Efficacy and Safety of Different Antibiotic Therapies for Bone and Joint Infections: A Network Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Although an increasing number of antibiotics are being used to treat bone and joint infections, their specific efficacy remains controversial. Thus, we aimed to systematically compare the efficacy and safety of antibiotic therapies for orthopedic infections. METHODS: PubMed, Embase, The Cochrane Library, and Web of Science databases were searched from inception to April 2022. Two authors independently and rigorously conducted the screening, data extraction, and quality assessment of the relevant studies. All the extracted data were evaluated using traditional metaanalysis and network meta-analysis by STATA SE 16.0. RESULTS: A total of eleven randomized controlled trials (RCTs) involving 1,063 patients were included for data analysis. The analysis results from the NMA indicated that in terms of the clinical effectiveness rate, linezolid (OR: 1.75, 95% CI: 1.01 to 3.02) showed significant efficacy compared to ampicillin/sulbactam. With regard to the microbiological eradication rate, linezolid showed significant efficacy compared to cephalosporins (OR: 8.13, 95% CI: 1.16 to 57.09) and quinolones (OR: 3.51, 95% CI: 1.18 to 10.49). Similar findings were obtained for subgroup populations with diabetic foot infections (DFI). However, linezolid was significantly related to higher adverse events than ampicillin/sulbactam (OR: 3.25, 95% CI: 1.68 to 6.30) and cephalosporins (OR: 18.29, 95% CI: 1.59 to 209.76). CONCLUSION: Linezolid appeared to be the most promising treatment regimen for staphylococcal bone and joint infections. However, due to the overall limited evidence, the research results need further high-quality RCTs for confirmation.

Mechanical properties evaluation of metacarpophalangeal joint prosthesis with new titanium-nickel memory alloy: a cadaver study.

OBJECTIVE: Ni-Ti memory alloys are unusual materials for hard-tissue replacement because of their unique superelasticity, good biocompatibility, high strength, low specific gravity, low magnetism, wear resistance, corrosion resistance and fatigue resistance. The current study aims to evaluate its mechanical properties and provide biomechanical basis for the clinical application of the prosthesis. METHODS: Ten adult metacarpophalangeal joint specimens were randomly divided into a prosthesis group (n = 5, underwent metacarpophalangeal joint prosthesis) and a control group (n = 5, underwent sham operation). Firstly, the axial compression strength was tested with BOSE material testing machine to evaluate its biomechanical strength. Secondly, these specimens were tested for strain changes using BOSE material testing machine and GOM non-contact optical strain measurement system to evaluate the stress changes. Thirdly, fatigue test was performed between groups. Lastly, the mechanical wear of the metacarpophalangeal joint prosthesis was tested with ETK5510 material testing machine to study its mechanical properties. RESULTS: Axial compression stiffness in the prosthesis group was greater than that in the control group in terms of 30 ° and 60 ° flexion positions (P < 0.05). There was no statistically significant difference between two groups with regards to axial compression stiffness and stress change test (P > 0.05). In the fatigue wear test, the mean mass loss in the prosthesis group's prosthesis was 17.2 mg and 17.619 mm3, respectively. The mean volume wear rate was 0.12%. There was no statistically significant difference in the maximum pull-out force of the metacarpal, phalangeal, and polymer polyethylene pads between the prosthesis group and the control group specimens. CONCLUSIONS: Ni-Ti memory alloy metacarpophalangeal joint prosthesis conforms to the biomechanical characteristics of metacarpophalangeal joints without implants, and the fatigue strength can fully meet the needs of metacarpophalangeal joint activities after joint replacement.

Knee osteoarthritis: Current status and research progress in treatment (Review).

