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.

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.

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.

Characterization of avian influenza A (H4N2) viruses isolated from wild birds in Shanghai during 2019 to 2021.

The H4 subtype of avian influenza viruses has been widely distributed among wild birds. During the surveillance of the avian influenza virus in Shanghai from 2019 to 2021, a total of 4,451 samples were collected from wild birds, among which 46 H4 subtypes of avian influenza viruses were identified, accounting for 7.40% of the total positive samples. The H4 subtype viruses have a wide range of hosts, including the spot-billed duck, common teal, and other wild birds in Anseriformes. Among all H4 subtypes, the most abundant are the H4N2 viruses. To clarify the genetic characteristics of H4N2 viruses, the whole genome sequences of 20 H4N2 viruses were analyzed. Phylogenetical analysis showed that all 8 genes of these viruses belonged to the Eurasian lineage and closely clustered with low pathogenic avian influenza viruses from countries along the East Asia-Australia migratory route. However, the PB1 gene of 1 H4N2 virus (NH21920) might provide its internal gene for highly pathogenic avian influenza H5N8 viruses in Korea and Japan. At least 10 genotypes were identified in these viruses, indicating that they underwent multiple complex recombination events. Our study has provided a better epidemiological understanding of the H4N2 viruses in wild birds. Considering the mutational potential, comprehensive surveillance of the H4N2 virus in both poultry and wild birds is imperative.

[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.

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.

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 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.

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.

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 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.

Core-Shell Structured Porous Calcium Phosphate Bioceramic Spheres for Enhanced Bone Regeneration.

Adequate new bone regeneration in bone defects has always been a challenge as it requires excellent and efficient osteogenesis. Calcium phosphate (CaP) bioceramics, including hydroxyapatite (HA) and biphasic calcium phosphates (BCPs), have been extensively used in clinical bone defect filling due to their good osteoinductivity and biodegradability. Here, for the first time, we designed and fabricated two porous CaP bioceramic granules with core-shell structures, named in accordance with their composition as BCP@HA and HA@BCP (core@shell). The spherical shape and the porous structure of these granules were achieved by the calcium alginate gel molding technology combined with a H2O2 foaming process. These granules could be stacked to build a porous structure with a porosity of 65-70% and a micropore size distribution between 150 and 450 µm, which is reported to be good for new bone ingrowth. In vitro experiments confirmed that HA@BCP bioceramic granules could promote the proliferation and osteogenic ability when cocultured with bone marrow mesenchymal stem cells, while inhibiting the differentiation of RAW264.7 cells into osteoclasts. In vivo, 12 weeks of implantation in a critical-sized femoral bone defect animal model showed a higher bone volume fraction and bone mineral density in the HA@BCP group than in the BCP@HA or pure HA or BCP groups. From histological analysis, we discovered that the new bone tissue in the HA@BCP group was invading from the surface to the inside of the granules, and most of the bioceramic phase was replaced by the new bone. A higher degree of vascularization at the defect region repaired by HA@BCP was revealed by 3D microvascular perfusion angiography in terms of a higher vessel volume fraction. The current study demonstrated that the core-shell structured HA@BCP bioceramic granules could be a promising candidate for bone defect repair.

What Is the Normal Trajectory of C-Reactive Protein, Erythrocyte Sedimentation Rate, Plasma Fibrinogen and D-Dimer after Two-Stage Exchange for Periprosthetic Joint Infection?

OBJECTIVE: C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), plasma fibrinogen and D-Dimer are used as diagnostic biomarkers of prosthetic joint infection (PJI) after total joint arthroplasty (TJA). The purpose of the study was to investigate the normal trajectory of CRP, ESR, plasma fibrinogen and D-Dimer at different time points after two-stage exchange arthroplasty for PJI. METHODS: We studied 53 patients undergoing two-stage exchange for PJI at five time points: preoperatively (T0), duration of hospital stays (T1), 30 days (T2), 30-90 days (T3), and 90-180 days (T4) after surgery. The medical records of all patients were well documented and carefully reviewed. The Shapiro-Wilk test was utilized to compare the normal distribution for continuous variables, and the nonnormally distributed data were used for Friedmann's one-way repeat measures analysis of variances. Post hoc Dunnett's test was used to compare each pair of data to find differences from baseline. RESULTS: Compare with T0 point, the levels of CRP and ESR increased significantly and reached peak values at T1 point (all P < 0.001), with median values of 56.40 mg/L (range, 5.54-161.0 mg/L) and 49.00 mm/h (range, 13.00-113.0 mm/h), respectively. In addition, the levels of plasma fibrinogen and D-Dimer increased significantly and reached peak values at T1 point (all P < 0.001), with median values of 4.13g/L (range, 2.27-6.80 mg/L) and 4.00 mg/L (range, 0.19-14.01 mg/L), respectively. CRP and ESR rapidly declined at the T2 point with significantly compared with T0 point (P = 0.001 and P < 0.001). The levels of CRP, ESR, plasma fibrinogen and D-Dimer returned to preoperative levels of 5.23 mg/L (range, 1.01-21.70 mg/L), 19.00 mm/h (range, 6.00-60.00 mm/h), 3.38g/L (range, 1.71-5.10 g/L) and 2.33 mm/h (range, 0.19-6.87 mg/L) at T4 point, and there was no significant difference compared with T0 point (all P > 0.05). CONCLUSIONS: The study demonstrated the normal trajectory of CRP, ESR, plasma fibrinogen and D-Dimer at five time points in patients who underwent two-stage exchange for PJI. Thus, the results have the possibility of providing signs of infection after the patient receives two-stage exchange arthroplasty for PJI, which can benefit from early treatment.

