Injectable Temperature-Sensitive Hydrogel Loaded with IL-36Ra for the Relief of Osteoarthritis.

Osteoarthritis (OA) is an inflammatory disease accompanied by synovial joint inflammation, and IL-36 plays an important role in this process. Local application of IL-36 receptor antagonist (IL-36Ra) can effectively control the inflammatory response, thereby protecting cartilage and slowing down the development of OA. However, its application is limited by the fact that it is rapidly metabolized locally. We designed and prepared a temperature-sensitive poly(lactic-co-glycolic acid)-poly(ethylene glycol)-poly(lactic-co-glycolic acid) (PLGA-PEG-PLGA) hydrogel (IL-36Ra@Gel) system carrying IL-36Ra and evaluated its basic physicochemical characteristics. The drug release curve of IL-36Ra@Gel indicated that this system could slowly release the drug over a longer period. Furthermore, degradation experiments showed that it could be largely degraded from the body within 1 month. The biocompatibility-related results showed that it had no significant effect on cell proliferation compared to the control group. In addition, the expression of MMP-13 and ADAMTS-5 was lower in IL-36Ra@Gel-treated chondrocytes than in the control group, and the opposite results appeared in aggrecan and collagen X. After 8 weeks of treatment with IL-36Ra@Gel by joint cavity injection, HE and Safranin O/Fast green staining showed that the degree of cartilage tissue destruction in the IL-36Ra@Gel-treated group was less than those in other groups. Meanwhile, the joints of mice in the IL-36Ra@Gel group had the most intact cartilage surface, the smallest thickness of cartilage erosion, and the lowest OARSI and Mankins score among all groups. Consequently, the combination of IL-36Ra and PLGA-PLEG-PLGA temperature-sensitive hydrogels can greatly improve the therapeutic effect and prolong the drug duration time, thus effectively delaying the progression of degenerative changes in OA, providing a new feasible nonsurgical treatment for OA.

Correlation between Surface Area Ratio of Medial to Lateral Tibial Plateau and Knee Alignment in Adults.

OBJECTIVE: This study aimed to investigate the correlation between the surface area ratio of medial tibial plateau (MTP) to lateral tibial plateau (LTP) and the mechanical tibiofemoral angle (mTFA). METHODS: Lower limb computed tomography (CT) images were collected at our hospital. Then, the original CT data were analyzed and reconstructed using medical image processing software. The proximal and distal centres of the femur and tibia were marked. The surface areas of MTP and LTP were identified using image processing software. GraphPad Prism 8.0.2 was used to perform the statistical analysis. RESULTS: The surface area ratio of MTP to LTP was significantly correlated with the mTFA in all patients (P<0.0001), male group (P<0.0001), female group (P<0.0001), varus group (P<0.0001), and valgus group (P=0.002). Furthermore, the surface area of MTP and LTP was significantly greater in the male group than in the female group (P<0.0001). There was significant difference in the surface area of the MTP between the varus and valgus groups (P<0.0001). Significant difference was also observed in the surface area ratio of MTP to LTP between the varus and valgus groups (P<0.0001). CONCLUSION: The surface area ratio of MTP to LTP was correlated with the mTFA. Within a certain range, the smaller the mTFA, the greater the surface area ratio of MTP to LTP. For patients undergoing total knee arthroplasty, of whom the surface area of the MTP was basically equal to that of the LTP, it is recommended that the osteotomy should be performed in accordance with mechanical alignment standards, and that a symmetrical tibial plateau prosthesis should be used. For patients whose surface area of MTP is significantly greater than that of the LTP, it is recommended that the osteotomy should be performed in accordance with kinematic alignment standards, and that an anatomical tibial plateau prosthesis should be used.

Vancomycin or Daptomycin Plus a ß-Lactam Versus Vancomycin or Daptomycin Alone for Methicillin-Resistant Staphylococcus aureus Bloodstream Infections: A Systematic Review and Meta-Analysis.