Knee osteoarthritis (KOA) is a common chronic articular disease worldwide. It is also the most common form of OA and is characterized by high morbidity and disability rates. With the gradual increase in life expectancy and ageing population, KOA not only affects the quality of life of patients, but also poses a burden on global public health. OA is a disease of unknown etiology and complex pathogenesis. It commonly affects joints subjected to greater loads and higher levels of activity. The knee joint, which is the most complex joint of the human body and bears the greatest load among all joints, is therefore most susceptible to development of OA. KOA lesions may involve articular cartilage, synovium, joint capsule and periarticular muscles, causing irreversible articular damage. Factors such as mechanical overload, inflammation, metabolism, hormonal changes and ageing serve key roles in the acceleration of KOA progression. The clinical diagnosis of KOA is primarily based on combined analysis of symptoms, signs, imaging and laboratory examination results. At present, there is no cure for KOA and the currently available therapies primarily focus on symptomatic treatment and delay of disease progression. Knee replacement surgery is typically performed in patients with advanced disease. The current study presents a review of epidemiological characteristics, risk factors, histopathological manifestations, pathogenesis, diagnosis, treatment modalities and progress in KOA research.

Identification of molecular subgroups in osteomyelitis induced by staphylococcus aureus infection through gene expression profiles.

BACKGROUND: Staphylococcus aureus (S. aureus) infection-induced osteomyelitis (OM) is an inflammatory bone disease accompanied by persistent bone destruction, and the treatment is challenging because of its tendency to recur. Present study was aimed to explore the molecular subgroups of S. aureus infection-induced OM and to deepen the mechanistic understanding for molecularly targeted treatment of OM. METHODS: Integration of 164 OM samples and 60 healthy samples from three datasets of the Gene Expression Omnibus (GEO) database. OM patients were classified into different molecular subgroups based on unsupervised algorithms and correlations of clinical characteristics between subgroups were analyzed. Next, The CIBERSORT algorithm was used to evaluate the proportion of immune cell infiltration in different OM subgroups. Weighted gene co-expression analysis (WGCNA) was used to identify different gene modules and explore the relationship with clinical characteristics, and further annotated OM subgroups and gene modules by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. RESULTS: Two subgroups with excellent consistency were identified in this study, subgroup and hospital length of stay were independent predictors of OM. Compared with subgroup I, OM patients in subgroup II had longer hospital length of stay and more severe disease. Meanwhile, the infiltration proportions of monocytes and macrophages M0 were higher in patients of OM subgroup II. Finally, combined with the characteristics of the KEGG enrichment modules, the expression of osteoclast differentiation-related genes such as CTSK was upregulated in OM subgroup II, which may be closely associated with more severe OM patients. CONCLUSION: The current study showed that OM subgroup II had longer hospital length of stay and more severe disease, the osteoclast differentiation pathway and the main target CTSK contribute to our deeper understanding for the molecular mechanisms associated with S. aureus infection-induced OM, and the construction of molecular subgroups suggested the necessity for different subgroups of patients to receive individualized treatment.

Identification of Ferroptosis-Related Biomarkers for Diagnosis and Molecular Classification of Staphylococcus aureus-Induced Osteomyelitis.

Objective: Staphylococcus aureus (SA)-induced osteomyelitis (OM) is one of the most common refractory diseases in orthopedics. Early diagnosis is beneficial to improve the prognosis of patients. Ferroptosis plays a key role in inflammation and immune response, while the mechanism of ferroptosis-related genes (FRGs) in SA-induced OM is still unclear. The purpose of this study was to determine the role of ferroptosis-related genes in the diagnosis, molecular classification and immune infiltration of SA-induced OM by bioinformatics. Methods: Datasets related to SA-induced OM and ferroptosis were collected from the Gene Expression Omnibus (GEO) and ferroptosis databases, respectively. The least absolute shrinkage and selection operator (LASSO) and support vector machine-recursive feature elimination (SVM-RFE) algorithms were combined to screen out differentially expressed-FRGs (DE-FRGs) with diagnostic characteristics, and gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were used to explore specific biological functions and pathways. Based on these key DE-FRGs, a diagnostic model was established, and molecular subtypes were divided to explore the changes in the immune microenvironment between molecular subtypes. Results: A total of 41 DE-FRGs were identified. After screening and intersecting with LASSO and SVM-RFE algorithms, 8 key DE-FRGs with diagnostic characteristics were obtained, which may regulate the pathogenesis of OM through the immune response and amino acid metabolism. The ROC curve indicated that the 8 DE-FRGs had excellent diagnostic ability for SA-induced OM (AUC=0.993). Two different molecular subtypes (subtype 1 and subtype 2) were identified by unsupervised cluster analysis. The CIBERSORT analysis revealed that the subtype 1 OM had higher immune cell infiltration rates, mainly in T cells CD4 memory resting, macrophages M0, macrophages M2, dendritic cells resting, and dendritic cells activated. Conclusion: We developed a diagnostic model related to ferroptosis and molecular subtypes significantly related to immune infiltration, which may provide a novel insight for exploring the pathogenesis and immunotherapy of SA-induced OM.

