Exploring Causal Relationships between Leukocyte Telomere Length, Sex Hormone-Binding Globulin Levels, and Osteoporosis Using Univariable and Multivariable Mendelian Randomization.

OBJECTIVE: Recent evidence supports that leukocyte telomere length (LTL) may be positively associated with healthy living and inversely correlated with the risk of age-related diseases, including osteoporosis. Furthermore, it is important to note that sex hormone-binding globulin (SHBG) levels play a crucial role in the regulation of osteoporosis by influencing the availability of sex hormones. Hence, this study holds significant importance as it aims to unravel the roles of LTL and SHBG levels and determine which one acts as a predominant intermediary factor in influencing osteoporosis. Using Mendelian randomization (MR), we can gain valuable insights into the intricate relationships between aging, sex hormones, and bone health. METHODS: Univariable and multivariable and MR analyses were employed in this study. First, we used genetic variants associated with both LTL, as determined from a study involving 472,174 European participants by Codd et al., and SHBG levels, as identified in a study conducted by Ruth et al. with 370,125 participants, as instrumental variables (IVs). Then we aimed to establish a causal relationship between LTL and SHBG levels and their potential impact on osteoporosis using univariable MR. Finally, we conducted multivariable MR to provide insights into the independent and combined effects of LTL, SHBG levels on osteoporosis risk. We used various MR methods, with the primary analysis employing the inverse-variance weighted (IVW) model. RESULTS: Univariable MR analysis reveals a potential causal effect of longer LTL on reduced risk of osteoporosis [odds ratio (OR): 0.85; 95% confidence interval (CI): 0.73-0.99; p = 0.03]. Conversely, higher genetically determined SHBG levels affect the risk of osteoporosis positively. (OR: 1.38; 95% CI: 1.09-1.75; p < 0.01). We observed a negative causal effect for LTL on the occurrence of SHBG (OR: 0.96; 95% CI 0.94-0.98, p < 0.01). After adjustment of using multivariable MR, the causal effect of LTL on osteoporosis (OR: 0.92; 95% CI: 0.84-1.03; p = 0.14), and the effect of SHBG on osteoporosis (OR: 1.43; 95% CI: 1.16-1.75; p < 0.01) were observed. CONCLUSION: Longer LTL may confer a protective effect against osteoporosis. Additionally, the levels of SHBG appear to play a crucial role in mediating the relationship between LTL and osteoporosis. By understanding the interplay between these factors, we can gain valuable insights into the mechanisms underlying bone health and aging and potentially identify new avenues for prevention and intervention strategies.

Exosomes from bone marrow mesenchymal stem cells ameliorate glucocorticoid-induced osteonecrosis of femoral head by transferring microRNA-210 into bone microvascular endothelial cells.

OBJECTIVES: Bone microvascular endothelial cells (BMECs) played an important role in the pathogenesis of glucocorticoid-induced osteonecrosis of femoral head (GCS-ONFH), and exosomes derived from bone marrow mesenchymal stem cells (BMSC-Exos) may provide an effective treatment. This study aimed to evaluate the effects of BMSC-Exos and internal microRNA-210-3p (miRNA-210) on GCS-ONFH in an in vitro hydrocortisone-induced BMECs injury model and an in vivo rat GCS-ONFH model. METHODS: BMECs, BMSCs and BMSC-Exos were isolated and validated. BMECs after the treatment of hydrocortisone were cocultured with different concentrations of BMSC-Exos, then proliferation, migration, apoptosis and angiogenesis of BMECs were evaluated by CCK-8, Annexin V-FITC/PI, cell scratch and tube formation assays. BMSCs were transfected with miRNA-210 mimics and miRNA-210 inhibitors, then BMSC-ExosmiRNA-210 mimic and BMSC-ExosmiRNA-210 inhibitor secreted from such cells were collected. The differences between BMSC-Exos, BMSC-ExosmiRNA-210 mimic and BMSC-ExosmiRNA-210 inhibitor in protecting BMECs against GCS treatment were analyzed by methods mentioned above. Intramuscular injections of methylprednisolone were performed on Sprague-Dawley rats to establish an animal model of GCS-ONFH, then tail intravenous injections of BMSC-Exos, BMSC-ExosmiRNA-210 mimic or BMSC-ExosmiRNA-210 inhibitor were conducted after methylprednisolone injection. Histological and immunofluorescence staining and micro-CT were performed to evaluate the effects of BMSC-Exos and internal miRNA-210 on the in vivo GCS-ONFH model. RESULTS: Different concentrations of BMSC-Exos, especially high concentration of BMSC-Exos, could enhance the proliferation, migration and angiogenesis ability and reduce the apoptosis rates of BMECs treated with GCS. Compared with BMSC-Exos, BMSC-ExosmiRNA-210 mimic could further enhance the proliferation, migration and angiogenesis ability and reduce the apoptosis rates of BMECs, while BMECs in the GCS + BMSC-ExosmiRNA-210 inhibitor group showed reduced proliferation, migration and angiogenesis ability and higher apoptosis rates. In the rat GCS-ONFH model, BMSC-Exos, especially BMSC-ExosmiRNA-210 mimic, could increase microvascular density and enhance bone remodeling of femoral heads. CONCLUSIONS: BMSC-Exos containing miRNA-210 could serve as potential therapeutics for protecting BMECs and ameliorating the progression of GCS-ONFH.

