Inhibitory protein-protein interactions of the SIRT1 deacetylase are choreographed by post-translational modification.

Regulation of SIRT1 activity is vital to energy homeostasis and plays important roles in many diseases. We previously showed that insulin triggers the epigenetic regulator DBC1 to prime SIRT1 for repression by the multifunctional trafficking protein PACS-2. Here, we show that liver DBC1/PACS-2 regulates the diurnal inhibition of SIRT1, which is critically important for insulin-dependent switch in fuel metabolism from fat to glucose oxidation. We present the x-ray structure of the DBC1 S1-like domain that binds SIRT1 and an NMR characterization of how the SIRT1 N-terminal region engages DBC1. This interaction is inhibited by acetylation of K112 of DBC1 and stimulated by the insulin-dependent phosphorylation of human SIRT1 at S162 and S172, catalyzed sequentially by CK2 and GSK3, resulting in the PACS-2-dependent inhibition of nuclear SIRT1 enzymatic activity and translocation of the deacetylase in the cytoplasm. Finally, we discuss how defects in the DBC1/PACS-2-controlled SIRT1 inhibitory pathway are associated with disease, including obesity and non-alcoholic fatty liver disease.

Octogenarians fare better under local anesthesia for elective endovascular aortic aneurysm repair.

OBJECTIVE: With an aging patient population, an increasing number of octogenarians are undergoing elective endovascular abdominal aortic aneurysm repair (EVAR) in the United States. Multiple studies have shown that, for the general population, use of local anesthetic (LA) for EVAR is associated with improved short-term and long-term outcomes as compared with performing these operations under general anesthesia (GA). Therefore, this study aimed to study the association of LA for elective EVARs with perioperative outcomes, among octogenarians. METHODS: The Vascular Quality Initiative database (2003-2021) was used to conduct this study. Octogenarians (Aged ≥80 years) were selected and sorted into two study groups: LA (Group I) and GA (Group II). Our primary outcomes were length of stay and mortality. Secondary outcomes included operative time, estimated blood loss, return to operating room, cardiopulmonary complications, and discharge location. RESULTS: Of the 16,398 selected patients, 1197 patients (7.3%) were included in Group I, and 15,201 patients (92.7%) were in Group II. Procedural time was significantly shorter for the LA group (114.6 vs 134.6; P < .001), as was estimated blood loss (152 vs 222 cc; P < .001). Length of stay was significantly shorter (1.8 vs 2.6 days; P < .001), and patients were more likely to be discharged home (LA 88.8% vs GA 86.9%; P = .036) in the LA group. Group I also experienced fewer pulmonary complications; only 0.17% experienced pneumonia and 0.42% required ventilator support compared with 0.64% and 1.02% in Group II, respectively. This finding corresponded to fewer days in the intensive care unit for Group I (0.41 vs 0.69 days; P < .001). No significant difference was seen in 30-day mortality cardiac, renal, or access site-related complications. Return to operating room was also equivocal between the two groups. Multivariate regression analysis confirmed GA was associated with a significantly longer length of stay and significantly higher rates of non-home discharge (adjusted odds ratio [AOR], 1.59; P < .001 and AOR, 1.40; P = .025, respectively). When stratified by the New York Heart Association classification system, classes I, II, III, and IV (1.55; P < .001; 1.26; P = .029; 2.03; P < .001; 4.07; P < .001, respectively) were associated with significantly longer hospital stays. CONCLUSIONS: The use of LA for EVARs in octogenarians is associated with shorter lengths of stay, fewer respiratory complications, and home discharge. These patients also experienced shorter procedure times and less blood loss. There was no statistically significant difference in 30-day mortality, return to operating room, or access-related complications. LA for octogenarians undergoing EVAR should be considered more frequently to shorten hospital stays and decrease complication rates.

Black or African American patients undergo great saphenous vein ablation procedures for advanced venous disease and have the least improvement in their symptoms after these procedures.

OBJECTIVE: Chronic venous insufficiency is an increasingly prevalent problem in the United States, with >25 million individuals currently affected. Previous work has shown that racial minorities and low socioeconomic status are associated with a worse clinical presentation and response to treatment. The present study aimed to determine the relationship between race, patient variables, hospital outcomes, and response to treatment for patients presenting for chronic venous insufficiency intervention. METHODS: We performed a retrospective analysis of all patients who underwent endovenous ablation (radiofrequency or laser) of the great saphenous vein to treat symptomatic, chronic venous insufficiency using Vascular Quality Initiative data from 2014 to 2020. Patient characteristics and outcomes were analyzed stratified by patient race. The χ2 test and the Kruskal-Wallis equality-of-populations rank test were used to measure the study outcomes. The primary outcomes were an improved venous clinical severity score and improvement in patient-reported outcomes. Patient characteristics, CEAP (clinical, etiologic, anatomic, pathophysiologic) classification, prior venous interventions, length of stay, and time to follow-up were compared between races. RESULTS: The database consisted of 9009 predominantly female patients (n = 6041; 67.1%), with a mean age distribution of 56 years. Of the 9009 patients, 7892 are White (87.6%), 627 Hispanic (6.9%), and 490 Black or African American (18.3%). The Hispanic cohort was younger than their White and Black/African American counterparts. Black/African American patients presented with more advanced clinical stages than did the White and Hispanic groups. The clinical stage according to race was as follows: C3-Black/African American, 32.9%; Hispanic, 38.9%; White, 46%; C5-Black/African American, 4.7%; Hispanic, 2.1%; White, 2.3%; and C6-Black/African American, 12.7%; Hispanic, 3.2%; White, 6.2%. Black/African American patients were more likely to present as overweight or obese (66%; P < .001) and less likely to be taking anticoagulation medication preoperatively (11%; P < .001). Non-White race was associated with a higher probability of treatment in the hospital setting (Black/African American, 63.6%; Hispanic, 87.5%; P < .001). Black/African American patients (3.25 ± 4.4; P < .001) demonstrated lower mean improvement postoperatively in both the venous clinical severity score and patient-reported outcomes than their White (4.25 ± 4.13, P <.001) and Hispanic (4.42 ± 3.78; P < .001) counterparts. CONCLUSIONS: Differences exist in the clinical severity and symptom presentation based on race. Black/African American patients present with more advanced chronic venous insufficiency than do their White and Hispanic counterparts. Furthermore, the postprocedural analysis showed inferior clinical and self-reported improvement in chronic venous insufficiency for the Black/African American patients. Although the Hispanic population was younger, the White and Hispanic patients experienced similar responses to treatment.