Evaluation of the Addition of Angiotensin II in Patients With Shock After Cardiac Surgery at a Veterans Affairs Medical Center.

BACKGROUND: Vasoplegic shock occurs in up to 37% of cardiac surgery patients. We investigated the use of angiotensin II for treating vasoplegic shock in these patients. OBJECTIVES: We assessed clinical outcomes and mortality in patients undergoing cardiac surgery at our center between March 1, 2018 and October 31, 2020 who developed vasoplegic shock, comparing those who received angiotensin II with those who did not. METHODS: This was a retrospective chart review. Response to angiotensin II was defined as increase in or maintenance of mean arterial pressure (MAP) and decrease in background vasopressor dosage. RESULTS: Angiotensin II was administered to 7 patients (postoperatively in 4 patients [57.1%]) with vasoplegic shock and baseline norepinephrine equivalent (NEE) of 0.49 ± 0.08 µg/kg/min; 12 patients with vasoplegic shock did not receive angiotensin II. Within 3 hours of angiotensin II administration, NEE decreased by 38.0 ± 33.1%. Angiotensin patients were more likely to newly require renal replacement therapy (66.7% vs 9.1%, P = 0.03) and had a longer, although not statistically significant, postoperative stay (23.1 vs 14.0 days, P = 0.16). Despite higher NEE requirements at baseline (0.49 vs 0.30, P = 0.03) and over the next 48 hours in the angiotensin group, no between-group differences in 7-day mortality (14.3% vs 0.0%, P = 0.37) or 30-day mortality (28.6% vs 8.3%, P = 0.52) were noted. CONCLUSION AND RELEVANCE: In patients who developed vasoplegic shock after cardiac surgery, angiotensin II administration allowed immediate dosage reductions of other vasopressors while maintaining MAP. Despite its small sample size, this study adds to the paucity of data in these patients and highlights future research needs.

Ribosomal S6 kinase 4 (RSK4) tumor suppressor gene promoter methylation status in ovarian cancer.

BACKGROUND: Previously, we reported lower RSK4 mRNA and protein levels in malignant ovarian tumors compared to normal and benign ovarian tissues. Also, we observed a significant inverse correlation between the advanced ovarian cancer stages and RSK4 mRNA levels. We did not investigate the mechanisms involved in RSK4-reduced expression in ovarian cancer. Thus, this study investigates whether RSK4 promoter methylation in ovarian cancer tissues is responsible for its low expression. Additionally, the reactivation of RSK4 expression and its effect was studied in ovarian cancer cell lines. METHODS AND RESULTS: RSK4 promoter methylation percentage in malignant and benign ovarian tumors and normal ovary tissues was determined by combined bisulfite restriction analysis. The reactivation of RSK4 expression by decitabine treatment was studied in OVCAR3, SKOV3, TOV-112D, and TOV-21G cells by Western blotting. Cell proliferation was determined by XTT. A significantly high methylation percentage of the RSK4 promoter was observed among malignant and benign ovarian tumors but not in normal ovarian tissue. RSK4 promoter methylation was not associated with age, histological subtype, or stages of ovarian cancer. RSK4 promoter methylation correlates weakly but not significantly with RSK4 protein expression. No correlation was shown between RSK4 methylation and RSK4 mRNA expression. Decitabine induces RSK4 reactivation in all cell lines. However, cell proliferation was reduced only in TOV-112D cells. CONCLUSION: These data indicate that although RSK4 promoter methylation is increased in malignant ovarian tumors, this mechanism is unlikely to regulate its expression in ovarian cancer. RSK4 reactivation reduced cell proliferation only in the endometroid histological subtype.

Coronary Artery Bypass Grafting Versus Percutaneous Coronary Intervention in Patients with Left Ventricular Systolic Dysfunction.

PURPOSE: There is a paucity of comparative data examining the optimal revascularization strategy in patients with left ventricular systolic dysfunction (LVD). METHODS: We performed an aggregate data meta-analysis of clinical outcomes comparing percutaneous coronary intervention (PCI) versus coronary artery bypass (CABG) in patients with LVD (left ventricle ejection fraction (LVEF) of ≤ 40%), using the random effects model. Effects size is reported as odds ratio (OR) and a 95% confidence interval. Outcomes included all-cause mortality, myocardial infarction, stroke, repeat revascularization, and a composite of major adverse cardiac and cerebrovascular events (MACCE) at 30-day, 3-year, and long-term (6.3 ± 0.9 years) follow-ups. Seventeen studies (16 observational, 1 randomized) and 18,599 patients (CABG 9651; PCI 8948) were included. RESULTS: PCI and CABG had comparable all-cause mortality at 30 days (OR 0.78, 95% CI 0.49-1.23) and 3 years (OR 1.05, 95% CI 0.91-1.21); however, PCI was associated with increased long-term morality after a mean follow-up of 6.3 ± 0.9 years (31.6% vs. 24.3%, OR 1.41, 95% CI 1.21-1.64). A similar mortality trend was observed in the subgroup of patients with EF ≤ 35%. PCI had a higher rate of repeat revascularization at 3-year and long-term follow-ups. The long-term rates of stroke and MI were comparable. PCI, on the other hand, had lower rates of stroke at 30-day and 3-year follow-ups. CONCLUSION: CABG was associated with lower rates of long-term mortality and revascularization but higher rate of upfront stroke in patients with LVD. However, the data included consisted predominantly of observational studies, highlighting the paucity and need for randomized trials.