The Genetic Causal Association between Educational Attainment and Risk of 12 Common Musculoskeletal Disorders: A Two-Sample Mendelian Randomization.

OBJECTIVE: In numerous observational studies, there has been an indication that educational attainment (EA) can impact the intensity of pain and disability resulting from chronic musculoskeletal disorders. Nonetheless, the association observed in these studies is not entirely conclusive. The aim of this study was to investigate the genetic causal relationship between educational attainment and 12 musculoskeletal disorders using Mendelian randomization (MR). METHODS: The meta-analysis of genome-wide association studies (GWAS) identified 3952 single-nucleotide polymorphisms (SNPs) associated with educational attainment (EA) from the Social Science Genetic Association Consortium (SSGAC). Genetic data for 12 musculoskeletal disorders, including osteonecrosis, osteoporosis, osteomyelitis, low back pain, gout, spinal stenosis, rheumatoid arthritis, meniscus derangement, rotator cuff syndrome, ankylosing spondylitis, cervicobrachial syndrome, and lateral epicondylitis, were obtained from the FinnGen consortium. We conducted a two-sample Mendelian randomization analysis to examine the causal effect of EA on the risk of these musculoskeletal disorders using the TwoSampleMR package in R. RESULTS: Based on the inverse-variance weighted (IVW) method, we found that a genetically predicted per standard deviation (SD) increase in EA was inversely associated with low back pain [odds ratio (OR) 0.46, 95% confidence interval (Cl) 0.51-0.61, p < 0.001], spinal stenosis (OR 0.62, 95% Cl 0.54-0.71, p < 0.001), rheumatoid arthritis (OR 0.65, 95% Cl 0.55-0.76, p < 0.001), meniscus derangement (OR 0.73, 95% Cl 0.65-0.82, p < 0.001), rotator cuff syndrome (OR 0.55, 95% Cl 0.49-0.61, p < 0.001), cervicobrachial syndrome (OR 0.50, 95% Cl 0.42-0.60, p < 0.001), and lateral epicondylitis (OR 0.30, 95% Cl 0.24-0.37, p < 0.001). There was no causal association between EA and osteonecrosis (OR 1.11, 95% CI 0.76-1.72, p = 0.60), osteoporosis (OR 0.91, 95% CI 0.65-1.27, p = 0.59), or osteomyelitis (OR 0.90, 95% CI 0.75-1.01, p = 0.22). Genetic predisposition to EA had a suggestive causal association with gout (OR 0.80, 95% CI 0.68-0.95, p = 0.01) and ankylosing spondylitis (OR 0.64, 95% CI 0.45-0.91, p = 0.01) after Bonferroni correction. None of the analyses revealed any horizontal pleiotropy or heterogeneity. CONCLUSION: In our investigation, we have uncovered evidence supporting a causal relationship between low level of EA and the incidence of certain musculoskeletal disorders. In the future, it is imperative to ascertain risk factors such as lifestyle patterns linked with EA to uncover the underlying causal relationship and offer informed interventions for individuals.

Assessing the Casual Association between Sex Hormone Levels and Fracture Risk: A Two-Sample Mendelian Randomization Study.

OBJECTIVE: Prior observational studies have reported that levels of sex hormones constitute a risk factor for the fracture. The aim of this study was to ascertain whether there is a causal relationship between the levels of sex hormones and the risk of fracture through Mendelian randomization (MR). METHODS: Single-nucleotide polymorphisms (SNPs) associated with two indicators of sex hormone levels, circulating sex hormone-binding globulin (SHBG) and bioavailable testosterone levels, as exposures were selected from a large genome-wide association study (GWAS) from UK Biobank. The summary statistics for 11 different types of fracture as outcomes from the FinnGen consortium. This study employed the two-sample MR approach. For the main analysis, the inverse-variance-weighted (IVW) method was utilized. To assess the heterogeneity of MR results, the IVW method and MR-Egger method were utilized. To evaluate potential pleiotropy, MR-Egger regression was conducted. Additionally, a leave-one-SNP-out test was performed to assess the robustness of MR results to the exclusion of any individual SNP. RESULTS: The MR analyses demonstrated a conspicuous impact of SHBG on the risk of pathological fracture with osteoporosis (OP). We found that an increase of one standard deviation (SD) in SHBG correspondingly increased the risk of pathological fracture with OP [odds ratio (OR) 2.42, 95% confidence interval (CI), 1.52-3.85; p = 1.93 × 10-4 ]. The bioavailable testosterone showed the negative casual genetic associations with fractures of foot and forearm. An increase of one SD in the genetically predetermined bioavailable testosterone was associated with a reduction of 37% in the risk of fracture of foot (OR 0.63, 95% Cl 0.49 to 0.81; p = 3.37 × 10-4 ), as well as a 39% decrease in the risk of fracture of forearm (OR 0.61, 95% Cl 0.50 to 0.76; p = 5.40 × 10-6 ). CONCLUSIONS: Our study confirms that individuals experiencing elevated SHBG concentrations showed a major causal effect on pathological fracture with OP. High bioavailable testosterone levels play an important role in preventing the fractures of foot and forearm. Although increasing bioavailable testosterone and decreasing SHBG levels had no casual effect on most fractures in the general population, they are likely to have the most clinically relevant effect on certain fracture risk reduction.