Aims: Several in vitro and in vivo studies demonstrated that adding a ß-lactam to vancomycin (VAN) or daptomycin (DAP) can provide synergy against methicillin-resistant Staphylococcus aureus (MRSA). However, the results from clinical studies were controversial. The objective of this systematic review and meta-analysis was to compare the efficacy and safety of using VAN or DAP plus a ß-lactam (combination therapy) and using VAN or DAP alone (monotherapy) in MRSA bloodstream infections. Methods: We included randomized controlled trials and observational studies evaluating whether combination therapy can improve clinical and microbiological outcomes and safety compared to monotherapy with VAN or DAP in MRSA-related bacteremia. Results: Literature search identified 3 randomized clinical trials and 10 observational studies involving at least 1,796 patients. There were no significant associations between the combination therapy and risk of mortality within 30 days (risk ratios [RRs], 1.10, 95% confidence interval [CI], 0.82-1.46), in-hospital mortality (RR, 0.59, 95% CI, 0.31-1.13) and mortality within 60-90 days (RR, 0.91, 95% CI, 0.64-1.29). There was also no evidence that there was a difference in length of hospital stay between the combination therapy and monotherapy (mean difference, -0.41 days, 95% CI, -3.41 to 2.59). However, compared with monotherapy, combination therapy seemed to have a shorter duration of bacteremia(mean difference, -1.06 days, 95% CI, -1.53 to -0.60), a lower risk of persistent bacteremia (RR, 0.63, 95% CI, 0.51-0.79) and a lower risk of bacteremia recurrence within 60-90 days (RR, 0.61, 95% CI, 0.40-0.92). There were no statistically significant differences in the total number of adverse events, including acute kidney injury (AKI) (RR, 1.52, 95% CI, 0.84-2.73), thrombocytopenia (RR, 1.13, 95% CI, 0.74-1.73), and diarrhea (RR, 1.36, 95% CI, 0.70-2.65), between patients with combination therapy and monotherapy. In subgroup analysis, when the analysis was limited to the studies comparing using DAP plus ceftaroline with monotherapy, we found that the former had a lower risk of mortality within 30 days. In addition, a subgroup analysis limited to randomized clinical trials showed that the combination therapy was associated with a higher risk of AKI compared with using VAN or DAP alone. Conclusions: Although adding a ß-lactam to standard therapy seemed to experience a higher clearance compared with monotherapy in patients with MRSA bacteremia, the combination therapy did not increase survival benefits. Based on the available evidence, the combination therapy was not supported as the routine management of MRSA-related bacteremia, and both its harms and benefits should be taken into account.

New Oral Anticoagulants for Venous Thromboembolism Prophylaxis in Total Hip and Knee Arthroplasty: A Systematic Review and Network Meta-Analysis.

Background: There is controversy over whether use of new oral anticoagulants (NOACs) associates with increased hemorrhage risk compared with non-NOAC. Meanwhile, determining which NOAC to use remains unclear. We aimed to summarize the evidence about NOACs in venous thromboembolism (VTE) prevention for patients with total hip and knee arthroplasty (THA and TKA). Methods: We searched RCTs assessing NOACs for VTE prophylaxis in adults undergoing THA and TKA in Medline, Embase, and Cochrane up to May 2021. Primary outcomes were VTE [included deep vein thrombosis (DVT) and pulmonary embolism (PE)], major VTE, and major bleeding. The rank probabilities of each treatment were summarized by the surface under the cumulative ranking curve area (SUCRA). Results: 25 RCTs with 42,994 patients were included. Compared with non-NOAC, NOACs were associated with a decreased risk of VTE (RR 0.68; 95% CI 0.55-0.84) and major VTE (RR = 0.52; 95% CI 0.35-0.76). Additionally, rivaroxaban, apixaban, and edoxaban but not dabigatran and betrixaban, did confer a higher efficacy compared with non-NOAC. None of the individual NOACs increased the risk of bleeding, while apixaban and betrixaban were even associated with a decreased risk of bleeding. In the comparison of different NOACs, rivaroxaban was associated with the greatest benefits in VTE (SUCRA = 79.6), DVT (SUCRA = 88.8), and major VTE (SUCRA = 89.9) prevention. Furthermore, subgroup analysis confirmed that NOACs associated with a higher efficacy tendency in patients with follow-up duration <60 days than follow-up duration ≥60 days. Conclusion: Evidence suggests that NOACs exert more benefits on VTE prophylaxis, and none of the individual NOACs increased hemorrhage compared with non-NOAC. Among various NOACs, rivaroxaban is recommended in patients with lower bleeding risk, and apixaban is recommended in patients with higher bleeding risk. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/], identifier [CRD42021266890].

Development and validation of a more accurate estimating equation for glomerular filtration rate in a Chinese population.

