Cell Sheet Technology: An Emerging Approach for Tendon and Ligament Tissue Engineering.

Tendon and ligament injuries account for a substantial proportion of disorders in the musculoskeletal system. While non-operative and operative treatment strategies have advanced, the restoration of native tendon and ligament structures after injury is still challenging due to its innate limited regenerative ability. Cell sheet technology is an innovative tool for tissue fabrication and cell transplantation in regenerative medicine. In this review, we first summarize different harvesting procedures and advantages of cell sheet technology, which preserves intact cell-to-cell connections and extracellular matrix. We then describe the recent progress of cell sheet technology from preclinical studies, focusing on the application of stem cell-derived sheets in treating tendon and ligament injuries, as well as highlighting its effects on mitigating inflammation and promoting tendon/graft-bone interface healing. Finally, we discuss several prerequisites for future clinical translation including the selection of appropriate cell source, optimization of preparation process, establishment of suitable animal model, and the fabrication of vascularized complex tissue. We believe this review could potentially provoke new ideas and drive the development of more functional biomimetic tissues using cell sheet technology to meet the needs of clinical patients.

Association between Antibiotic Exposure and Type 2 Diabetes Mellitus in Middle-Aged and Older Adults.

BACKGROUND: Although previous studies have shown an association between clinically used antibiotics and type 2 diabetes, the relationship between antibiotic exposure from food and drinking water and type 2 diabetes in middle-aged and older adults is unclear. OBJECTIVE: This study was aimed at exploring the relationship between antibiotic exposures from different sources and type 2 diabetes in middle-aged and older people, through urinary antibiotic biomonitoring. METHODS: A total of 525 adults who were 45-75 years of age were recruited from Xinjiang in 2019. The total urinary concentrations of 18 antibiotics in five classes (tetracyclines, fluoroquinolones, macrolides, sulfonamides and chloramphenicol) commonly used in daily life were measured via isotope dilution ultraperformance liquid chromatography coupled with high-resolution quadrupole time-of-flight mass spectrometry. The antibiotics included four human antibiotics, four veterinary antibiotics and ten preferred veterinary antibiotics. The hazard quotient (HQ) of each antibiotic and the hazard index (HI) based on the mode of antibiotic use and effect endpoint classification were also calculated. Type 2 diabetes was defined on the basis of international levels. RESULTS: The overall detection rate of the 18 antibiotics in middle-aged and older adults was 51.0%. The concentration, daily exposure dose, HQ, and HI were relatively high in participants with type 2 diabetes. After model adjustment for covariates, participants with HI > 1 for microbial effects (OR = 3.442, 95%CI: 1.423-8.327), HI > 1 for preferred veterinary antibiotic use (OR = 3.348, 95%CI: 1.386-8.083), HQ > 1 for norfloxacin (OR = 10.511, 96%CI: 1.571-70.344) and HQ > 1 for ciprofloxacin (OR = 6.565, 95%CI: 1.676-25.715) had a higher risk of developing type 2 diabetes mellitus. CONCLUSIONS: Certain antibiotic exposures, mainly those from sources associated with food and drinking water, generate health risks and are associated with type 2 diabetes in middle-aged and older adults. Because of this study's cross-sectional design, additional prospective studies and experimental studies are needed to validate these findings.

Association between abdominal obesity indices and risk of cardiovascular events in Chinese populations with type 2 diabetes: a prospective cohort study.