Comparison of clinical outcomes among total knee arthroplasties using posterior-stabilized, cruciate-retaining, bi-cruciate substituting, bi-cruciate retaining designs: a systematic review and network meta-analysis.

BACKGROUND: Despite the advent of innovative knee prosthesis design, a consistent first-option knee implant design in total knee arthroplasty (TKA) remained unsettled. This study aimed to compare the clinical effects among posterior-stabilized (PS), cruciate-retaining (CR), bi-cruciate substituting (BCS), and bi-cruciate retaining designs for primary TKA. METHODS: Electronic databases were systematically searched to identify eligible randomized controlled trials (RCTs) and cohort studies from inception up to July 30, 2021. The primary outcomes were the range of knee motion (ROM), and the secondary outcomes were the patient-reported outcome measures (PROMs) and complication and revision rates. Confidence in evidence was assessed using Confidence in Network Meta-Analysis. The Bayesian network meta-analysis was performed for synthesis. RESULTS: A total of 15 RCTs and 18 cohort studies involving 3520 knees were included. The heterogeneity and inconsistency were acceptable. There was a significant difference in ROM at the early follow-up when PS was compared with CR (mean difference [MD] = 3.17, 95% confidence interval [CI] 0.07, 7.18) and BCS was compared with CR (MD = 9.69, 95% CI 2.18, 17.51). But at the long-term follow-up, there was no significant difference in ROM in any one knee implant compared with the others. No significant increase was found in the PROMs and complication and revision rates at the final follow-up time. CONCLUSIONS: At early follow-up after TKA, PS and BCS knee implants significantly outperform the CR knee implant in ROM. But in the long run, the available evidence suggests different knee prostheses could make no difference in clinical outcomes after TKA with extended follow-up.

Transcriptome-wide association study reveals candidate causal genes for lumbar spinal stenosis.

Aims: Lumbar spinal stenosis (LSS) is a common skeletal system disease that has been partly attributed to genetic variation. However, the correlation between genetic variation and pathological changes in LSS is insufficient, and it is difficult to provide a reference for the early diagnosis and treatment of the disease. Methods: We conducted a transcriptome-wide association study (TWAS) of spinal canal stenosis by integrating genome-wide association study summary statistics (including 661 cases and 178,065 controls) derived from Biobank Japan, and pre-computed gene expression weights of skeletal muscle and whole blood implemented in FUSION software. To verify the TWAS results, the candidate genes were furthered compared with messenger RNA (mRNA) expression profiles of LSS to screen for common genes. Finally, Metascape software was used to perform enrichment analysis of the candidate genes and common genes. Results: TWAS identified 295 genes with permutation p-values < 0.05 for skeletal muscle and 79 genes associated for the whole blood, such as RCHY1 (PTWAS = 0.001). Those genes were enriched in 112 gene ontology (GO) terms and five Kyoto Encyclopedia of Genes and Genomes pathways, such as 'chemical carcinogenesis - reactive oxygen species' (LogP value = -2.139). Further comparing the TWAS significant genes with the differentially expressed genes identified by mRNA expression profiles of LSS found 18 overlapped genes, such as interleukin 15 receptor subunit alpha (IL15RA) (PTWAS = 0.040, PmRNA = 0.010). Moreover, 71 common GO terms were detected for the enrichment results of TWAS and mRNA expression profiles, such as negative regulation of cell differentiation (LogP value = -2.811). Conclusion: This study revealed the genetic mechanism behind the pathological changes in LSS, and may provide novel insights for the early diagnosis and intervention of LSS.

[Research progress of optic atrophy 1-mediated mitochondrial dynamics in skeletal system diseases].

