Background: Tranexamic acid (TXA) is an antifibrinolytic drug that reduces surgical blood loss. Evidence supporting its efficacy in surgery for adolescent idiopathic scoliosis is not robust. This trial was designed to validate the clinical efficacy of TXA in surgery for adolescent idiopathic scoliosis. Methods: This institutional review board-approved prospective double-blinded trial involved 111 patients with adolescent idiopathic scoliosis who were randomized to receive either a placebo or TXA (50-mg/kg loading dose and 10-mg/kg/h infusion). Power analysis indicated that 50 patients per group would provide power to detect a >20% difference in blood loss. Two-way analysis of variance (ANOVA) was applied to compare blood loss rates (slopes) using the group-by-time interaction F test. Results: The risk of clinically relevant blood loss (>20 mL/kg) was more than twice as high in the placebo group than in the TXA group (44% versus 21%, relative risk = 2.1, 95% confidence interval = 1.2 to 3.7). Compared with the placebo group, the TXA group had a 27% reduction in intraoperative blood loss, a significantly lower rate of intraoperative bleeding per hour (mean and standard deviation, 190 ± 73 versus 230 ± 80 mL, p = 0.01; F = 9.77, p < 0.001) and per fused spinal level (82 ± 32 versus 110 ± 40 mL, p < 0.001), less intraoperative blood loss (836 ± 373 versus 1,031 ± 484 mL, p = 0.02), and less postoperative bleeding (in the drain) (498 ± 228 versus 645 ± 318 mL, p = 0.009). Six patients who received a placebo and no patient who received TXA required an allogenic blood transfusion. No perioperative adverse events, including thromboembolic events or seizures, were observed. Three independent factors were predictive of blood loss: TXA administration, duration of surgery, and number of levels fused. Greater intraoperative blood loss was the only independent variable predictive of a longer hospital stay. Conclusions: Use of TXA in patients undergoing surgery for adolescent idiopathic scoliosis significantly reduced blood loss, by 27%, compared with that in the placebo group. The rate of intraoperative blood loss per hour and per level fused and the amount of postoperative blood loss were significantly lower in the TXA group. More placebo-treated patients received allogenic blood. Patients with greater intraoperative blood loss spent a longer time in the hospital. Level of Evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Summary: Clinical prediction models in anesthesia and surgery research have many clinical applications including preoperative risk stratification with implications for clinical utility in decision-making, resource utilization, and costs. It is imperative that predictive algorithms and multivariable models are validated in a suitable and comprehensive way in order to establish the robustness of the model in terms of accuracy, predictive ability, reliability, and generalizability. The purpose of this article is to educate anesthesia researchers at an introductory level on important statistical concepts involved with development and validation of multivariable prediction models for a binary outcome. Methods covered include assessments of discrimination and calibration through internal and external validation. An anesthesia research publication is examined to illustrate the process and presentation of multivariable prediction model development and validation for a binary outcome. Properly assessing the statistical and clinical validity of a multivariable prediction model is essential for reassuring the generalizability and reproducibility of the published tool.

Combining BRAF inhibitor and anti PD-L1 antibody dramatically improves tumor regression and anti tumor immunity in an immunocompetent murine model of anaplastic thyroid cancer Combining BRAF inhibitor and anti PD-L1 antibody dramatically improves tumor regression and anti tumor immunity in an immunocompetent murine model of anaplastic thyroid cancer

Joints that have degenerated as a result of aging or injury contain dead chondrocytes and damaged cartilage. Some studies have suggested that chondrocyte death precedes cartilage damage, but how the loss of chondrocytes affects cartilage integrity is not clear. In this study, we examined whether chondrocyte death undermines cartilage integrity in aging and injury using a rapid 3D confocal cartilage imaging technique coupled with standard histology. We induced autonomous expression of diphtheria toxin to kill articular surface chondrocytes in mice and determined that chondrocyte death did not lead to cartilage damage. Moreover, cartilage damage after surgical destabilization of the medial meniscus of the knee was increased in mice with intact chondrocytes compared with animals whose chondrocytes had been killed, suggesting that chondrocyte death does not drive cartilage damage in response to injury. These data imply that chondrocyte catabolism, not death, contributes to articular cartilage damage following injury. Therefore, therapies targeted at reducing the catabolic phenotype may protect against degenerative joint disease.

