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Item does not contain fulltext, BACKGROUND: Intraoperative adverse events (iAEs) are associated with adverse postoperative outcomes and cause a significant healthcare burden. However, a critical appraisal of iAEs is lacking. Considering the details of iAEs could benefit postoperative care. We comprehensively analyzed iAEs in a large series including all types of operations and their relation to postoperative complications. METHODS: All patients enrolled in the multicenter ClassIntra(®) validation study (NCT03009929) were included in this analysis. The surgical and anesthesia team prospectively recorded all iAEs. Two researchers, blinded to each other's ratings, appraised all recorded iAEs according to their origin into four categories: surgery, anesthesia, organization, or other, including subcategories such as organ injury, arrhythmia, or instrument failure. They further descriptively analyzed subcategories of all iAEs. Postoperative complications were assessed using the Comprehensive Complication Index (CCI(®)), a weighted sum of all postoperative complications according to the Clavien-Dindo classification. The association of iAE origins in addition to the severity grade of ClassIntra(®) on CCI(®) was assessed with a multivariable mixed-effects generalized linear regression analysis. RESULTS: Of 2520 included patients, 778 iAEs were recorded in 610 patients. The origin was surgical in 420 (54%), anesthesia in 283 (36%), organizational in 34 (4%), and other in 41 (5%) events. Bleeding (n = 217, 28%), hypotension (n = 118, 15%), and organ injury (n = 98, 13%) were the three most frequent subcategories in surgery and anesthesia, respectively. In the multivariable mixed-effect analysis, no significant association between the origin and CCI(®) was observed. CONCLUSION: Analyzing the type and origin of an iAE offers individualized and contextualized information. This detailed descriptive information can be used for targeted surveillance of intra- and postoperative care, even though the overall predict

Enzymes are highly specific catalysts delivering improved drugs and greener industrial processes. Naturally occurring enzymes must typically be optimized which is often accomplished through directed evolution; however, this is still a labor- and capital-intensive process, due in part to multiple molecular biology steps including DNA extraction, in vitro library generation, transformation, and limited screening throughput. We present an effective and broadly applicable continuous evolution platform that enables controlled exploration of fitness landscape to evolve enzymes at ultrahigh throughput based on direct measurement of enzymatic activity. This drop-based microfluidics platform cycles cells between growth and mutagenesis followed by screening with minimal human intervention, relying on the nCas9 chimera with mutagenesis polymerase to produce in vivo gene diversification using sgRNAs tiled along the gene. We evolve alditol oxidase to change its substrate specificity towards glycerol, turning a waste product into a valuable feedstock. We identify a variant with a 10.5-fold catalytic efficiency.

Contains fulltext : 251509.pdf (Publisher’s version ) (Open Access), BACKGROUND: Intraoperative adverse events (iAEs) are frequent in visceral surgery, but severity and related postoperative outcome are poorly investigated. A novel classification of intraoperative adverse events, ClassIntra, includes surgical and anesthesiologic intraoperative adverse events using 5 severity grades and showed a high criterion and construct validity across all surgical disciplines. ClassIntra was studied for reproducibility in a prespecified group of patients undergoing visceral surgery. METHODS: iAEs were recorded in all patients enrolled in the ClassIntra validation study (NCT03009929). Postoperative complications were assessed daily according to the Clavien-Dindo classification. Results of the visceral group were compared with those of the non-visceral group and the full cohort. The risk-adjusted association between most severe intra and postoperative complications was investigated in a multivariable proportional odds model. Second, risk-adjusted association between ClassIntra grade and Comprehensive Complication Index, and postoperative length of stay was investigated. RESULTS: In total, 1,270 out of 2,520 patients (50%) underwent visceral surgery. Compared with the nonvisceral group and full cohort, more intraoperative (337/1270 [27%] vs 273/1250 [22%] vs 610/2520 [24%] patients) and postoperative complications (457/1270 [36%] vs 381/1250 [30%] vs 838/2520 [33%] patients) occurred. The risk for a more severe postoperative complication increased with each ClassIntra grade (odds ratio [95% confidence interval] I vs 0 1.10 [0.73 to 1.66], II vs 0 1.69 [1.10 to 2.60], III vs 0 2.31 [1.21 to 4.41], IV vs 0 2.35 [0.69 to 8.06]). Accordingly, CCI and postoperative length of stay increased with each ClassIntra grade in the visceral group, comparable with the nonvisceral and full cohort. CONCLUSION: Consistent results for the association of intraoperative adverse events and patient outcomes render ClassIntra a valuable instrument in visceral surgery.

Purpose: We previously demonstrated that sex influences response to immune checkpoint inhibitors. In this article, we investigate sex-based differences in the molecular mechanisms of anticancer immune response and immune evasion in patients with NSCLC. Experimental Design: We analyzed (i) transcriptome data of 2,575 early-stage NSCLCs from seven different datasets; (ii) 327 tumor samples extensively characterized at the molecular level from the TRACERx lung study; (iii) two independent cohorts of 329 and 391 patients, respectively, with advanced NSCLC treated with anti–PD-1/anti–PD-L1 drugs. Results: As compared with men, the tumor microenvironment (TME) of women was significantly enriched for a number of innate and adaptive immune cell types, including specific T-cell subpopulations. NSCLCs of men and women exploited different mechanisms of immune evasion. The TME of females was characterized by significantly greater T-cell dysfunction status, higher expression of inhibitory immune checkpoint molecules, and higher abundance of immune-suppressive cells, including cancer-associated fibroblasts, MDSCs, and regulatory T cells. In contrast, the TME of males was significantly enriched for a T-cell–excluded phenotype. We reported data supporting impaired neoantigens presentation to immune system in tumors of men, as molecular mechanism explaining the findings observed. Finally, in line with our results, we showed significant sex-based differences in the association between TMB and outcome of patients with advanced NSCLC treated with anti–PD-1/PD-L1 drugs. Conclusions: We demonstrated meaningful sex-based differences of anticancer immune response and immune evasion mechanisms, that may be exploited to improve immunotherapy efficacy for both women and men.

Summary: Background: Virtual reality (VR) simulation is increasingly used in surgical disciplines. Since VR simulators measure multiple outcomes, standardized reporting is needed. Methods: We present an algorithm for combining multiple VR outcomes into dimension summary measures, which are then integrated into a meaningful total score. We reanalyzed the data of two VR studies applying the algorithm. Results: The proposed algorithm was successfully applied to both VR studies. Conclusions: The algorithm contributes to standardized and transparent reporting in VR-related research.