Genetic Causal Association between Iron Status and Osteoarthritis: A Two-Sample Mendelian Randomization.

Objective: Observational studies have shown the association between iron status and osteoarthritis (OA). However, due to difficulties of determining sequential temporality, their causal association is still elusive. Based on the summary data of genome-wide association studies (GWASs) of a large-scale population, this study explored the genetic causal association between iron status and OA. Methods: First, we took a series of quality control steps to select eligible instrumental SNPs which were strongly associated with exposure. The genetic causal association between iron status and OA was analyzed using the two-sample Mendelian randomization (MR). Inverse-variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode methods were used for analysis. The results were mainly based on IVW (random effects), followed by sensitivity analysis. IVW and MR-Egger were used for heterogeneity testing. MR-Egger was also used for pleiotropy testing. Leave-one-SNP-out analysis was used to identify single nucleotide polymorphisms (SNPs) with potential impact. Maximum likelihood, penalized weighted median, and IVW (fixed effects) were performed to further validate the reliability of results. Results: IVW results showed that transferrin saturation had a positive causal association with knee osteoarthritis (KOA), hip osteoarthritis (HOA) and KOA or HOA (p < 0.05, OR > 1), and there was a negative causal association between transferrin and HOA and KOA or HOA (p < 0.05, OR < 1). The results of heterogeneity test showed that our IVW analysis results were basically free of heterogeneity (p > 0.05). The results of the pleiotropy test showed that there was no pleiotropy in our IVW analysis (p > 0.05). The analysis results of maximum likelihood, penalized weighted median and IVW (fixed effects) were consistent with our IVW results. No genetic causal association was found between serum iron and ferritin and OA. Conclusions: This study provides evidence of the causal association between iron status and OA, which provides novel insights to the genetic research of OA.

Exosomes rewire the cartilage microenvironment in osteoarthritis: from intercellular communication to therapeutic strategies.

Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by cartilage loss and accounts for a major source of pain and disability worldwide. However, effective strategies for cartilage repair are lacking, and patients with advanced OA usually need joint replacement. Better comprehending OA pathogenesis may lead to transformative therapeutics. Recently studies have reported that exosomes act as a new means of cell-to-cell communication by delivering multiple bioactive molecules to create a particular microenvironment that tunes cartilage behavior. Specifically, exosome cargos, such as noncoding RNAs (ncRNAs) and proteins, play a crucial role in OA progression by regulating the proliferation, apoptosis, autophagy, and inflammatory response of joint cells, rendering them promising candidates for OA monitoring and treatment. This review systematically summarizes the current insight regarding the biogenesis and function of exosomes and their potential as therapeutic tools targeting cell-to-cell communication in OA, suggesting new realms to improve OA management.

Complications Associated with Rhinoplasty: An Umbrella Review of Meta-analyses.

BACKGROUND: An increasing number of studies have investigated the effect of various methods in avoiding complications in rhinoplasty. Our study aims to analyze the connections between various choices in rhinoplasty and the rate of multiple complications by summarizing results in related meta-analyses. MATERIALS AND METHODS: Through Pubmed, MEDLINE, Embase, and the Cochrane Database were associated systematic reviews searched to gather and review the available evidence of different plans and health outcomes in rhinoplasty for this umbrella review. RESULTS: The study included 14 systematic reviews with 128 meta-analyses of randomized clinical trials. Edema and ecchymosis were the two most investigated outcomes. The implementations of steroid, tranexamic acid, periosteal preservation, external approach in lateral osteotomy, and piezoelectric osteotomy were linked with significantly lower incidence of several complications. Multiple administration of steroids was found to be associated with fewer complications in a prolonged time. CONCLUSIONS: With summarized evidence of complications related to rhinoplasty, this research can help surgeons to avert patients from suffering complications and optimize cosmetic outcomes. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Comparison of PICU Cost and Severity-Adjusted Cost Between Patients With SIRS-Defined Sepsis and Those With Age-Adapted SOFA-Defined Sepsis.