BACKGROUND: Waist circumference (WC), visceral adiposity index (VAI), lipid accumulation product (LAP), and Chinese visceral adiposity index (CVAI) are considered surrogate indicators of abdominal fat deposition, but the longitudinal association of these indices with cardiovascular (CV) events in adults with type 2 diabetes (T2D) remains unclear. Our study aimed to examine the associations between abdominal obesity indices and incident CV events among people with T2D and to compare their predictive performance in risk assessment. METHODS: The present study included 2328 individuals with T2D from the Xinjiang Multi-Ethnic Cohort. Multivariable Cox regression analyses were applied to assess the associations between abdominal obesity indices and CV events. Harrell's concordance statistic (C-statistic), net reclassification improvement (NRI) index, and integrated discrimination improvement (IDI) index were utilized to evaluate the predictive performance of each abdominal obesity index. RESULTS: At a median follow-up period of 59 months, 289 participants experienced CV events. After multivariable adjustment, each 1-SD increase in WC, VAI, LAP, and CVAI was associated with a higher risk of CV events in people with T2D, with adjusted hazard ratios (HRs) being 1.57 [95% CI (confidence interval): 1.39-1.78], 1.11 (95% CI 1.06-1.16), 1.46 (95% CI 1.36-1.57), and 1.78 (95% CI 1.57-2.01), respectively. In subgroup analyses, these positive associations appeared to be stronger among participants with body mass index (BMI) < 25 kg/m2 compared to overweight/obese participants. As for the predictive performance, CVAI had the largest C-statistic (0.700, 95% CI 0.672-0.728) compared to VAI, LAP, WC, and BMI (C-statistic: 0.535 to 0.670, all P for comparison < 0.05). When the abdominal obesity index was added to the basic risk model, the CVAI index also showed the greatest incremental risk stratification (C-statistic: 0.751 vs. 0.701, P < 0.001; IDI: 4.3%, P < 0.001; NRI: 26.6%, P < 0.001). CONCLUSIONS: This study provided additional evidence that all abdominal obesity indices were associated with the risk of CV events and highlighted that CVAI might be a valuable abdominal obesity indicator for identifying the high risk of CV events in Chinese populations with T2D. These results suggest that proactive assessment of abdominal obesity could be helpful for the effective clinical management of the diabetic population.

Urinary Antibiotics and Dietary Determinants in Adults in Xinjiang, West China.

The Xinjiang autonomous region, located in west China, has a unique ethnic structure and a well-developed livestock industry. People in this region have a high risk of exposure to antibiotics, but the exposure level to antibiotics in relation to dietary determinants is unknown. In this study, 18 antibiotics, including four human antibiotics (HAs), four veterinary antibiotics (VAs), and 10 preferred veterinary antibiotics (PVAs) were detected in the urine of approximately half of the 873 adults in Xinjiang, including Han Chinese (24.6%), Hui (25.1%), Uighur (24.6%), and Kazakh (25.7%). Logistic regression was used to analyze the association between antibiotic exposure levels and adult diet and water intake. The detection percentage of antibiotics in the urine of adults in Xinjiang ranged from 0.1% to 30.1%, with a total detection percentage of all antibiotics of 49.8%. HAs, VAs and PVAs were detected in 12.3%, 10.3%, and 40.5%, respectively. Fluoroquinolones were the antibiotics with the highest detection percentage (30.1%) and tetracyclines were the antibiotics with the highest detected concentration (17 ng/mL). Adults who regularly ate pork, consumed fruit daily, and did not prefer a plant-based diet were associated with thiamphenicol, norfloxacin, and fluoroquinolones, respectively. These results indicated that adults in the Xinjiang autonomous region were extensively exposed to multiple antibiotics, and some types of food were potential sources of exposure. Special attention should be paid to the health effects of antibiotic exposure in humans in the future.

Plasma VWF: Ag levels predict long-term clinical outcomes in patients with acute myocardial infarction.

Background: A vital role in coronary artery disease is played by Von Willebrand factor (VWF), which serves as a bridge between platelets and the subendothelial matrix after vessel damage. The purpose of the study was to assess the validity of plasma VWF antigen (VWF: Ag) levels as a predictor of clinical outcomes after acute myocardial infarction (AMI). Methods: Three hundred and seventy-four patients were studied following coronary angiography, including 209 patients suffering from acute myocardial infarction and 165 healthy participants. Coronary angiography was followed by measurement of plasma VWF: Ag levels. Over a 2-year follow-up period, major adverse cardiopulmonary and cerebrovascular events (MACEs) were the primary endpoint. All-cause mortality was investigated as a secondary endpoint. Results: When compared to controls, patients with AMI had mean plasma VWF: Ag levels that were ~1.63 times higher (0.860 ± 0.309 vs. 0.529 ± 0.258 IU/ml; P < 0.001). The plasma VWF: Ag levels were substantially higher in patients who experienced MACEs after myocardial infarction vs. those without MACEs (1.088 ± 0.253 vs. 0.731 ± 0.252 IU/ml; P < 0.001). For predicting long-term MACEs using the optimal cut-off value (0.7884 IU/ml) of VWF: Ag, ROC curve area for VWF: Ag was 0.847, with a sensitivity of 87.2% and a specificity of 66.3% (95%CI: 0.792-0.902; P = 0.001). Two-year follow-up revealed a strong link between higher plasma VWF: Ag levels and long-term MACEs. At the 2-year follow-up, multivariate regression analysis revealed an independent relationship between plasma VWF: Ag levels and MACEs (HR = 6.004, 95%CI: 2.987-12.070). Conclusion: We found evidence that plasma VWF: Ag levels were independent risk factors for AMI. Meanwhile, higher plasma VWF: Ag levels are associated with long-term MACEs in people with AMI.