Marked virulence and azole resistance in Candida albicans isolated from patients with periodontal disease.

Candida albicans is an opportunistic fungus frequently associated with periodontal diseases. The objective of this study was to determine the expression patterns of virulence genes associated with those of azole resistance among the strains of C. albicans isolated from patients with periodontal disease. We isolated 80 strains of C. albicans from patients with periodontal disease enrolled from two dental clinics and their antifungal susceptibilities were evaluated using the disc diffusion method. C. albicans and its virulence genes were identified using PCR. The expressions of the virulence genes of C. albicans were analyzed using real-time PCR post in vitro infection of the cell line A549. The phenotype for resistance against azoles such as ketoconazole and fluconazole was observed in all analyzed strains (n = 80), which coincided with the high frequency of occurrence of the genes CDR1 and MDR1 associated with resistance. The frequencies of detection and expression of the genes HWP1 (47/15), ALS1 (80/66), ALS3 (70/30), LIP1 (78/44), LIP4 (77/65), LIP5 (79/58), LIP6 (79/58), PLB1 (79/65), and PLB2 (80/66) were found to be higher in the strains of C. albicans isolated from patients with moderate periodontitis and different expression patterns associated with those for azole resistance were identified. It could be elucidated that the high expression of virulence markers associated with azole resistance in C. albicans might be contributing to the chronicity of periodontal infections.

Temporal trends, outcomes, and predictors of mortality after pericardiocentesis in the United States.

BACKGROUND: Data regarding the temporal trends, outcomes, and predictors of in-hospital mortality after pericardiocentesis are limited. METHODS: The National Inpatient Sample database was used to extract hospitalizations of patients who underwent pericardiocentesis from January 2007 to September 2015. We examined the rates of in-hospital mortality, its predictors, and the temporal trends of pericardiocentesis utilization in the United States during the study period. We also examined trends and outcomes of pericardiocentesis associated with different cardiovascular procedures. RESULTS: A total of 96,377 hospitalizations with pericardiocentesis were examined. The number of pericardiocentesis procedures performed trended up significantly between 2007 and 2015 (p trend <.001), and this increase was observed predominantly in patients with unstable conditions. In-hospital mortality after pericardiocentesis decreased over time (14.6% in 2007 vs. 12.0% in 2015, p trend <.001), but remained higher than that after surgical pericardial intervention (13.1 vs. 8.9%, p value <.0001), predominantly attributable to a higher patient risk profile. Rates of in-hospital mortality were not statistically different between the procedural cohort and the nonprocedural cohort, 13.5 versus 13.0%, p value = .051. After multivariable adjustment, structural heart interventions (odds ratio [OR] 2.86; 95% confidence interval [CI] 2.35-3.49), bacterial and/or infective endocarditis (OR 2.09; 95% CI 1.72-2.54) and active neoplasms (OR 1.72; 95% CI 1.6-1.85) were independently associated with increased in-hospital mortality in pericardiocentesis patients. CONCLUSION: In this nationwide analysis, the number of pericardiocentesis procedures increased significantly over time. Structural interventions, endocarditis, and active neoplasms were associated with increased in-hospital mortality after pericardiocentesis.

Re-evaluating the Role of CABG in Acute Coronary Syndromes.

PURPOSE OF REVIEW: The use of coronary artery bypass grafting (CABG) in patients with acute coronary syndrome (ACS) has markedly declined during the past decade, with an increase in the use of percutaneous coronary intervention (PCI). However, long-term data continues to show survival advantages for patients undergoing CABG over PCI. We describe the current indications for and outcomes of CABG in patients who present with ACS. RECENT FINDINGS: Real-world studies demonstrate better long-term outcomes with CABG than with PCI after NSTE-ACS. Staged CABG after culprit-vessel PCI for STEMI is also a feasible option in certain patients. In patients presenting with ACS and cardiogenic shock who are treated with CABG, the use of mechanical circulatory support has produced a limited but significant reduction in mortality. The optimal revascularization strategy after ACS depends on many variables. The pre-eminent factor in selecting the best mode of revascularization and improving outcomes is careful patient selection based on deliberation by an interdisciplinary heart team.

