorexia nervosa (AN) and bulimia nervosa (BN) were included. Demographic data and DTI were collected for all patients. Features for machine learning included Fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD). Support vector machine was constructed by LIBSVM, MATLAB2013b, and FSL5.0.9 software. Results: A total of 58 female patients (24 AN, 34 BN) were included in this study. Statistical analysis revealed no significant differences in age, years of education, or course of illness between the two groups. AN patients had significantly lower BMI than BN patients. The AD model exhibited an area under the curve was 0.793 (accuracy: 75.86%, sensitivity: 66.67%, specificity: 88.23%), highlighting the left middle temporal gyrus (MTG_L) and the left superior temporal gyrus (STG_L) as differentiating brain regions. AN patients exhibited lower AD features in the STG_L and MTG_L than BN. Machine learning analysis indicated no significant differences in FA, MD, and RD values between AN and BN groups (p > 0.001). Conclusion: Machine learning based on DTI could effectively distinguish between AN and BN, with MTG_L and STG_L potentially serving as neuroimaging biomarkers.

A multicenter study of bodily distress syndrome in Chinese outpatient hospital care: prevalence and associations with psychosocial variables.

BACKGROUND: Bodily distress syndrome (BDS) is a new, empirical-based diagnosis of functional somatic symptoms. This study aimed to explore the prevalence of BDS and its association with psychosocial variables in a Chinese clinical population. METHODS: A multicentre cross-sectional study of 1269 patients was conducted in 9 different Chinese tertiary outpatient hospitals. The BDS was identified by trained interviewers face-to face, based on a brief version of the Schedules for Assessment in Neuropsychiatry (RIFD) and the BDS Checklist-25. Sociodemographic data and further information were characterised from psychometric questionnaires (The Patient Health Questionnaire-15, the Patient Health Questionnaire-9, the General Anxiety Disorder-7, the Whiteley scale-8) . RESULTS: Complete data were available for 697 patients. The prevalence of BDS was 26.8% (95% confidence interval (CI): 23.5-30.1). Among the participants, 5.8% (95% CI: 4.1-7.6) fulfilled the criteria for single-organ BDS, while 20.9% (95%CI: 17.9-24.0) had multi-organ BDS. Comparison of the PHQ-15, PHQ-9, GAD-7, and WI-8 scores revealed higher scores on all dimensions for patients with BDS. In a binary logistic regression analysis, BDS was significantly associated with increased health-related anxiety (WI-8) and depression (PHQ-9). The explained variance was Nagelkerke's R2 = 0.42. CONCLUSIONS: In China, the BDS is a common clinical condition in tertiary outpatient hospital settings with high prevalence, and is associated with health anxiety and depressive symptoms. In this clinical population, the severe multi-organ subtype of BDS was the most frequent.

Efficacy and Safety of Iclaprim for the Treatment of Skin Structures and Soft Tissue Infections: A Methodological Framework.

Background: Skin and soft tissue infections (SSTIs) are among the most common infections worldwide. They manifest in a variety of forms, such as erysipelas, cellulitis, and necrotizing fasciitis. Antibiotics are the significant method for clinical treatment of SSTIs. This study reported a methodology framework to determine the efficacy and safety of iclaprim in treatment of SSTIs. Methods: We will search the PubMed, EMbase, CNKI, WanFang Data, VIP, and ClinicalTrials.gov from their inception to June 2022 for randomized controlled trials and cohort studies on iclaprim with SSTIs. Two authors will independently screen the eligible studies, assess the quality of the included papers, and extract the required information. Randomized controlled trials will be assessed using the Cochrane risk-of-bias tool. The Newcastle-Ottawa Scale will be used to evaluate observational studies. The quality of the evidence will be evaluated using the Grading of Recommendations Assessment Development and Evaluation system. RevMan 5.3 will be used for the data synthesis and quantitative analysis. Results and Discussions: This study will provide the clinicians with more high-quality evidence to choose iclaprim for patients with SSTIs. Ethics and Dissemination: This systematic review and meta-analysis will be based on published data, so ethical approval is not necessary. The results of this meta-analysis will be published in a peer-reviewed journal.

Limited value of serum neutrophil-to-lymphocyte ratio in the diagnosis of chronic periprosthetic joint infection.