Background: The 2005 International Pediatric Sepsis Consensus definition is considered to lack specificity and may lead to the admission of low-risk patients to the pediatric intensive care unit (PICU). The aim of this study was to compare the PICU cost and the severity-adjusted cost between patients with sepsis defined by the 2005 International Pediatric Sepsis Consensus and those diagnosed using the age-adapted Sepsis-3 criteria. Methods: Septic children identified by the 2005 Consensus were screened for enrollment. The enrolled children were stratified into two subgroups using the age-adapted Sepsis 3.0 definition. A comparison was made between the subgroups of sepsis 3.0-defined children and non-sepsis 3.0-defined septic children. The Severity Adjusted ICU Cost (SAIC) was used to evaluate the case-mixed severity-adjusted costs of the study population. Coefficients in linear regression analyses in subgroups were calculated for presenting variation of PICU costs for every unit change of PRISM score. Results: A total of 397 children were enrolled. The PICU length of stay was longer in the sepsis 3.0 group than in the non-sepsis 3.0 group [median (IQR), 9.0 (5.0, 15.0) vs. 6.0 (3.0, 9.0); P < 0.001]. Pediatric risk of mortality (PRISM) scores and mortality were significantly higher in sepsis 3.0-defined septic patients. The total costs and daily costs in the PICU were both significantly lower in the non-sepsis 3.0 group (P < 0.001). The severity-adjusted ICU cost in the non-sepsis 3.0 group was lower than that in the sepsis 3.0 group [median (IQR), 7,125 (3,588, 11,134) vs. 9,364 (5,680, 15,876); P = 0.001]. There was no significant difference among the regression coefficients. Conclusions: The 2005 International Pediatric Sepsis Consensus definition does not lead to more PICU costs after considering illness severity. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03598127.

Surgical procedures in the pilonidal sinus disease: a systematic review and network meta-analysis.

The most appropriate surgical treatment for pilonidal sinus disease (PSD) is still in dispute. This study aims to comprehensively compare the outcomes of surgical interventions using network meta-analysis. Randomized controlled trial studies were searched systematically to identify all eligible studies in multiple databases and previous publications and Bayesian network meta-analysis was performed. Our primary outcome was the recurrence rate. Differences in the findings of the studies were explored in meta regressions and sensitivity analyses. The risk of bias of each study was assessed using the Cochrane risk of bias tool. Confidence in evidence was assessed using CINeMA (Confidence in Network Meta-Analysis). A total of 39 studies and 5,061 patients were identified and the most common surgical intervention was the Limberg flap. In network meta-analysis, modified Limberg flap and off-midline closure were associated with the lowest recurrence rate. However, the Karydakis flap was associated with shorter operation time by several minutes compared with other interventions and few significant results were found in other outcomes. Modified Limberg flap and off-midline closure provided relatively low recurrence and complications rates. Therefore, they could be two promising surgical interventions for PSD patients.

Breast Implants for Mammaplasty: An Umbrella Review of Meta-analyses of Multiple Complications.

BACKGROUND: The association of breast implants and complications after mammaplasty has been extensively researched. The aim of this study is to summarize all available results in meta-analysis investigating the association between implants and the incidence of various complications. METHODS: An umbrella review for breast implants and associated complications was performed by searching related reviews from electronic databases including Pubmed, Ovid and CINAHL. We collected and reviewed evidence across meta-analyses of observational and interventional studies of implants and any health outcome. The quality of the reviews was assessed using the AMSTAR tool (A measurement tool to assess systematic reviews). RESULTS: The research included 92 meta-analyses of 609 studies concerning various areas. Capsular contracture was the most investigated outcome. Radiotherapy, human acellular dermal matrix application, direct-to-implant reconstruction, smooth implant, silicone-filled implant and periareolar incision were significantly associated with higher rates of some of the complications. CONCLUSIONS: This umbrella review provides surgeons with summarized evidence of the association between the complications and implant-related factors in mammaplasty surgery to help surgeons make informed choices in the future. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Facile preparation of salivary extracellular vesicles for cancer proteomics.

Extracellular vesicles (EVs) are membrane surrounded structures released by cells, which have been increasingly recognized as mediators of intercellular communication. Recent reports indicate that EVs participate in important biological processes and could serve as potential source for cancer biomarkers. As an attractive EVs source with merit of non-invasiveness, human saliva is a unique medium for clinical diagnostics. Thus, we proposed a facile approach to prepare salivary extracellular vesicles (SEVs). Affinity chromatography column combined with filter system (ACCF) was developed to efficiently remove the high abundant proteins and viscous interferences of saliva. Protein profiling in the SEVs obtained by this strategy was compared with conventional centrifugation method, which demonstrated that about 70% more SEVs proteins could be revealed. To explore its utility for cancer proteomics, we analyzed the proteome of SEVs in lung cancer patients and normal controls. Shotgun proteomic analysis illustrated that 113 and 95 proteins have been identified in cancer group and control group, respectively. Among those 63 proteins that have been consistently discovered only in cancer group, 12 proteins are lung cancer related. Our results demonstrated that SEVs prepared through the developed strategy are valuable samples for proteomics and could serve as a promising liquid biopsy for cancer.