Objective: To review the research progress of mitochondrial dynamics mediated by optic atrophy 1 (OPA1) in skeletal system diseases. Methods: The literatures about OPA1-mediated mitochondrial dynamics in recent years were reviewed, and the bioactive ingredients and drugs for the treatment of skeletal system diseases were summarized, which provided a new idea for the treatment of osteoarthritis. Results: OPA1 is a key factor involved in mitochondrial dynamics and energetics and in maintaining the stability of the mitochondrial genome. Accumulating evidence indicates that OPA1-mediated mitochondrial dynamics plays an important role in the regulation of skeletal system diseases such as osteoarthritis, osteoporosis, and osteosarcoma. Conclusion: OPA1-mediated mitochondrial dynamics provides an important theoretical basis for the prevention and treatment of skeletal system diseases.

The Interval of Two-Stage Bilateral Total Hip Arthroplasty under Enhanced Recovery Affects Perioperative Complications and Cost of Hospitalization: A Retrospective Study.

OBJECTIVES: Perioperative enhanced recovery after surgery (ERAS) protocols can improve the quality of healthcare and reduce hospitalization for patients who underwent total hip arthroplasty (THA). The interval of staged bilateral THA under ERAS is still unclear. We attempt to ascertain the optimal interval of staged bilateral THA for reducing the perioperative complications and the cost of hospitalization. METHODS: We retrospectively reviewed patients who received staged bilateral THA under ERAS performed at West China Hospital of Sichuan University from 2018 to 2021. The staged time was divided into two groups using four different cutoff points: (1) ≤3 months versus >3 months, (2) ≤4 months versus >4 months, (3) ≤5 months versus >5 months and (4) ≤6 months versus >6 months. Primary outcomes included the rate of perioperative complications and the cost of hospitalization. The secondary outcomes were the length of hospital stay (LOS), the rates of transfusion and albumin (Alb) administration, hemoglobin (Hb) decrease and serum Alb decrease. The categorical variables were compared using chi-squared and/or two-tailed Fisher's exact tests, whereas continuous variables were compared using two-tailed independent t-tests, the continuous variables which were asymmetrical distributions used a Kruskal-Wallis test. RESULTS: With the application of ERAS, the rate of perioperative complications in the >5 months group was significantly lower than that in the ≤5 months group (13/195 vs. 45/307, p < 0.05). Concerning the cost of hospitalization, the >5 monthly intervals spent significantly less than the ≤5 monthly intervals ($ 8695.91 vs. $ 8919.71, p < 0.05). However, no significant difference was found for secondary outcomes such as the rate of transfusions and Alb administrations or decreases of Hb and Alb in the 5 months threshold. CONCLUSIONS: More than 5 months maybe a reasonable period to perform the first contralateral THA under ERAS regarding the rate of perioperative complications and the cost of hospitalization. However, more high-quality research will include a larger sample size in the future to validate the appropriate time of staged bilateral THA.

The Optimal Dose, Efficacy and Safety of Tranexamic Acid and Epsilon-Aminocaproic Acid to Reduce Bleeding in TKA: A Systematic Review and Bayesian Network Meta-analysis.

OBJECTIVE: The optimal dose and efficacy of tranexamic acid (TXA) and epsilon-aminocaproic acid (EACA) in total knee arthroplasty (TKA) were under controversial, and we aimed to make comparisons between different doses of TXA and EACA in intravenous (IV) or intra-articular (IA) applications in patients undergoing TKA. METHODS: This network meta-analysis was guided by the Priority Reporting Initiative for Systematic Assessment and Meta-Analysis (PRISMA). According to the administrations of antifibrinolytic agents, patients in eligible studies were divided into three subgroups: (i) IA applications of TXA and EACA; (ii) IV applications (g) of TXA and EACA; (iii) IV applications (mg/kg) of TXA and EACA. Total blood loss (TBL), hemoglobin (HB) drops and transfusion rates were the primary outcomes, while drainage volume, pulmonary embolism (PE) or deep vein thrombosis (DVT) risk were the secondary outcomes. A multivariate Bayesian random-effects model was adopted in the network analysis. RESULTS: A total of 38 eligible trials with different regimens were assessed. Overall inconsistency and heterogeneity were acceptable. Taking all primary outcomes into account, 1.0-3.0 g TXA were most effective in IA applications, 1-6 g TXA and 10-14 g EACA were most effective in IV applications (g), while 30 mg/kg TXA and 150 mg/kg EACA were most effective in IV applications (mg/kg). None of the regimens showed increasing risk for pulmonary embolism (PE) or deep vein thrombosis (DVT) compared with placebo. CONCLUSION: 0 g IA TXA, 1.0 g IV TXA or 10.0 g IV EACA, as well as 30 mg/kg IV TXA or 150 mg/kg IV EACA were most effective and enough to control bleeding for patients after TKA. TXA was at least 5 times more potent than EACA.

The Optimal Period of Staged Bilateral Total Knee Arthroplasty Procedures under Enhanced Recovery: A Retrospective Study.

