The contemporary management of perforated appendicitis in adults: To operate or wait?

Objectives: The optimal management of perforated appendicitis remains controversial. Many studies advocate for antibiotics and an interval appendectomy whereas others suggest that performing an appendectomy at the time of presentation decreases post-operative morbidity. Confounding this argument further are the patients who fail non-operative management and end up requiring surgery during their initial hospitalization. This study aims to determine if early operative intervention should be considered for perforated appendicitis. Methods: This was a retrospective review of all patients who underwent an appendectomy (both laparoscopic or open) for perforated appendicitis between 2015 and 2020 at our institution. Results: A total of 271 patients met inclusion criteria for this study. Of this group, 250 patients underwent an immediate appendectomy whereas the remaining 21 patients underwent a trial of non-operative management and eventually required an appendectomy during their initial admission. When comparing the immediate versus delayed operative groups, there were no differences in demographic data including age and gender, and no differences in various imaging findings including AAST Grade IV or V appendicitis. Operatively, patients in the delayed group had a longer operative time (83.1 ± 32.9 vs. 64.1 ± 26.2, p = 0.01), were more likely to require an open operation (23.8 % vs. 2.8 %, p < 0.0001), and were more likely to have a drain placed intra-operatively (42.9 % vs 14.4 %, p = 0.004). While there were no differences in 30-day readmission rates, patients in the delayed group had a significantly longer hospital length of stay than patients in the immediate group (9.4 ± 7.4 vs. 3.1 ± 3.3, p = 0.008). Conclusions: Patients undergoing an immediate appendectomy for perforated appendicitis can discharge from the hospital sooner and demonstrate no increase in post-operative morbidity suggesting that surgeons can initially manage this disease process in an operative fashion.

Nuclear Smooth Muscle α-actin in Vascular Smooth Muscle Cell Differentiation.

Missense variants throughout ACTA2, encoding smooth muscle α-actin (αSMA), predispose to adult onset thoracic aortic disease, but variants disrupting arginine 179 (R179) lead to Smooth Muscle Dysfunction Syndrome (SMDS) characterized by childhood-onset diverse vascular diseases. Our data indicate that αSMA localizes to the nucleus in wildtype (WT) smooth muscle cells (SMCs), enriches in the nucleus with SMC differentiation, and associates with chromatin remodeling complexes and SMC contractile gene promotors, and the ACTA2 p.R179 variant decreases nuclear localization of αSMA. SMCs explanted from a SMC-specific conditional knockin mouse model, Acta2SMC-R179/+, are less differentiated than WT SMCs, both in vitro and in vivo, and have global changes in chromatin accessibility. Induced pluripotent stem cells from patients with ACTA2 p.R179 variants fail to fully differentiate from neural crest cells to SMCs, and single cell transcriptomic analyses of an ACTA2 p.R179H patient's aortic tissue shows increased SMC plasticity. Thus, nuclear αSMA participates in SMC differentiation and loss of this nuclear activity occurs with ACTA2 p.R179 pathogenic variants.

Nuclear Smooth Muscle α-actin Participates in Vascular Smooth Muscle Cell Differentiation.

Missense variants throughout ACTA2, encoding smooth muscle α-actin (αSMA), predispose to adult-onset thoracic aortic disease, but variants disrupting arginine 179 (R179) lead to Smooth Muscle Dysfunction Syndrome (SMDS) characterized by diverse childhood-onset vascular diseases. Here we show that αSMA localizes to the nucleus in wildtype (WT) smooth muscle cells (SMCs), enriches in the nucleus with SMC differentiation, and associates with chromatin remodeling complexes and SMC contractile gene promotors. The ACTA2 p.R179 αSMA variant shows decreased nuclear localization. Primary SMCs from Acta2 SMC-R179C/+ mice are less differentiated than WT SMCs in vitro and in vivo and have global changes in chromatin accessibility. Induced pluripotent stem cells from patients with ACTA2 p.R179 variants fail to fully differentiate from neuroectodermal progenitor cells to SMCs, and single-cell transcriptomic analyses of an ACTA2 p.R179H patient's aortic tissue show increased SMC plasticity. Thus, nuclear αSMA participates in SMC differentiation, and loss of this nuclear activity occurs with ACTA2 p.R179 pathogenic variants.