Midterm Durability and Structural Valve Degeneration of Transcatheter Aortic Valve Replacement in a Federal Facility.

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.

Data Analytics of Electronic Medical Record to Study Racial Diversities in Cardiovascular Diagnosis and Treatment.

The study of precision medicine that measures the effects of social, cultural, and environmental influences on health is essential to improve health outcomes. Race is a social concept used historically to divide, track, control populations, and reinforce social hierarchies. Beyond genetics, race is also a surrogate for other socioeconomic factors affecting patient outcomes. Our data analytics study aims to analyze the Electronic Medical Record (EMR) to study patients of different races in diagnosing and treating Coronary Artery Disease (CAD). We found no race discrepancies at the University of California San Francisco Medical Centers. This study opens several new hypotheses for further research in this crucial field.

An Ontology for Cardiothoracic Surgical Education and Clinical Data Analytics.

The development of an ontology facilitates the organization of the variety of concepts used to describe different terms in different resources. The proposed ontology will facilitate the study of cardiothoracic surgical education and data analytics in electronic medical records (EMR) with the standard vocabulary.

Minimally Invasive Mitral Valve Surgery After Transcatheter Edge-to-Edge Repair.

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.

Acute Exercise Induced Compartment Syndrome in an 22-Year-Old Active-Duty Man and Review of the Literature.

Acute exercise induced compartment syndrome is a rare clinical diagnosis with serious long-term ramifications if not diagnosed in a timely fashion. We present a case of acute exercise induced compartment syndrome of the right lower extremity in a 22-year-old active-duty man that occurred during a physical fitness assessment. He was treated with a two incision four compartment fasciotomy, however required debridement of muscle from the anterior compartment on subsequent washouts of the wound that led to significant foot drop postoperatively. We reviewed the literature for published cases of acute exercise induced compartment syndrome and provide some information from the 47 patients identified in our review. This case highlights a unique pathology for which military providers should have a strong index of suspicion. It additionally stresses the importance of adequate hydration and musculoskeletal conditioning in the setting of military fitness assessments.

Objective comparison of animal training versus artificial simulation for initial cricothyroidotomy training.

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.

Comparison of self-efficacy and its improvement after artificial simulator or live animal model emergency procedure training.

The objective of this study is to compare post-training self-efficacy between artificial simulators and live animal training for the performance of emergency medical procedures. Volunteer airmen of the 81st Medical Group, without prior medical procedure training, were randomly assigned to two experimental arms consisting of identical lectures and training of diagnostic peritoneal lavage, thoracostomy (chest tube), and cricothyroidotomy on either the TraumaMan (Simulab Corp., Seattle, Washington) artificial simulator or a live pig (Sus scrofa domestica) model. Volunteers were given a postlecture and postskills training assessment of self-efficacy. Twenty-seven volunteers that initially performed artificial simulator training subsequently underwent live animal training and provided assessments comparing both modalities. The results were first, postskills training self-efficacy scores were significantly higher than postlecture scores for either training mode and for all procedures (p < 0.0001). Second, post-training self-efficacy scores were not statistically different between live animal and artificial simulator training for diagnostic peritoneal lavage (p = 0.555), chest tube (p = 0.486), and cricothyroidotomy (p = 0.329). Finally, volunteers undergoing both training modalities indicated preference for live animal training (p < 0.0001). We conclude that artificial simulator and live animal training produce equivalent levels of self-efficacy after initial training, but there is a preference in using a live animal model to achieve those skills.

Phosphorylation of adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain, and leucine zipper motif 1 (APPL1) at Ser430 mediates endoplasmic reticulum (ER) stress-induced insulin resistance in hepatocytes.

APPL1 is an adaptor protein that plays a critical role in regulating adiponectin and insulin signaling. However, how APPL1 is regulated under normal and pathological conditions remains largely unknown. In this study, we show that APPL1 undergoes phosphorylation at Ser(430) and that this phosphorylation is enhanced in the liver of obese mice displaying insulin resistance. In cultured mouse hepatocytes, APPL1 phosphorylation at Ser(430) is stimulated by phorbol 12-myristate 13-acetate, an activator of classic PKC isoforms, and by the endoplasmic reticulum (ER) stress inducer, thapsigargin. Overexpression of wild-type but not dominant negative PKCα increases APPL1 phosphorylation at Ser(430) in mouse hepatocytes. In addition, suppressing PKCα expression by shRNA in hepatocytes reduces ER stress-induced APPL1 phosphorylation at Ser(430) as well as the inhibitory effect of ER stress on insulin-stimulated Akt phosphorylation. Consistent with a negative regulatory role of APPL1 phosphorylation at Ser(430) in insulin signaling, overexpression of APPL1(S430D) but not APPL1(S430A) impairs the potentiating effect of APPL1 on insulin-stimulated Akt phosphorylation at Thr(308). Taken together, our results identify APPL1 as a novel target in ER stress-induced insulin resistance and PKCα as the kinase mediating ER stress-induced phosphorylation of APPL1 at Ser(430).