OBJECTIVE: The implications of the interval of staged bilateral total knee arthroplasty (TKA) procedures for postoperative complications and costs are not clear. We aimed to determine the optimal time interval between the two stages of bilateral TKA procedures under the enhanced recovery after surgery (ERAS) protocol. METHODS: This retrospective study of collected data included bilateral TKA cases under the ERAS protocol performed between 2018 and 2021 at the West China Hospital of Sichuan University. The staged time was subdivided into three groups according to the interval between the first TKA and second contralateral TKA: group 1: 2- to 6-month, group 2: 6- to 12-month, and group 3: >12 months. The primary outcome was the incidence of postoperative complications. The secondary outcomes were the length of hospital stay (LOS), hemoglobin (Hb) decrease, hematocrit (Hct) decrease, and albumin (Alb) decrease. RESULTS: We analyzed 281 patients who underwent staged bilateral TKAs between 2018 and 2021 at the West China Hospital of Sichuan University. Regarding postoperative complications, there were no statistically significant differences among the three groups (P = 0.21). For the mean LOS, the 6- to 12-month group had a significantly shorter LOS compared with the 2- to 6-month group (P < 0.01). There was also a significant decrease in Hct of the 2- to 6-month group compared with the 6- to 12-month group and the >12 months group (P = 0.02; P < 0.05, respectively). CONCLUSION: Staging the second arthroplasty for more than a half year seems to offer a reduction in the rate of postoperative complications and LOS under ERAS protocol. ERAS shortens the interval of staged bilateral TKA by at least 6 months for patients who might receive their second surgery without the need to wait for an extended period.

Influence of patellofemoral joint degeneration on clinical outcomes after medial unicompartmental knee arthroplasty.

BACKGROUND: Patellofemoral joint (PFJ) degeneration has traditionally been regarded as a contraindication to unicompartmental knee arthroplasty (UKA). More recently, some researchers have proposed that PFJ degeneration can be ignored in medial UKA, and others have proposed that this change should be reviewed in PFJ degenerative facets and severity. This study aimed to systematically evaluate the effect of PFJ degeneration on patient-reported outcome measures (PROMs) and revision rates after medial UKA. METHODS: Electronic databases (PubMed, Embase, Web of Science, etc.) were searched for studies assessing the influence of PFJ degeneration on medial UKA. A random-effects meta-analysis was conducted for the Oxford knee score (OKS), Knee society score (KSS), and revision rates and stratified by PFJ degenerative facets (medial/lateral/trochlear/unspecified), severe PFJ degeneration (bone exposed), and bearing type (mobile/fixed). Heterogeneity was assessed by the Cochran Q test statistic and chi-squared tests with the I-squared statistic. RESULTS: A total of 34 articles with 7007 knees (2267 with PFJ degeneration) were included (5762 mobile-bearing and 1145 fixed-bearing and 100 unspecified). Slight to moderate degenerative changes in the medial and trochlear facets did not decrease the OKS and KSS, and only lateral facets significantly decreased the OKS (mean difference [MD] = -2.18, P   <  0.01) and KSS (MD = -2.61, P   <  0.01). The severity degree of PFJ degeneration had no additional adverse effect on the OKS, KSS, or revision rates. For mobile-bearing UKA, only lateral PFJ degeneration significantly decreased the OKS (MD = -2.21, P  < 0.01) and KSS (MD = -2.44, P  < 0.01). For fixed-bearing UKA, no correlation was found between PROMs/revision rates and PFJ degeneration. CONCLUSION: For medial mobile-bearing UKA, slight to moderate degenerative changes in the PFJ, except lateral facet, did not compromise PROMs or revision rates. For medial fixed-bearing UKA, although it might not be conclusive enough, PROMs or revision rates were not adversely affected by PFJ degeneration (regardless of the facet).

C-reactive protein/albumin and C-reactive protein/fibrinogen ratios for the diagnosis of periprosthetic joint infection in revision total joint arthroplasty.

AIM: Testing for systemic inflammation markers is considered a simpler method for diagnosing periprosthetic joint infection (PJI). Changes in the C-reactive protein/albumin ratio (CRP/Alb ratio) and C-reactive protein/fibrinogen ratio (CRP/Fib ratio) are associated with PJI. This study aimed to evaluate the application of CRP/Alb and CRP/Fib ratios as novel inflammation-based markers for the diagnosis of PJI. METHODS: We retrospectively evaluated 445 patients who underwent total hip and knee revision arthroplasties between January 2010 and February 2021. Of these, 129 patients were also independently evaluated for PJI with coagulation-related comorbidities. The patients were divided into two groups: the aseptic revision (268 patients) and PJI revision groups (187 patients). Subsequently, we evaluated the diagnostic value of the CRP/Alb and CRP/Fib ratios compared to other inflammation-based diagnoses using the area under the curve (AUC) values. RESULTS: The AUC values of the CRP/Alb and CRP/Fib ratios were 0.880 and 0.872, respectively, suggesting similar diagnostic potentials for PJI. The CRP/Alb and CRP/Fib ratios were better than the erythrocyte sedimentation rate (ESR), Alb, and Fib, whose AUC values were 0.765, 0.352, and 0.730, respectively, for the diagnosis of PJI. The optimal cut-off for the CRP/Alb ratio was 0.13, with good sensitivity (85.0%) and specificity (78.4%). The optimal cut-off CRP/Fib ratio was 2.04, with good sensitivity (81.3%) and specificity (80.6%). Notably, the CRP/Alb and CRP/Fib ratios had the highest sensitivity, followed by four conventional inflammatory markers, namely, CRP, ESR, Alb, and Fib, which had sensitivities of 80.2%, 67.4%, 50.8%, and 54.0%, respectively. Similar findings were observed in patients with coagulation-related comorbidities. CONCLUSION: Both the CRP/Alb and CRP/Fib ratios were significantly higher in patients with PJI than in those with aseptic failure and showed better sensitivity and specificity for diagnosing PJI than classical inflammatory markers.