Positive Feedback Regulation of Circular RNA Hsa_circ_0000566 and HIF-1α promotes Osteosarcoma Progression and Glycolysis Metabolism.

Hypoxia is an indispensable factor for cancer progression and is closely associated with the Warburg effect. Circular RNAs (CircRNA) have garnered considerable attention in molecular malignancy therapy as they are potentially important modulators. However, the roles of circRNAs and hypoxia in osteosarcoma (OS) progression have not yet been elucidated. This study reveals the hypoxia-sensitive circRNA, Hsa_circ_0000566, that plays a crucial role in OS progression and energy metabolism under hypoxic stress. Hsa_circ_0000566 is regulated by hypoxia-inducible factor-1α (HIF-1α) and directly binds to it as well as to the Von Hippel-Lindau (VHL) E3 ubiquitin ligase protein. Consequentially, binding between VHL and HIF-1α is impeded. Furthermore, Hsa_circ_0000566 contributes to OS progression by binding to HIF-1α (while competing with VHL) and by confers protection against HIF-1α against VHL-mediated ubiquitin degradation. These findings demonstrate the existence of a positive feedback loop formed by HIF-1α and Hsa_circ_0000566 and the key role they play in OS glycolysis. Taken together, these data indicate the significance of Hsa_circ_0000566 in the Warburg effect and suggest that Hsa_circ_0000566 could be a potential therapeutic target to combat OS progression.

Downregulated annexin A1 expression correlates with poor prognosis, metastasis, and immunosuppressive microenvironment in Ewing's sarcoma.

OBJECTIVE: Ewing's sarcoma (ES) is a common bone malignancy in children and adolescents that severely affects the prognosis of patients. The aim of this study was to identify novel biomarkers and potential therapeutic targets for ES. METHODS: Highly prognosis-related hub genes were identified by independent prognostic analysis in the GSE17679 dataset. We then performed survival analysis, Cox regression analysis and clinical correlation analysis on the key gene and validated them with the GSE63157, GSE45544 and GSE73166 datasets. Differentially expressed genes (DEGs) were screened based on the high and low expression of key gene, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, Gene Set Enrichment Analysis (GSEA), and Gene Set Variation Analysis (GSVA) were performed to explore the underlying mechanisms of ES, and significant module genes were established based on protein-protein interaction (PPI) networks. Furthermore, the correlations between module genes and the immune microenvironment were analyzed and the correlations between the key gene and immune infiltration levels in sarcoma were investigated using TIMER and TISIDB. Finally, the expression levels of these key genes in ES cell lines (RD-ES and A673 cells) were further validated by real-time quantitative PCR (RT-qPCR). CCK-8 and EdU assays were performed to assess the effect of ANXA1 knockdown on RD-ES cell proliferation. RESULTS: ANXA1 was identified as a key gene for ES prognosis. The overall survival (OS) time of patients with low ANXA1 expression was shorter, and the expression level of ANXA1 in the metastatic group was significantly lower than that in the primary group (P<0.01). Additionally, the abundance of 12 immune cells in the ANXA1 low-expression group was significantly lower than that in the high-expression group (all P<0.05), which may be related to the inhibition of the immune microenvironment. A PPI network was constructed based on 96 DEGs to further identify the five ANXA1-related module genes (COL1A2, MMP9, VIM, S100A11 and S100A4). The expression levels of ANXA1, COL1A2, MMP9, VIM, S100A11 and S100A4 were significantly different between ES cell lines and mesenchymal stem cells after validation in two ES cell lines (all P<0.01). Among these genes, ANXA1, COL1A2, MMP9, VIM and S100A4 were significantly associated with the prognosis of ES patients (all P<0.05). Importantly, ANXA1 knockdown significantly promoted the proliferation of RD-ES cells, which may explain the susceptibility to ES metastasis in the ANXA1 low-expression group. CONCLUSIONS: ANXA1 may serve as an independent prognostic biomarker for ES patients and is associated with metastasis and the immunosuppressive microenvironment in ES, which needs to be validated in further studies.

