3-Phosphoinositide-dependent protein kinase-1 (PDK1) mediates phosphorylation and activation of members of the AGC protein kinase family and plays an essential role in insulin signaling and action. However, whether and how PDK1 activity is regulated in cells remains largely uncharacterized. In the present study, we show that PDK1 undergoes insulin-stimulated and phosphatidylinositol 3-kinase-dependent phosphorylation at Ser²⁴⁴ in the activation loop and at a novel site: Ser¹⁶³ in the hinge region between the two lobes of the kinase domain. Sequence alignment studies revealed that the residue corresponding to Ser¹⁶³ of PDK1 in all other AGC kinases is glutamate, suggesting that a negative charge at this site may be important for PDK1 function. Replacing Ser¹⁶³ with a negatively charged residue, glutamate, led to a 2-fold increase in PDK1 activity. Molecular modeling studies suggested that phosphorylated Ser¹⁶³ may form additional hydrogen bonds with Tyr¹⁴⁹ and Gln²²³. In support of this, mutation of Tyr¹⁴⁹ to Ala is sufficient to reduce PDK1 activity. Taken together, our results suggest that PDK1 phosphorylation of Ser¹⁶³ may provide a mechanism to fine-tune PDK1 activity and function in cells.

This manuscript aims to determine if there is a difference in performance outcomes after initial training with either animals or simulators. Volunteers without prior experience performing emergency procedures were randomly assigned to receive training in cricothyroidotomy on either a pig model or on an artificial simulator. Volunteers were given identical lectures and trained to proficiency. Two weeks after training, trainees were tested using human cadavers as to their performance with time, incision size, incision start location, initial placement attempt, and final accuracy. Overall success rate of the animal-trained group was 64 per cent and in the artificial simulator group, 73 per cent (P = 0.431). Median time to completion in the animal group and artificial simulator group was 143 s and 105 s (P = 0.482), and incision lengths 4.0 cm and 3.2 cm (P = 0.173), respectively. Accuracy of initially attempted incision placement and final cricothyroidotomy tube placement was also compared. Initially attempted site accuracy in the animal-trained group was 93 per cent and correct final position 79 per cent, and in the artificial group, 100 per cent (P = 0.452) and 88 per cent (P = 0.782), respectively. There was no statistically significant, objective difference in any metric between animal- and simulator-trained groups after cricothyroidotomy training. For initial training, there is no objective benefit of animal training.

Objective: Up to 28% of patients may need mitral valve (MV) surgery after transcatheter edge-to-edge repair (TEER). This study evaluates the outcomes of minimally invasive MV surgery after TEER. Methods: International multicenter registry of minimally invasive MV surgery after TEER between 2013 and 2020. Subgroups were stratified by the number of devices implanted (≤1 vs >1), as well as time interval from TEER to surgery (≤1 year vs >1 year). Results: A total of 56 patients across 13 centers were included with a mean age of 73 ± 11 years, and 50% were female. The median Society of Thoracic Surgeons Predicted Risk of Mortality (STS PROM) score for MV replacement was 8% (Q1-Q3 = 5% to 11%) and the ratio of observed to expected mortality was 0.9. The etiology of mitral regurgitation (MR) prior to TEER was primary MR in 75% of patients and secondary MR in 25%. There were 30 patients (54%) who had >1 device implanted. The median time between TEER and surgery was 252 days (33 to 636 days). Hemodynamics, including MR severity, MV area, and mean gradient, significantly improved after minimally invasive surgery and sustained to 1-year follow-up. In-hospital and 30-day mortality was 7.1%, and 1-year actuarial survival was 85.6% ± 6%. Conclusions: Minimally invasive MV surgery after TEER may be achieved as predicted by the STS PROM. Most patients underwent MV replacement instead of repair. As TEER is applied more widely, patients should be informed about the potential need for surgical intervention over time after TEER. These discussions will allow better informed consent and post-procedure planning.