Transcriptome-wide association study identifies new susceptibility genes for degenerative cervical spondylosis.

AIMS: Degenerative cervical spondylosis (DCS) is a common musculoskeletal disease that encompasses a wide range of progressive degenerative changes and affects all components of the cervical spine. DCS imposes very large social and economic burdens. However, its genetic basis remains elusive. METHODS: Predicted whole-blood and skeletal muscle gene expression and genome-wide association study (GWAS) data from a DCS database were integrated, and functional summary-based imputation (FUSION) software was used on the integrated data. A transcriptome-wide association study (TWAS) was conducted using FUSION software to assess the association between predicted gene expression and DCS risk. The TWAS-identified genes were verified via comparison with differentially expressed genes (DEGs) in DCS RNA expression profiles in the Gene Expression Omnibus (GEO) (Accession Number: GSE153761). The Functional Mapping and Annotation (FUMA) tool for genome-wide association studies and Meta tools were used for gene functional enrichment and annotation analysis. RESULTS: The TWAS detected 420 DCS genes with p < 0.05 in skeletal muscle, such as ribosomal protein S15A (RPS15A) (PTWAS = 0.001), and 110 genes in whole blood, such as selectin L (SELL) (PTWAS = 0.001). Comparison with the DCS RNA expression profile identified 12 common genes, including Apelin Receptor (APLNR) (PTWAS = 0.001, PDEG = 0.025). In total, 148 DCS-enriched Gene Ontology (GO) terms were identified, such as mast cell degranulation (GO:0043303); 15 DCS-enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were identified, such as the sphingolipid signalling pathway (ko04071). Nine terms, such as degradation of the extracellular matrix (R-HSA-1474228), were common to the TWAS enrichment results and the RNA expression profile. CONCLUSION: Our results identify putative susceptibility genes; these findings provide new ideas for exploration of the genetic mechanism of DCS development and new targets for preclinical intervention and clinical treatment.Cite this article: Bone Joint Res 2023;12(1):80-90.

Transcriptome-wide association study identifies novel genes associated with bone mineral density and lean body mass in children.

OBJECTIVE: To identify novel candidate genes whose expression is associated with bone mineral density (BMD) and body lean mass (LM) in children. METHODS: A tissue-specific transcriptome-wide association study (TWAS) was conducted utilizing a large-scale genome-wide association study (GWAS) dataset associated with BMD and LM and involving 10,414 participants. The measurement of BMD and LM phenotypes was made based on total-body dual-energy X-ray absorptiometry (TB-DXA) scans. TWAS was conducted by using FUSION software. Reference panels for muscle skeleton (MS), peripheral blood (NBL) and whole blood (YBL) were used for TWAS analysis. Functional enrichment and protein-protein interaction (PPI) analyses of the genes identified by TWAS were performed by using the online tool Metascape ( http://metascape.org ). RESULTS: For BMD, we identified 174 genes with P < 0.05, such as IKZF1 (P = 1.46 × 10-9) and CHKB (P = 8.31 × 10-7). For LM, we identified 208 genes with P < 0.05, such as COPS5 (P = 3.03 × 10-12) and MRPS33 (P = 5.45 × 10-10). Gene ontology (GO) enrichment analysis of the BMD-associated genes revealed 200 GO terms, such as protein catabolic process (Log P = -5.09) and steroid hormone-mediated signaling pathway (Log P = -3.13). GO enrichment analysis of the LM-associated genes detected 287 GO terms, such as the apoptotic signaling pathway (Log P = -8.08) and lipid storage (Log P = -3.55). CONCLUSION: This study identified several candidate genes for BMD and LM in children, providing novel clues to the genetic mechanisms underlying the development of childhood BMD and LM.

Elevated Red Blood Cell Distribution Width Is Associated with Poor Prognosis in Fractured Patients Admitted to Intensive Care Units.