A case report of lymphangioleiomyomatosis presenting as spontaneous pneumothorax.

Spontaneous pneumothorax is a commonly encountered problem in the Emergency Department. Patients are often treated without further investigation for an underlying etiology. We present a patient who was unable to completely resolve a pneumothorax and was found to have lymphangioleiomyomatosis (LAM), a rare cystic lung disease. In the past, LAM was difficult to diagnose and had a mortality of 100% after 10 years, but now there is a 71% survival after 10 years. Recent research has led to increased characterization of the pathology and radiographic findings. This article briefly presents the case and discusses the etiology, diagnosis, and treatment of LAM.

Answer to last month's radiology case and image: Bilateral patellar tendon rupture.

Patellar tendon rupture is a rare occurrence usually associated with chronic degeneration within the tendon, systemic illness, and fluoroquinolone therapy as mentioned previously. However in healthy adults, overweight men in their 3rd or 4th decade of life may be at increased risk when partaking in athletic activities, especially jumping activities. Patella alta is a key finding on physical exam and on radiographs as was evident in our case. Imaging can also be performed with ultrasound and MRI to confirm tendon rupture and rule out other concurrent injuries. Prompt surgical management and early rehabilitation are key to regaining normal function of the extensor mechanism. Preventive medicine education may be important for those at increased risk of injury.

Protein kinase C theta (PKCtheta)-dependent phosphorylation of PDK1 at Ser504 and Ser532 contributes to palmitate-induced insulin resistance.

Clinical, epidemiological, and biochemical studies have highlighted the role of obesity-induced insulin resistance in various metabolic diseases. However, the underlying molecular mechanisms remain to be established. In the present study, we show that palmitate-induced serine phosphorylation of phosphoinositide-dependent protein kinase-1 (PDK1) negatively regulates insulin signaling. PDK1-mediated Akt phosphorylation at Thr308 in the activation loop is reduced in C2C12 myotubes treated with palmitate or overexpressing protein kinase C theta (PKCtheta), a kinase that has been implicated in hyperlipidemia-induced insulin resistance. Palmitate treatment also inhibited platelet-derived growth factor-stimulated Akt phosphorylation, suggesting that the inhibition could occur at a site independent of IRS1/2. The inhibitory effect of palmitate on PDK1 and Akt was diminished in PKCtheta-deficient mouse embryonic fibroblasts (MEFs) by treating C2C12 myotubes with PKCtheta pseudosubstrates. In vivo labeling studies revealed that PDK1 undergoes palmitate-induced phosphorylation at two novel sites, Ser504 and Ser532. Replacing Ser504/532 with alanine disrupted PKCtheta-catalyzed PDK1 phosphorylation in vitro and palmitate-induced PDK1 phosphorylation in cells. PDK1-deficient MEFs transiently expressing PDK1S504A/S532A but not PDK1S504E/S532D showed increased basal and insulin-stimulated Akt phosphorylation at Thr308 when compared with MEFs expressing wild-type PDK1. Taken together, our results identify PDK1 as a novel target in free fatty acid-induced insulin resistance and PKCtheta as the kinase mediating the negative regulation.

Fine tuning PDK1 activity by phosphorylation at Ser163.

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.

APPL1 binds to adiponectin receptors and mediates adiponectin signalling and function.

Adiponectin, also known as Acrp30, is an adipose tissue-derived hormone with anti-atherogenic, anti-diabetic and insulin sensitizing properties. Two seven-transmembrane domain-containing proteins, AdipoR1 and AdipoR2, have recently been identified as adiponectin receptors, yet signalling events downstream of these receptors remain poorly defined. By using the cytoplasmic domain of AdipoR1 as bait, we screened a yeast two-hybrid cDNA library derived from human fetal brain. This screening led to the identification of a phosphotyrosine binding domain and a pleckstrin homology domain-containing adaptor protein, APPL1 (adaptor protein containing pleckstrin homology domain, phosphotyrosine binding (PTB) domain and leucine zipper motif). APPL1 interacts with adiponectin receptors in mammalian cells and the interaction is stimulated by adiponectin. Overexpression of APPL1 increases, and suppression of APPL1 level reduces, adiponectin signalling and adiponectin-mediated downstream events (such as lipid oxidation, glucose uptake and the membrane translocation of glucose transport 4 (GLUT4)). Adiponectin stimulates the interaction between APPL1 and Rab5 (a small GTPase) interaction, leading to increased GLUT4 membrane translocation. APPL1 also acts as a critical regulator of the crosstalk between adiponectin signalling and insulin signalling pathways. These results demonstrate a key function for APPL1 in adiponectin signalling and provide a molecular mechanism for the insulin sensitizing function of adiponectin.