BACKGROUND: Diagnosing chronic periprosthetic joint infection (PJI) is challenging. No single biomarker can accurately recognize PJI preoperatively in a timely manner. Therefore, the aim of the present study was to investigate the usefulness of the serum neutrophil-to-lymphocyte ratio (NLR) in aiding the diagnosis of chronic PJI. MATERIALS AND METHODS: We retrospectively evaluated the medical records of 158 patients who had undergone revision arthroplasty (104 with aseptic mechanic failure and 54 with chronic PJI) from July 2011 to July 2020. Univariate analysis followed by multivariate logistic regression was applied to compare NLR, C-reactive protein (CRP), and erythrocyte sedimentation ratio (ESR) between the two groups. The receiver operating characteristic (ROC) curve was used to assess the diagnostic performance of NLR alone and in combination with CRP and ESR. RESULTS: NLR, CRP, and ESR were significantly higher in patients with chronic PJI than in the aseptic revision group (p < 0.05). ROC curve analysis revealed that NLR had a sensitivity of 57.41% and a specificity of 77.88% with an optimal threshold of 2.56. The optimal threshold for CRP and ESR was 7.00 mg/L (sensitivity 62.50% and specificity 83.12%) and 43 mm/h (sensitivity 59.38% and specificity 80.52%), respectively. The combined diagnostic value of NLR with CRP and ESR was shown to have no additional diagnostic value in predicting chronic PJI. CONCLUSION: Compared with traditional inflammatory biomarkers (ESR and CRP), the value of serum NLR alone or combined with CRP and ESR for diagnosing chronic PJI is limited. LEVEL OF EVIDENCE: Level 3.

Autophagy inhibitors 3-MA and LY294002 repress osteoclastogenesis and titanium particle-stimulated osteolysis.

Aseptic loosening caused by peri-implant osteolysis (PIO) is a common complication after joint replacement, and there is still no better treatment than revision surgery. The wear particle-induced inflammation response, especially subsequent osteoclastic bone resorption, is responsible for PIO. As the importance of wear particles in inducing autophagy in cells around the prosthesis in PIO has been discovered, this might be a central process underlying aseptic loosening. However, the role of autophagy induced by wear particles in osteoclastogenesis during PIO remains unclear. In this study, we investigated the role of autophagy in osteoclastogenesis and verified it in a mouse calvarial osteolysis model. We found that osteoclasts were increased in the interface membranes of patients with aseptic loosening. In vitro, knocking down the Atg5 gene or using autophagy inhibitors (3-MA, LY294002) to inhibit autophagy was found to repress osteoclastogenesis and decrease expression of the osteoclast-related genes TRAP, cathepsin K, and matrix metalloprotein 9 (MMP-9) with or without titanium (Ti) particles. In vivo, 3-MA and LY294002 repressed Ti particle-stimulated osteolysis and osteoclastogenesis and reduced expression of the pro-inflammatory factors TNF-α, IL-1ß, and IL-6. Our results suggest that 3-MA and LY294002 might be the potential medicines to prevent and treat PIO and aseptic loosening.

Identification of abnormally methylated-differentially expressed genes and pathways in osteoarthritis: a comprehensive bioinformatic study.

OBJECTIVES: To investigate abnormally methylated-differentially expressed genes (DEGs) and their related pathways in osteoarthritis (OA) by comprehensive bioinformatic analysis. METHODS: Gene expression profiles of GSE51588 and GSE114007, and a gene methylation microarray data GSE63695 were downloaded from the Gene Expression Omnibus (GEO) repository. Abnormally methylated DEGs were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of these genes were subsequently performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID). The protein-protein interaction (PPI) network was built from STRING. Module analysis and hub gene identification were performed by using Cytoscape. Co-expression analysis was also constructed using the CEMiTool package. RESULTS: In total, 133 abnormally methylated DEGs were identified, including 85 hypomethylation high-expression genes and 48 hypermethylation low-expression genes. Among biological processes and KEGG pathways of abnormally methylated DEGs, collagen fibril organization was enriched most frequently, and pathways of oxidative stress and aging were enriched, including HIF-1 signaling pathway, AMPK signaling pathway, and FoxO signaling pathway. In PPI networks, the hub genes of hypomethylation high-expression genes were COL1A1, COL3A1, COL1A2, COL5A2, LUM, MMP2, SPARC, COL2A1, COL6A2, and COL7A1, and the hub genes of hypermethylation low-expression genes were VEGFA, SLC2A1, LDHA, PDK1, and BNIP3. Combined with co-expression analysis, COL3A1, LUM, and MMP2 were the critical hypomethylation high-expression hub genes in medial tibia subchondral bone. CONCLUSIONS: Our study implied abnormally methylated DEGs and dysregulated pathways in OA. Common methylation biomarkers included COL3A1, LUM, and MMP2, and we also found that THBS2 may serve as a novel biomarker in end-stage OA. Key Points • Abnormally methylated differentially expressed genes regulate osteoarthritis. • Hypomethylation high-expression genes were related to the extracellular matrix. • Hypermethylation low-expression genes were related to oxidative stress and aging. • COL3A1, LUM, and MMP2 were potential methylation biomarkers for osteoarthritis.

The role of metabolism in chondrocyte dysfunction and the progression of osteoarthritis.