OBJECTIVES: Red blood cell distribution width (RDW) with prognosis in various infectious diseases. For fractured patients admitted to the intensive care units (ICU), an accurate and fast appraisal is essential. To investigate the association between RDW and prognosis in fractured patients admitted to the ICU utilizing the MIMIC-III database. METHODS: A retrospective cohort from the MIMIC III database from 2001 and 2012 was constructed. RDW and other information were collected with in-hospital mortality as the primary outcome and 90-day mortality and hospital and intensive care unit (ICU) length of stay (LOS) as secondary outcomes. Univariate and multivariate logistic regression models with propensity score inverse probability of treatment weighting (IPTW) were used to investigate the prognostic value of RDW. A nomogram was built with significant prognostic factors to predict in-hospital mortality, and the performance of the nomogram was evaluated and compared with other severity assessment scores. Subgroup analysis was also conducted. RESULTS: A total of 2721 fracture patients admitted to the ICU were identified. After IPTW, the group with higher RDW was significantly associated with elevated in-hospital mortality (odds ratio [OR]: 1.68, 95% confidence interval [CI]: 1.19-2.37), 90-day mortality (OR: 1.39, 95% CI: 1.04-1.86), prolonged hospital LOS (OR: 1.25, 95% CI: 1.03-1.50), and ICU LOS significantly (OR: 1.26, 95% CI: 1.05-1.53) in the multivariate logistics model. The nomogram showed optimal discriminative ability and predictive accuracy with an area under the receiver operating characteristic curve of 0.77. CONCLUSION: RDW independently predicted in-hospital mortality, 90-day mortality, and hospital and ICU LOS in fractured patients admitted to ICU. The nomogram including RDW could also be a promising tool with potential clinical benefits.

The optimal regimen, efficacy and safety of tranexamic acid and aminocaproic acid to reduce bleeding for patients after total hip arthroplasty: A systematic review and Bayesian network meta-analysis.

OBJECTIVES: We aimed to evaluate the optimal regimen, efficacy and safety of tranexamic acid (TXA) and aminocaproic acid (EACA) for patients after total hip arthroplasty (THA). METHODS: The network meta-analysis was guided by the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guideline. The outcomes were total blood loss, transfusion rates, hemoglobin (HB) drop, and risk for pulmonary embolism (PE) or deep vein thrombosis (DVT). Subgroup analyses were performed among most effective regimens to determine the influences of timing and number of doses. RESULTS: A total of 56 eligible RCTs with different regimens were assessed. For reducing total blood loss, all high doses of TXA and EACA except high dose of intra-articular (IA) TXA, as well as medium dose of combination of intravenous and intra-articular (combined IV/IA) TXA were most effective. All high doses of TXA, as well as medium dose of combined IV/IA TXA did not show inferiority in reducing transfusion rates and HB drop compared with other regimens. No regimens showed higher risk for PE or DVT compared with placebo, and no statistical differences were seen among most effective regimens in subgroup analyses. CONCLUSIONS: As effective as high doses of EACA and TXA, medium dose (20-40 mg/kg or 1.5-3.0 g) of combined IV/IA TXA was enough to control bleeding for patients after THA without increasing risk for PE/DVT. TXA was at least 5 times more potent than EACA. Timing and number of doses had few influences on blood conserving efficacy. LEVEL OF EVIDENCE: Level I.

Comparisons of Different Bearing Surfaces in Cementless Total Hip Arthroplasty: A Systematic Review and Bayesian Network Analysis.

BACKGROUND: We aimed to make comparisons of different bearing surfaces in patients after cementless total hip arthroplasty. METHODS: The network meta-analysis was guided by the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guideline. The primary outcomes were implant survival and Harris hip score (HHS). Secondary outcomes included linear wear rates and serum level of metal ions. Subgroup analyses were performed by: (1) classifying head sizes as small and large; (2) femoral heads as ceramic and metal; and (3) liners as metal, ceramic, polyethylene, highly cross-linked polyethylene (HXP), or vitamin E-infused highly cross-linked polyethylene (HXPE). A total of 64 eligible RCTs with different bearings were assessed. Overall inconsistency and heterogeneity were acceptable. RESULTS: In the 10 years follow-up, metal-on-polythene and ceramic-on-polythene bearings with small heads showed higher risk for revisions compared with metal-on-HXP and ceramic-on-HXP bearings with small heads. Similarly, only metal or ceramic-on-polythene bearings with small heads showed inferiority in HHS compared with other bearings. Conventional polyethylene liners showed higher linear wear rates compared with HXP, HXPE, and ceramic liners at 5 and 10 years after surgery, while metal-on-metal and ceramic-on-metal bearings showed higher serum level of cobalt and chromium. CONCLUSION: Bearings containing HXP, HXPE, and ceramic liners showed comparable survivorship and hip function at follow-up of 5 and 10 years. Hard-on-hard bearings containing metal had higher serum level of metal ions than others. Bearings containing conventional polyethylene had worse performance in terms of implant survival, hip function, and wear rates. LEVEL OF EVIDENCE: Level I.