Knockdown of long non-coding RNA KCNQ1OT1 suppresses the progression of osteoarthritis by mediating the miR-211-5p/TCF4 axis in vitro.

Numerous studies have reported the critical roles of long non-coding RNAs (lncRNAs) in the regulation of osteoarthritis (OA) development. The present study aimed to assess the function and regulatory mechanism of a lncRNA, KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1), in OA in vitro. C28/I2 cells were treated with lipopolysaccharide (LPS) to generate an in vitro OA model. The relative expression levels of KCNQ1OT1, microRNA (miR)-211-5p and transcription factor 4 (TCF4) were determined via reverse transcription-quantitative polymerase chain reaction. The associations between KCNQ1OT1, miR-211-5p and TCF4 were confirmed using a dual-luciferase reporter assay. Furthermore, cell viability was assessed using the MTT assay. Inflammatory cytokine levels were measured using ELISA. The protein expression levels of matrix metalloproteinase-3/13, collagen II/X and TCF4 were detected by western blotting. KCNQ1OT1 and TCF4 were highly expressed in the cartilage tissues of patients with OA and C28/I2 cells treated with LPS (OA cells), whereas miR-211-5p was downregulated concomitantly in OA tissues and cells. Knockdown of KCNQ1OT1 stimulated cell viability, and suppressed the inflammation and degradation of the extracellular matrix (ECM) in OA cells. In addition, overexpression of miR-211-5p stimulated cell viability, and inhibited inflammation and degradation of the ECM in OA cells. Notably, miR-211-5p was revealed to be the target of, and was negatively regulated by, KCNQ1OT1. TCF4 was targeted and negatively modulated by miR-211-5p. Transfection of cells with the miR-211-5p inhibitor or pcDNA-TCF4 reversed the suppressive effects of short hairpin RNA (sh)-KCNQ1OT1 on inflammation and ECM degradation, as well as the promotive effect of sh-KCNQ1OT1 on viability in OA in vitro. Therefore, KCNQ1OT1 may regulate the miR-211-5p/TCF4 axis to ameliorate OA in vitro.

Is Lutikizumab, an Anti-Interleukin-1α/ß Dual Variable Domain Immunoglobulin, efficacious for Osteoarthritis? Results from a bayesian network meta-analysis.

OBJECTIVE: Most guidelines recommend the use of nonsteroidal anti-inflammatory drugs (NSAIDs), duloxetine, and tramadol for the nonoperative treatment of osteoarthritis (OA), but the use of them is limited by the tolerability and safety concerns. Lutikizumab is a novel anti-IL-1α/ß dual variable domain immunoglobulin that can simultaneously bind and inhibit IL-1α and IL-1ß to relieve the pain and dysfunction symptoms. We conducted this network meta-analysis to comprehensively compare the clinical efficacy and safety of lutikizumab with other drugs recommended by guidelines. METHODS: We conducted a Bayesian network and conventional meta-analyses to compare the efficacy and safety of lutikizumab with other traditional drugs. All eligible randomized clinical trials, in PubMed, CNKI, EMBASE, and Web of Science databases, from January 2000 to January 2020, were included. The Cochrane risk of the bias assessment tool was used for quality assessment. Pain relief, function improvement, and risk of adverse effects (AEs) were compared in this study. RESULTS: 24 articles with 11858 patients were included. Duloxetine (DUL) had the largest effect for pain relief (4.76, 95% CI [2.35 to 7.17]), and selective cox-2 inhibitors (SCI) were the most efficacious treatment for physical function improvement (SMD 3.94, 95% CI [2.48 to 5.40]). Lutikizumab showed no benefit compared with placebo for both pain relief (SMD 1.11, 95% CI [-2.29 to 4.52]) and function improvement (SMD 0.992, 95% CI [-0.433 to 4.25]). Lutikizumab and all other drugs are of favorable tolerance for patients in the treatment of OA compared with placebo. CONCLUSIONS: Lutikizumab, the new anti-Interleukin-1α/ß dual variable domain immunoglobulin, showed no improvement in pain or function when compared with placebo. Selective cox-2 inhibitors and duloxetine remain the most effective and safest treatment for OA. More high-quality trials are still needed to reconfirm the findings of this study.