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Objective: The nation's aging population presents novel perioperative challenges. Potential benefits of operative interventions must be scrutinized in relation to recoverable quality of life. The purpose of this study is to evaluate common risk calculators used for medical decision making in a nonagenarian patient population. Methods: Retrospective medical record review was performed on patients 90 years or older who underwent operative interventions requiring anesthesia at a large academic medical center between January 1, 2013, and December 31, 2017. GraphPad 8.2.1 was used for statistical analysis. Results: Significant differences were found when data were stratified by age for elective versus emergent cases (P value < .0001), ability to return to baseline function (P value = .0062), and mortality (P value < .0001). Significant differences were found in emergent and elective cases, ability to return to baseline function, readmissions, and mortality (all P values < .0001) when stratified by American Society of Anesthesiologists score. Ability of patients to return to baseline functionality after intervention was influenced by their preintervention level of functionality (P value = .0008). American College of Surgeons and Portsmouth Physiologic and Operative Severity Score for Enumeration of Mortality and Morbidity risk calculators underestimated the need for rehabilitation and overestimated mortality for this population (all P values < .0001). Conclusion: Perioperative cares of the extreme geriatric population are complex and should be approached collaboratively. Rehabilitation and postoperative assistance resources should be assessed and used fully. Input from palliative care teams should be sought appropriately. End-of-life and escalation-of-care discussions should ideally be organized prior to emergent interventions. Frailty and risk calculators should be used and considered for formal implementation into the preoperative workflow.

Background & Aims: The small intestine (SI) displays regionality in nutrient and immunological function. Following SI tissue loss (as occurs in short gut syndrome, or SGS), remaining SI must compensate, or “adapt”; the capacity of SI epithelium to reprogram its regional identity has not been described. Here, we apply single-cell resolution analyses to characterize molecular changes underpinning adaptation to SGS. Methods: Single-cell RNA sequencing was performed on epithelial cells isolated from distal SI of mice following 50% proximal small bowel resection (SBR) vs sham surgery. Single-cell profiles were clustered based on transcriptional similarity, reconstructing differentiation events from intestinal stem cells (ISCs) through to mature enterocytes. An unsupervised computational approach to score cell identity was used to quantify changes in regional (proximal vs distal) SI identity, validated using immunofluorescence, immunohistochemistry, qPCR, western blotting, and RNA-FISH. Results: Uniform Manifold Approximation and Projection-based clustering and visualization revealed differentiation trajectories from ISCs to mature enterocytes in sham and SBR. Cell identity scoring demonstrated segregation of enterocytes by regional SI identity: SBR enterocytes assumed more mature proximal identities. This was associated with significant upregulation of lipid metabolism and oxidative stress gene expression, which was validated via orthogonal analyses. Observed upstream transcriptional changes suggest retinoid metabolism and proximal transcription factor Creb3l3 drive proximalization of cell identity in response to SBR. Conclusions: Adaptation to proximal SBR involves regional reprogramming of ileal enterocytes toward a proximal identity. Interventions bolstering the endogenous reprogramming capacity of SI enterocytes—conceivably by engaging the retinoid metabolism pathway—merit further investigation, as they may increase enteral feeding tolerance, and obviate intestinal failure, in SGS. Keywords: Short Gut Syndrome, Enterocyte, Single-Cell RNA Sequencing, Creb3l3, Retinoid Metabolism

Receptor tyrosine kinases (RTKs) are important drug targets for cancer and immunological disorders. Crystal structures of individual RTK domains have contributed greatly to the structure-based drug design of clinically used drugs. Low-resolution structures from electron microscopy are now available for the RTKs, EGFR, PDGFR, and Kit. However, there are still no high-resolution structures of full-length RTKs due to the technical challenges of working with these complex, membrane proteins. Here, we review what has been learned from structural studies of these three RTKs regarding their mechanisms of ligand binding, activation, oligomerization, and inhibition. We discuss the implications for drug design. More structural data on full-length RTKs may facilitate the discovery of druggable sites and drugs with improved specificity and effectiveness against resistant mutants., (Copyright © 2021 Elsevier Inc. All rights reserved.)