Blood–brain barrier (BBB) dysfunction, e.g., increase in BBB permeability, has been reported to contribute to cognitive impairment. However, the effects of anesthesia and surgery on BBB permeability, the underlying mechanisms, and associated cognitive function remain largely to be determined. Here, we assessed the effects of surgery (laparotomy) under 1.4% isoflurane anesthesia (anesthesia/surgery) for 2 h on BBB permeability, levels of junction proteins and cognitive function in both 9- and 18-month-old wild-type mice and 9-month-old interleukin (IL)-6 knockout mice. BBB permeability was determined by dextran tracer (immunohistochemistry imaging and spectrophotometric quantification), and protein levels were measured by Western blot and cognitive function was assessed by using both Morris water maze and Barnes maze. We found that the anesthesia/surgery increased mouse BBB permeability to 10-kDa dextran, but not to 70-kDa dextran, in an IL-6-dependent and age-associated manner. In addition, the anesthesia/surgery induced an age-associated increase in blood IL-6 level. Cognitive impairment was detected in 18-month-old, but not 9-month-old, mice after the anesthesia/surgery. Finally, the anesthesia/surgery decreased the levels of β-catenin and tight junction protein claudin, occludin and ZO-1, but not adherent junction protein VE-cadherin, E-cadherin, and p120-catenin. These data demonstrate that we have established a system to study the effects of perioperative factors, including anesthesia and surgery, on BBB and cognitive function. The results suggest that the anesthesia/surgery might induce an age-associated BBB dysfunction and cognitive impairment in mice. These findings would promote mechanistic studies of postoperative cognitive impairment, including postoperative delirium.

Optical diodes are fundamental elements for optical computing and information processing. Attempts to realize such non-reciprocal propagation of light by breaking the time-reversal symmetry include using indirect interband photonic transitions, the magneto-optical effect, optical nonlinearity or photonic crystals. Alternatively, asymmetric reciprocal transmission of light has been proposed in photonic metamaterial structures for either circularly or linearly polarized waves. Here we employ the recent concept of gradient index metamaterials to demonstrate a waveguide with asymmetric propagation of light, independent of polarization. The device blocks both transverse electric and magnetic polarized modes in one direction but transmits them in the other for a broadband spectrum. Unlike previous works using chiral properties of metamaterials, our device is based on the principle of momentum symmetry breaking at interfaces with phase discontinuities. Experiments in the microwave region verify our findings, which may pave the way to feasible passive optical diodes.

There is a dearth of robust methods to estimate the causal effects of multiple treatments when the outcome is binary. This paper uses two unique sets of simulations to propose and evaluate the use of Bayesian additive regression trees in such settings. First, we compare Bayesian additive regression trees to several approaches that have been proposed for continuous outcomes, including inverse probability of treatment weighting, targeted maximum likelihood estimator, vector matching, and regression adjustment. Results suggest that under conditions of non-linearity and non-additivity of both the treatment assignment and outcome generating mechanisms, Bayesian additive regression trees, targeted maximum likelihood estimator, and inverse probability of treatment weighting using generalized boosted models provide better bias reduction and smaller root mean squared error. Bayesian additive regression trees and targeted maximum likelihood estimator provide more consistent 95% confidence interval coverage and better large-sample convergence property. Second, we supply Bayesian additive regression trees with a strategy to identify a common support region for retaining inferential units and for avoiding extrapolating over areas of the covariate space where common support does not exist. Bayesian additive regression trees retain more inferential units than the generalized propensity score-based strategy, and shows lower bias, compared to targeted maximum likelihood estimator or generalized boosted model, in a variety of scenarios differing by the degree of covariate overlap. A case study examining the effects of three surgical approaches for non-small cell lung cancer demonstrates the methods.

is an employee of Analysis Group, Inc., which received consultancy fees from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA to conduct this study. Jipan Xie is an employee of Analysis Group, Inc., which received consultancy fees from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA to conduct this study. Muhan Yuan is an employee of Analysis Group, Inc., which received consultancy fees from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA to conduct this study. John Cook received grants from Merck & Co., Inc. during the conduct of this study.

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Background: Pathologic complete response (pCR) is a common efficacy endpoint in neoadjuvant therapy trials for triple-negative breast cancer (TNBC). Previous studies have shown that pCR is strongly associated with improved long-term survival outcomes, including event-free survival (EFS) and overall survival (OS). However, the trial-level associations between treatment effect on pCR and long-term survival outcomes are not well established. This study sought to evaluate these associations by incorporating more recent clinical trials in TNBC. Methods: A literature review identified published randomized controlled trials (RCTs) of neoadjuvant therapy for TNBC that reported results for both pCR and EFS/OS. Meta-regression models were performed to evaluate the association of treatment effect on pCR and EFS/OS. Sensitivity analyses were conducted to assess the impact of divergent study designs. Results: Ten comparisons from 8 RCTs (N=2,478 patients) were identified from the literature review. The log (odds ratio) of pCR was a significant predictor of the log (hazard ratio) of EFS (P=.003), with a coefficient of determination of 0.68 (95% CI, 0.41–0.95). There was a weaker association between pCR and OS (P=.18), with a coefficient of determination of 0.24 (95% CI, 0.01–0.77). Consistent results were found in the exploratory analysis and sensitivity analyses. Conclusions: This is the first study that has shown a trial-level association between pCR and survival outcomes in TNBC. By incorporating the most up-to-date RCTs, this study showed a significant trial-level association between pCR and EFS. A positive association between pCR and OS was also recorded.

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Background Botulinum type A (BTX-A) injection is a promising corrective method for gummy smile (GS). However, its effect among patients is varied and inconsistent. Objective To explore the effect of individual factors on BTX-A treatment for GS and the degree of their influence, and to establish the indications of average-dose BTX-A injection for GS treatment. Methods In this prospective clinical study, a standardized BTX-A injection technique comprising bilateral single-point injections of 2 U BTX-A (total, 4 U) was administered to all GS patients. Data were collected at baseline and 4, 12, and 32 weeks of follow-up. Twenty-nine potential individual factors were analyzed using correlation and regression analysis to exclude confounding bias. Results In all, 94 patients completed the BTX-A injection. After adjusting for potential confounding factors such as exposed medial incisor, medial incisor length, width-to-length ratio of the medial incisor length, overbite and overjet of the anterior teeth, the correlation and regression analysis confirmed the following formula (adjusted R 2 = 0.617, P ≤ 0.001): anterior gingival exposure (GE) at 4 weeks = 1.44 + (0.94 × baseline anterior gingival exposure) – (1.88 × sex) (where male = 1 and female = 2). The confidence interval(CI) of the prediction showed that for all female participants with baseline anterior GE <5.3 mm, the 95%CI of anterior GE was 0.3–3.0 mm after 4 weeks of this average dose of BTX-A treatment, and it was 3.0–8.9 mm for all female participants with baseline anterior GE ≥6 mm. This value would likely be between 1.5 mm and 3.3 mm for male patients with a baseline anterior GE of 3 mm, which was between 3.2 mm and 8.9 mm for male patients with baseline anterior GE ≥4.6 mm. Conclusion The individual effect of the average dose of BTX-A treatment for GS was GS severity and patient’s sex, rather than GS etiology and other individual factors. Further, female participants with baseline anterior GE<5.3 mm were more likely to show complete improvement after 4 weeks of this average dose of BTX-A treatment. However, female participants with baseline anterior GE ≥6.0 mm or male participants were less likely to show complete improvement at 4 weeks.