OBJECTIVES: Type 2 diabetes causes mitochondrial dysfunction, which increases myocardial susceptibility to ischaemia–reperfusion injury. We investigated the efficacy of transplantation of mitochondria isolated from diabetic or non-diabetic donors in providing cardioprotection from warm global ischaemia and reperfusion in the diabetic rat heart.METHODS: Ex vivo perfused hearts from Zucker diabetic fatty (ZDF fa/fa) rats (n = 6 per group) were subjected to 30 min of warm global ischaemia and 120 min reperfusion. Immediately prior to reperfusion, vehicle alone (VEH) or vehicle containing mitochondria isolated from either ZDF (MTZDF) or non-diabetic Zucker lean (ZL +/?) (MTZL) skeletal muscle were delivered to the coronary arteries via the aortic cannula.RESULTS: Following 30-min global ischaemia and 120-min reperfusion, left ventricular developed pressure was significantly increased in MTZDF and MTZL groups compared to VEH group (MTZDF: 92.8 ± 5.2 mmHg vs MTZL: 110.7 ± 2.4 mmHg vs VEH: 44.3 ± 5.9 mmHg; P < 0.01 each); and left ventricular end-diastolic pressure was significantly decreased (MTZDF 12.1 ± 1.3 mmHg vs MTZL 8.6 ± 0.8 mmHg vs VEH: 18.6 ± 1.5 mmHg; P = 0.016 for MTZDF vs VEH and P < 0.01 for MTZL vs VEH). Total tissue ATP content was significantly increased in both MT groups compared to VEH group (MTZDF: 18.9 ± 1.5 mmol/mg protein/mg tissue vs MTZL: 28.1 ± 2.3 mmol/mg protein/mg tissue vs VEH: 13.1 ± 0.5 mmol/mg protein/mg tissue; P = 0.018 for MTZDF vs VEH and P < 0.01 for MTZL vs VEH). Infarct size was significantly decreased in the MT groups (MTZDF: 11.8 ± 0.7% vs MTZL: 9.9 ± 0.5% vs VEH: 52.0 ± 1.4%; P < 0.01 each).CONCLUSIONS: Mitochondrial transplantation significantly enhances post-ischaemic myocardial functional recovery and significantly decreases myocellular injury in the diabetic heart.

Propranolol and atenolol, current therapies for problematic infantile hemangioma (IH), are composed of R(+) and S(–) enantiomers: the R(+) enantiomer is largely devoid of beta blocker activity. We investigated the effect of R(+) enantiomers of propranolol and atenolol on the formation of IH-like blood vessels from hemangioma stem cells (HemSCs) in a murine xenograft model. Both R(+) enantiomers inhibited HemSC vessel formation in vivo. In vitro, similar to R(+) propranolol, both atenolol and its R(+) enantiomer inhibited HemSC to endothelial cell differentiation. As our previous work implicated the transcription factor sex-determining region Y (SRY) box transcription factor 18 (SOX18) in propranolol-mediated inhibition of HemSC to endothelial differentiation, we tested in parallel a known SOX18 small-molecule inhibitor (Sm4) and show that this compound inhibited HemSC vessel formation in vivo with efficacy similar to that seen with the R(+) enantiomers. We next examined how R(+) propranolol alters SOX18 transcriptional activity. Using a suite of biochemical, biophysical, and quantitative molecular imaging assays, we show that R(+) propranolol directly interfered with SOX18 target gene trans-activation, disrupted SOX18-chromatin binding dynamics, and reduced SOX18 dimer formation. We propose that the R(+) enantiomers of widely used beta blockers could be repurposed to increase the efficiency of current IH treatment and lower adverse associated side effects.