Macrophage migration inhibitory factor (MIF) inhibitor iSO-1 promotes staphylococcal protein A-induced osteogenic differentiation by inhibiting NF-κB signaling pathway.

BACKGROUND: Osteomyelitis is among the most difficult to treat diseases in the field of orthopedics, and there is a lack of effective treatment modalities. Exploring the mechanisms of its development is beneficial for finding molecular targets for treatment. Increasing evidence suggests that macrophage migration inhibitory factor (MIF), as a proinflammatory mediator, is not only involved in various pathophysiological processes of inflammation but also plays an important role in osteogenic differentiation, while its specific regulatory mechanism in osteomyelitis remains unclear. METHODS: In the present study, staphylococcal protein A (SPA)-treated rat bone marrow mesenchymal stem cells (rBMSCs) were used to construct cell models of osteomyelitis. Rat and cell models of osteomyelitis were used to validate the expression levels of MIF, and to further explore the regulatory mechanisms of the MIF inhibitor methyl ester of (S, R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid (iSO-1) and MIF knockdown on cell model of osteomyelitis toward osteogenic differentiation. RESULTS: We found that the expression level of MIF was upregulated in rat and cell models of osteomyelitis and subsequently demonstrated by the GSE30119 dataset that the expression level of MIF was also significantly upregulated in patients with osteomyelitis. Furthermore, SPA promotes MIF expression in rBMSCs while inhibiting the expression of osteogenic-related genes such as Runt-related transcription factor 2 (RUNX2), osteocalcin (OCN), osteopontin (OPN) and collagen type-1 (COL-1) through activation of the nuclear factor kappa-B (NF-κB) pathway. In vivo, we further demonstrated that local injection of iSO-1 significantly increased the osteogenic activity in rat model of osteomyelitis. Importantly, we also demonstrated that MIF knockdown and the MIF inhibitor iSO-1 reversed the SPA-mediated inhibition of osteogenic differentiation of rBMSCs by inhibiting the activation of the NF-κB pathway, as evidenced by the upregulation of osteogenic-related gene expression and enhanced bone mineralization. CONCLUSION: ISO-1 and MIF knockdown can reverse the SPA-mediated inhibition of osteogenic differentiation in the rBMSCs model of osteomyelitis by inhibiting the NF-κB signaling pathway, providing a potential target for the treatment of osteomyelitis.

Diagnostic signature, subtype classification, and immune infiltration of key m6A regulators in osteomyelitis patients.