Objective: Transcatheter aortic valve replacement (TAVR), previously reserved for patients of intermediate to prohibitive surgical risk, has now been expanded to patients of any surgical risk with severe aortic stenosis. Bioprostheses are prone to structural valve degeneration (SVD), a progressive and multifactorial process that limits valve durability. As the population undergoing TAVR shifts toward a lower-risk and younger profile, long-term durability is a crucial determinant for patient outcomes. Our objective was to determine the incidence and risk factors of SVD at midterm follow-up in a veteran TAVR population. Methods: Patients undergoing TAVR at our federal facility were retrospectively evaluated for SVD and other endpoints with standardized consensus criteria. Multivariable Cox proportional hazards analysis was performed to evaluate risk factors for mortality and SVD. Results: From 2013 to 2020, 344 patients (median age, 78 years) underwent TAVR. Survival from all-cause mortality was 91.3% at 1 year, 75.1% at 3 years, and 61.7% at 5 years. Cumulative freedom from SVD was 98.2% at 1 year, 96.5% at 3 years, and 93.7% at 5 years. All 13 patients with SVD met hemodynamic criteria, and 1 required intervention. Median time to hemodynamic SVD was 1.04 years. Independent risk factors for SVD included age (hazard ratio [HR] = 0.92, 95% confidence interval [CI]: 0.86 to 0.99) and valve size (HR = 0.19, 95% CI: 0.04 to 0.89). Conclusions: SVD was evident at a low but detectable rate at 5-year follow-up. Further understanding of TAVR biomechanics as well as continued longer-term follow-up will be essential for informing patient-specific risk of SVD.

For patients with alpha-1 antitrypsin (AAT) deficiency, AAT augmentation therapy can be an important part of care. However, for those who require a lung transplant (LT), there is currently only limited information to guide the use of AAT augmentation therapy post-LT. We identified all LT recipients from 2011-2021 in the Scientific Registry of Transplant Recipients with an AAT deficiency diagnosis. We categorized recipients by use of AAT augmentation therapy post-LT and compared their baseline characteristics using Fisher’s exact test and Wilcoxon rank-sum tests. We used Kaplan-Meier analyses and estimated the average treatment effect (ATE) of post-LT AAT augmentation therapy on mortality and all-cause graft failure (ACGF). The ATE measures the observed effect we would see if everyone in the population received the intervention as opposed to just a subset. Among the 447 recipients with AAT deficiency, 109 used AAT augmentation therapy pre-LT, of which 32 (29.4%) continued post-LT. Recipients who used augmentation therapy post-LT were younger (56.5 [53-59.75] vs 57 [53.75-63], p = 0.04) and had shorter ischemia time (mean 311 vs 363 minutes, p = 0.03) than those who did not. The age-adjusted ATE estimate of post-LT augmentation therapy use on time to death and ACGF was +1.69 and +1.48 years, respectively. Post-LT augmentation therapy use was associated with a mortality reduction in the top quartile bilirubin subgroup (p = 0.02, log-rank test). In our study, the use of augmentation therapy post-LT was associated with improved survival. Confirmatory prospective studies should be considered to inform post-LT AAT therapy guidelines.

Background: People who inject drugs (PWID) comprise the majority of patients with native tricuspid valve (TV) infective endocarditis (IE). Many patients require surgical repair or replacement of their TV, but some may be deemed ineligible for surgical management due to high operative risk or patient preference. Vacuum-assisted percutaneous mechanical aspiration (PMA) has emerged as a potential alternative to surgical management in this population. The objective of this study was to describe real-world patient characteristics and clinical outcomes in PWID who underwent PMA or surgical management of TV IE. Methods: We retrospectively reviewed PWID hospitalized with endocarditis at a single tertiary care center (2016–2025) who underwent an isolated PMA or surgical TV repair/replacement (TVR). Baseline demographic, clinical, microbiologic, and echocardiographic characteristics were described. Clinical outcomes were compared descriptively between groups, recognizing imbalances in treatment selection. Results: A total of 40 PWID met inclusion criteria; 17 underwent PMA and 23 underwent surgical TVR. There was substantial baseline clinical heterogeneity between the two groups. Procedural success was numerically higher with surgery than with PMA (95.7% vs. 88.2%). Clinical success, a composite of procedural success, treatment completion, and lack of need for reintervention, was numerically higher in the TVR group (73.9% vs. 52.9%). One-year mortality was similar between groups. Conclusions: In this single-center retrospective observational cohort of PWID with isolated TV IE, there was no statistical difference in composite clinical or procedural success between patients who underwent PMA or TVR. PMA may be a feasible source-control strategy for select patients not eligible for immediate surgery; however, larger prospective studies are needed to define optimal patient selection factors and comparative effectiveness.