The role of the sirtuin family in cartilage and osteoarthritis: molecular mechanisms and therapeutic targets.

Osteoarthritis (OA) is mainly characterized by the progressive destruction of articular cartilage. Mounting studies have revealed that disruption of extracellular matrix (ECM) homeostasis, aberrant chondrocyte metabolism, an increase in the number of senescent chondrocytes and abnormal activation of cell death such as chondrocyte apoptosis and autophagy, are the crucial steps in OA development. Additionally, mitochondrial dysfunction also participates in the abovementioned processes and is the key element of OA pathogenesis. Sirtuin (SIRT) is a family of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases that can actively participate and primarily regulate chondrocyte function in OA pathophysiological processes. Some members of the SIRT family located in mitochondria can regulate mitochondrial function and mediate mitochondrial homeostasis via deacetylation to protect chondrocytes. In addition, SIRT can maintain ECM homeostasis, regulate chondrocyte metabolism, inhibit chondrocyte apoptosis and autophagy, and prevent chondrocyte senescence in cartilage by exerting its deacetylation activity. However, the molecular mechanism of the SIRT family against the onset and development of OA remains poorly elucidated. In this review, we will discuss the potential protective role of SIRT in the progression of OA and summarize several sirtuin-activating molecules as well as their potential therapeutic applications for OA.

No genetic causal association between iron status and osteoporosis: A two-sample Mendelian randomization.

Objective: To explore the genetic causal association between osteoporosis (OP) and iron status through Mendelian randomization (MR). Methods: Publicly available genome-wide association study (GWAS) summary data were used for MR analysis with four iron status-related indicators (ferritin, iron, total iron binding capacity, and transferrin saturation) as exposures and three different types of OP (OP, OP with pathological fracture, and postmenopausal OP with pathological fracture) as outcomes. The inverse-variance weighted (IVW) method was used to analyze the genetic causal association between the four indicators of iron status and OP. The heterogeneity of MR results was determined using IVW and MR-Egger methods. The pleiotropy of MR results was determined using MR-Egger regression. A leave-one-SNP-out test was performed to determine whether the MR results were affected by a single nucleotide polymorphism (SNP). The weighted median method was conducted to further validate our results. Results: Based on IVW, MR-Egger and weighted median models, we found no causal association between iron status (ferritin, iron, total iron binding capacity, or transferrin saturation) and OP (Pbeta > 0.05 in all models). IVW and MR-Egger analysis of OP with pathological fracture and iron status indicators showed no potential genetic causal association (Pbeta> 0.05 in the two analyses). The results of the weighted median were consistent with those of IVW (Pbeta> 0.05 in all analyses). There was no potential genetic causal association between iron status and postmenopausal OP with pathological fracture based on serum iron (Pbeta>0.05 in all models). No heterogeneity or horizontal pleiotropy was found in any of the analyses. None of the leave-one-out tests in the analyses found any SNP that could affect the results of MR. Conclusion: Our results demonstrate that there is no genetic causal association between OP and iron status, but the effects of other factors were not excluded.

Eight-year trajectories of malalignment progression in symptomatic knee osteoarthritis.

BACKGROUND: Although various therapies have been developed to treat malalignment in osteoarthritic knees, the pattern of malalignment progression is still unclear. This study aimed to identify homogeneous subgroups with distinct trajectories of malalignment progression in subjects with symptomatic knee osteoarthritis (KOA) and to determine corresponding risk factors. METHODS: Eight-year follow-up (from 2004 to 2012) data on 1252 participants with symptomatic KOA from the Osteoarthritis Initiative were included. Varus/valgus angle progression was characterized by group-based trajectory models. Time-varying covariates were introduced into the model to investigate how they affected trajectories. Multinomial logistic regression for trajectory group membership was applied to ascertain risk factors. RESULTS: Five subgroups were identified. Participants in the varus worsening trajectory (n = 166) or valgus worsening trajectory (n = 118) proceeded to worsen malalignment over time. The neutral trajectory (n = 378), varus stable trajectory (n = 328), and valgus stable trajectory (n = 262) maintained close to the initial varus/valgus angle over 8 years. Higher baseline Kellgren and Lawrence grade (odds ratio [OR] = 4.35, P  < 0.001 for varus; OR = 3.85, P  < 0.001 for valgus) and "severe" baseline malalignment (OR = 13.57, P < 0.001 for varus; OR = 23.04, P < 0.001 for valgus) were risk factors for worsening trajectories. The cutoff point of the baseline varus/valgus angle to discriminate between stable or worsening trajectory was -4.5° for varus and 3.6° for valgus. CONCLUSIONS: This study identified the malalignment progression pattern - minor malalignment (-4.5° to +3.6°) tends to remain stable, while major baseline malalignment is likely to progress. This provides a reference for therapy to prevent malalignment from deteriorating and emphasizes the necessity of determining the trigger factors for malalignment onset.