Osteoarthritis (OA) is a degenerative joint disease characterized by low-grade inflammation and high levels of clinical heterogeneity. Aberrant chondrocyte metabolism is a response to changes in the inflammatory microenvironment and may play a key role in cartilage degeneration and OA progression. Under conditions of environmental stress, chondrocytes tend to adapt their metabolism to microenvironmental changes by shifting from one metabolic pathway to another, for example from oxidative phosphorylation to glycolysis. Similar changes occur in other joint cells, including synoviocytes. Switching between these pathways is implicated in metabolic alterations that involve mitochondrial dysfunction, enhanced anaerobic glycolysis, and altered lipid and amino acid metabolism. The shift between oxidative phosphorylation and glycolysis is mainly regulated by the AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) pathways. Chondrocyte metabolic changes are likely to be a feature of different OA phenotypes. Determining the role of chondrocyte metabolism in OA has revealed key features of disease pathogenesis. Future research should place greater emphasis on immunometabolism and altered metabolic pathways as a means to understand the pathophysiology of age-related OA. This knowledge will advance the development of new drugs against therapeutic targets of metabolic significance.

Prognostic role of platelet-to-lymphocyte ratio in oral cancer: A meta-analysis.

BACKGROUND AND OBJECTIVE: Platelet-to-lymphocyte ratio (PLR) has been suggested to be associated with the progression of oral cancer with inconclusive results. The objective of the current study was to assess the prognostic role of oral cancer by meta-analysis. METHOD: PubMed, EMbase(Ovid), CNKI, WanFang Data, VIP, and CBM databases were searched up to August 24, 2018. Studies investigating the association between PLR and progression of oral cancer were included. Meta-analysis was performed by using Revman 5.3 software. The protocol of the study was registered on PROSPERO (CRD42018106836). RESULTS: A total of five studies were included in the meta-analysis. The results of the meta-analysis showed that higher PLR was associated with the poor progress of oral cancer (overall survival: OR = 2.06, 95 CI: 1.49-2.86, P < 0.0001; disease-specific survival: OR = 2.12, 95 CI: 1.59-2.82, P < 0.00001). CONCLUSION: The current meta-analysis showed that higher PLR is a poor progression factor for oral cancer. However, larger sample, multi-center studies should be carried out in the future to validate the above conclusion.

SPHK Inhibitors and Zoledronic Acid Suppress Osteoclastogenesis and Wear Particle-Induced Osteolysis.

Background: Inflammatory osteolysis induced by wear particles is the major cause of prosthetic loosening after artificial joint replacement, and its prevention and treatment are difficult worldwide. Our previous study confirmed that sphingosine kinases (SPHKs) are important mediators regulating the wear particle-induced macrophage inflammatory response. However, it is unclear whether SPHKs can modulate chronic inflammation and alleviate osteolysis. Zoledronic acid (ZA), an imidazole-containing bisphosphonate, directly affects osteoclasts and prevents bone mineral-related diseases. However, the effects of SPHK inhibitors and ZA used to treat periprosthetic osteolysis are unknown. Methods: We applied tartrate-resistant acid phosphatase (TRAP) staining to evaluate bone destruction in the interface membranes of patients with aseptic loosening and a control group. A murine calvarial osteolysis model was used to examine the preventative effect of SPHK inhibitors and ZA on osteolysis. Micro-CT scanning, immunohistochemistry (IHC), and histomorphometric analysis were conducted to determine the variations in inflammatory osteolysis. The effects of different drug concentrations on cell viability were evaluated using the Cell Counting Kit-8 (CCK-8) assay. Real-time quantitative polymerase chain reaction (RT-qPCR) analysis was performed to confirm the reduced expression of osteoclast-specific genes after drug and titanium treatment. The osteoclast formation and functions of the drugs were analyzed using TRAP staining in vivo and in vitro. The effect of SPHKs/S1P-TRAF2-BECN1 signaling pathways was verified via RT-qPCR and tissue IHC. Results: In this study, we found that SPHK inhibitors (ABC294640 and FTY720) combined with ZA decreased the degree of inflammatory osteolysis in vivo. However, ABC294640 and ZA suppressed osteoclast differentiation and osteoclast-specific genes in vitro. SPHKs regulate the inflammatory osteolysis induced by wear particles by increasing the expression of SPHKs/S1P-TRAF2-BECN1. Conclusion: Our study revealed that wear particles could induce inflammatory osteolysis by upregulating SPHKs/S1P-TRAF2-BECN1 and SPHK inhibitors/ZA inhibit osteoclastogenesis in vitro and prevent inflammatory osteolysis in vivo, suggesting that SPHK inhibitors and ZA can be a new perspective and scientific basis for the prevention and treatment of prosthesis loosening.