Background: As a recurrent inflammatory bone disease, the treatment of osteomyelitis is always a tricky problem in orthopaedics. N6-methyladenosine (m6A) regulators play significant roles in immune and inflammatory responses. Nevertheless, the function of m6A modification in osteomyelitis remains unclear. Methods: Based on the key m6A regulators selected by the GSE16129 dataset, a nomogram model was established to predict the incidence of osteomyelitis by using the random forest (RF) method. Through unsupervised clustering, osteomyelitis patients were divided into two m6A subtypes, and the immune infiltration of these subtypes was further evaluated. Validating the accuracy of the diagnostic model for osteomyelitis and the consistency of clustering based on the GSE30119 dataset. Results: 3 writers of Methyltransferase-like 3 (METTL3), RNA-binding motif protein 15B (RBM15B) and Casitas B-lineage proto-oncogene like 1 (CBLL1) and three readers of YT521-B homology domain-containing protein 1 (YTHDC1), YT521-B homology domain-containing family 3 (YTHDF2) and Leucine-rich PPR motif-containing protein (LRPPRC) were identified by difference analysis, and their Mean Decrease Gini (MDG) scores were all greater than 10. Based on these 6 significant m6A regulators, a nomogram model was developed to predict the incidence of osteomyelitis, and the fitting curve indicated a high degree of fit in both the test and validation groups. Two m6A subtypes (cluster A and cluster B) were identified by the unsupervised clustering method, and there were significant differences in m6A scores and the abundance of immune infiltration between the two m6A subtypes. Among them, two m6A regulators (METTL3 and LRPPRC) were closely related to immune infiltration in patients with osteomyelitis. Conclusion: m6A regulators play key roles in the molecular subtypes and immune response of osteomyelitis, which may provide assistance for personalized immunotherapy in patients with osteomyelitis.

Comparing the efficacy of different antibiotic regimens on osteomyelitis: A network meta-analysis of animal studies.

Background: Despite the surge in the number of antibiotics used to treat preclinical osteomyelitis (OM), their efficacy remains inadequately assessed. Objective: To establish network comparisons on the efficacy of antibiotic regimens on OM in animal studies. Methods: PubMed, Embase, Web of Science, and The Cochrane Library were searched from inception to March 2022 for relevant articles. Odds ratios (ORs) were generated for dichotomous variants, and the standard mean difference (SMD) was calculated for constant variables. The predominant outcomes were the effective rate of sterility, also known as sterility rates, as well as the bacterial counts at the end of the experiments and antibiotic concentrations in serum or bone. All the network meta-analyses were performed using STATA MP 16.0. This study was registered in the International Prospective Register of Systematic Reviews (PROSPERO; no. CRD42022316544). Results: A total of 28 eligible studies with 1,488 animals were included for data analysis, including 13 antibiotic regimens. Regarding the effective rate of sterility, glycopeptides (GLY), linezolid (LIN), rifampicin (RIF)+ß-Lactam, and ß-Lactam showed significant efficacy compared with placebo (OR ranging from 0.01 to 0.08). For radiological grade, only RIF+GLY (SMD: -5.92, 95%CI: -11.65 to -0.19) showed significant efficacy compared with placebo. As for reducing bacteria count, fosfomycin (FOS), tigecycline (TIG), GLY, LIN, RIF, RIF+ß-Lactam, RIF+GLY, aminoglycosides (AMI), and clindamycin (CLI) showed significant efficacy compared with placebo (SMD ranging from -6.32 to -2.62). Moreover, the bone concentrations of GLY were higher 1 h after administration and the higher blood concentrations were higher after 1 h and 4 h compared with the other antibiotics. Conclusion: Multiple antibiotic regimens showed significant efficacy in animals with OM, including increasing effective rates of sterility, reducing bacterial counts, and lowering radiological scores. Among them, RIF+GLY was the most promising treatment regimen owing to its optimal efficacy. Based on the preclinical studies included in our meta-analysis, head-to-head clinical randomized controlled trials are required to confirm these findings in humans.

[Regulation of long non-coding RNA in signal pathways related to osteogenic differentiation].

Objective: To summarize the mechanism of long non-coding RNA (lncRNA) in signal pathways related to osteogenic differentiation. Methods: Relevant domestic and foreign researches in recent years were consulted. The characteristics and biological functions of lncRNA were introduced, and the specific mechanism of lncRNA regulating related signal pathways in osteogenic differentiation was elaborated. Results: The exertion and maintenance of normal function of bone requires the closed coordination of transcription networks and signal pathways. However, most of these signal pathways or networks are dysregulated under pathological conditions that affect bone homeostasis. lncRNA can regulate the differentiation of various bone cells by activating or inhibiting signal pathways to achieve the balance of bone homeostasis, thereby reversing the pathological state of bones and achieving the purpose of treating bone metabolic diseases. Conclusion: At present, the research on the mechanism of lncRNA regulating various osteogenic differentiation pathways is still in the early stage. Its in-depth regulator mechanism, especially the cross-talk of complex signal pathways needs to be further studied. And how to apply these molecular targets to clinical treatment is also a big challenge.