Previously published equations to estimate glomerular filtration rate (GFR) have limited accuracy in Asian populations. We aimed to develop and validate a more accurate equation for estimated GFR (eGFR) in the Chinese population, using data from 8571 adults who were referred for direct measurement of GFR by renal dynamic imaging (mGFR) at 3 representative hospitals in China. Patients from the Third Xiangya Hospital were included in our development (n=1730) and internal validation sets (n=1042) and patients from the other hospitals comprised the external validation set (n=5799). We excluded patients who were prescribed medications known to influence the tubular secretion of creatinine, patients on dialysis, kidney transplant recipients, and patients with missing creatinine values or with creatinine >700 µmol/l. We derived a novel eGFR equation by linear regression analysis and compared the performance to 12 creatinine-based eGFR equations, including previously published equations for use in Chinese or Asian populations. In the development and internal validation sets, the novel Xiangya equation had high accuracy (accuracy within 30% [P30], 79.21% and 84.33%, respectively), low bias (mean difference between mGFR and eGFR, -1.97 and -1.85 ml/min per 1.73 m2, respectively), and high precision (interquartile range of the differences, 21.13 and 18.88 ml/min per 1.73 m2, respectively). In external validation, the Xiangya equation had the highest P30 among all eGFR equations, with P30 ≤ 75% for the other 12 equations. This novel equation provides more accurate GFR estimates in Chinese adults and could replace existing eGFR equations for use in the Chinese population.

A Simple Clinical Pre-procedure Risk Model for Predicting Thrombocytopenia Associated With Periprocedural Use of Tirofiban in Patients Undergoing Percutaneous Coronary Intervention.

Background: No risk model for predicting thrombocytopenia associated with periprocedural tirofiban exposure is available. The purpose of this study was to develop a simple clinical pre-procedure risk model based on pre-procedural characteristics for early prediction of thrombocytopenia before patients were exposed to tirofiban. Methods: The series included 1862 patients who underwent percutaneous coronary intervention with tirofiban exposure. Baseline demographic and clinical characteristics were collected from the hospital information system on admission. The earliest pro-procedural platelets within 72 h were used to evaluate the thrombocytopenia incidence. Risk factors associated with thrombocytopenia in patients with tirofiban exposure were investigated by univariable and multivariable analyses. Locally weighted scatterplot smoothing procedure was used to identify the cut points for the numeric variables. The discriminatory power of the scoring system was assessed with the receiver operating characteristic (ROC) curve analysis. Results: The occurrence of thrombocytopenia was 4.02% (75 of 1862), 4.01% (56 of 1396), and 4.08% (19 of 466) in the overall, developmental, and validation data sets, respectively. The risk score was developed based on five independent predictors: age ≥65y, white blood cell ≥12 × 109/L, diabetes mellitus, congestive heart failure, and chronic kidney disease. This tool was well calibrated (Hosmer Lemeshow χ2 = 6.914; P = 0.546) and good discrimination was well obtained in validation data set (C-statistic, 0.82). Conclusion: The clinical pre-procedure risk model is a simple and accurate tool for early identification of high-risk patients of thrombocytopenia before tirofiban exposure, allowing for timely and appropriate intervention.

Preprocedural Prediction Model for Contrast-Induced Nephropathy Patients.

BACKGROUND: Several models have been developed for prediction of contrast-induced nephropathy (CIN); however, they only contain patients receiving intra-arterial contrast media for coronary angiographic procedures, which represent a small proportion of all contrast procedures. In addition, most of them evaluate radiological interventional procedure-related variables. So it is necessary for us to develop a model for prediction of CIN before radiological procedures among patients administered contrast media. METHODS AND RESULTS: A total of 8800 patients undergoing contrast administration were randomly assigned in a 4:1 ratio to development and validation data sets. CIN was defined as an increase of 25% and/or 0.5 mg/dL in serum creatinine within 72 hours above the baseline value. Preprocedural clinical variables were used to develop the prediction model from the training data set by the machine learning method of random forest, and 5-fold cross-validation was used to evaluate the prediction accuracies of the model. Finally we tested this model in the validation data set. The incidence of CIN was 13.38%. We built a prediction model with 13 preprocedural variables selected from 83 variables. The model obtained an area under the receiver-operating characteristic (ROC) curve (AUC) of 0.907 and gave prediction accuracy of 80.8%, sensitivity of 82.7%, specificity of 78.8%, and Matthews correlation coefficient of 61.5%. For the first time, 3 new factors are included in the model: the decreased sodium concentration, the INR value, and the preprocedural glucose level. CONCLUSIONS: The newly established model shows excellent predictive ability of CIN development and thereby provides preventative measures for CIN.