Antibiotic-loaded calcium sulfate in clinical treatment of chronic osteomyelitis: a systematic review and meta-analysis.

BACKGROUND: Present work was aimed to gather accessible evidence on the eradication rates and related postoperative complications of antibiotic-loaded calcium sulfate (CS) as an implant in the treatment of chronic osteomyelitis (COM). METHODS: Databases including PubMed, EMBASE, Medline, Ovid and Cochrane library were searched from their dates of initiation until November 2021. Two independent authors scrutinized the relevant studies based on the effectiveness of radical debridement combined with antibiotic-loaded CS for COM; data extraction and quality assessment of the Methodological Index for Non-Randomized Studies (MINORS) criteria were also performed by the authors. In addition, clinical efficacy mainly depended on the evaluation of eradication rates and complications, and all the extracted data are pooled and analyzed by STATA 16.0. RESULTS: A total of 16 studies with 917 patients (920 locations) were recruited, with an overall eradication rate of 92%. Moreover, the overall reoperation rate, overall refracture rate, overall delayed wound healing rate, and the rate of aseptic wound leakage were 9.0%, 2.0%, 20.0%, and 12.0%, respectively. Moreover, the choice of tobramycin-loaded CS or vancomycin combined with gentamicin-loaded CS did not affect the eradication rate, and the incidence of postoperative complications in COM patients (all [Formula: see text]). The general quality of the included studies was fair. CONCLUSIONS: Our meta-analysis indicated that the overall eradication rate of COM treated with antibiotic-loaded CS was 92%. Delayed healing is the most common postoperative complication. The choice of tobramycin-loaded CS or vancomycin combined with gentamicin-loaded CS did not affect the eradication rate and the incidence of postoperative complications in COM patients.

Circular RNA circSIPA1L1 Contributes to Osteosarcoma Progression Through the miR-411-5p/RAB9A Signaling Pathway.

Recently, various studies have identified circular RNAs (circRNAs) to play a significant role in tumorigenesis, thereby showing potential as novel tumor biomarkers. circSIPA1L1 is a newly discoveredcircular RNA, which is formed by back-splicing of SIPA1L1 and is found increased in osteosarcoma (OS). Nevertheless, the specific functions of circSIPA1L1 in OS remain unknown. In the present study, circSIPA1L1 was obtained from a previously reported circRNA microarray in the GEO database (GSE96964). Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to assess the mRNA level of circSIPA1L1 in OS cell lines and tissue samples. Bioinformatics analysis, luciferase reporter assays, real-time PCR, RNA pull-down assays and RNA immunoprecipitation (RIP) were employed to verify the binding of circSIPA1L1 with miR-411-5p. Xenograft tumor models were established to identify the role of circSIPA1L1 in vivo. A series of in vitro experiments, such as western blotting, colony formation, transwell assays and anoikis assay were employed to confirm the relationship across circSIPA1L1, miR-411-5p, and RAB9A. Our study confirmed circSIPA1L1 to be upregulated in both human OS samples and OS cell lines. Mechanistically, circSIPA1L1 could serve as a miR-411-5p molecular sponge to increase RAB9A expression, which was confirmed to be a tumor promoter mediating carcinogenesis. Silencing of circSIPA1L1 attenuated the vitality, invasion, migration and proliferation of OS cell lines both in vivo and in vitro. miR-411-5p inhibition or RAB9A overexpression reversed the anti-tumor effects caused by circSIPA1L1 knockdown. Briefly, circSIPA1L1 could function as a driver gene in OS and initiate OS tumorigenesis through the miR-411-5p/RAB9A signaling pathway, which might become a potential therapeutic biomarker for OS treatment.