Chitosan hydrogels significantly limit left ventricular infarction and remodeling and preserve myocardial contractility.

BACKGROUND: Left ventricular myocardial infarctions (MIs) consist of a central area of myocardial necrosis that is surrounded by areas of myocardial injury and ischemia. We hypothesized that chitosan hydrogels, when injected around the perimeter of MIs in rats, could decrease left ventricle (LV) wall stress by the Law of LaPlace, and therefore myocardial oxygen requirements, and prevent the ischemic and injured myocardium from becoming necrotic. In this manner, chitosan gels could limit LV infraction size and LV remodeling. Chitosan hydrogels are liquid at 25°C but gel at 37°C. METHODS: Seventy Sprague-Dawley rats with ligation of the left coronary artery were treated with either Dulbecco's Modified Eagle Medium (DMEM) or chitosan hydrogel in DMEM, which was injected around the infarct perimeter. Echocardiograms were obtained before MI and at 2, 4, 8, 12, and 16 wk after MI. Hearts from randomly selected rats were harvested at baseline and at the time of echocardiography for determinations of LV infarct size, remodeling, and histopathology. RESULTS: Infarct sizes as a percentage of the total ventricular myocardium in the DMEM group averaged 17% versus 14% in the chitosan group at 4 wk (P < 0.05), 18% versus 14% at 8 wk (P < 0.01), 19% versus 14% at 12 wk (P < 0.001), and 20% versus 14% at 16 wk (P < 0.001). Injection of chitosan into the infarctions produced LV wall thicknesses in the MI border zones that averaged 0.66 cm at 4 wk, which were greater than the LV wall thicknesses in the border zones of rats treated with DMEM, which averaged 0.33 cm (P < 0.01). Arteriole densities in the MI border zones were 160/mm(2) in the chitosan group but only 92/mm(2) in the DMEM rats (P < 0.01). The left ventricular end-diastolic diameters (LVEDs) in the rats averaged 0.73 cm before MI. After MI, LVED increased in the DMEM rats to 0.84 cm at 2 wk, then 0.89 cm at 4 wk, 0.89 cm at 8 wk, 0.89 m at 12 wk, and 0.87 cm at 16 wk. In contrast, LVED in the chitosan rats were on average 19% smaller in comparison with the DMEM rats (P < 0.05) and did not significantly change in comparison with their baseline LVEDs. Left ventricular ejection fraction (LVEF) in the rats averaged 83% before infarctions. In the infarction + DMEM group, the LVEFs significantly decreased after MI and averaged 59.7% at 2 wk, 52.5% at 4 wk, 46.1% at 8 wk, 52.4% at 12 wk, and 53.6% at 16 wk (P < 0.05). In the infarction + chitosan-treated rats, the LVEFs were greater and averaged 67.8% at 2 wk (P < 0.02), 68.9% (P < 0.02) at 4 wk, 69% (P < 0.003) at 8 wk, 65.2% at 12 wk (P < 0.05), and 67% at 16 wk (P < 0.05). CONCLUSIONS: Chitosan gel can increase LV myocardial wall thickness, decrease infarct size and LV remodeling, and preserve LV contractility.

Human cord blood stem cell paracrine factors activate the survival protein kinase Akt and inhibit death protein kinases JNK and p38 in injured cardiomyocytes.

BACKGROUND AIMS: We hypothesized that paracrine factors from human umbilical cord blood mononuclear cells (hUCBC) activate in injured cardiomyocytes the survival protein kinase Akt and limit activation of death protein kinases JNK and p38. METHODS: We treated hUCBC with H2O2 and measured growth factors and cytokines secreted by hUCBC. We then treated cardiomyocytes with H2O2 for 24 h and measured Akt, JNK and p38 activation by means of Western blots. We also measured myocyte viability and apoptosis with the use of fluorescence-activated cell-sorting cytometry. We then investigated myocytes treated for 24 h with H2O2 plus hUCBC and myocytes without hUCBC or H2O2. Four million hUCBC were placed in transwells permeable only to hUCBC paracrine factors, and the transwells were placed in flasks with H2O2 + Dulbecco's modified Eagle's medium or in flasks with myocytes plus H2O2+Dulbecco's modified Eagle's medium. RESULTS: hUCBC increased secretion during H2O2 of hepatocyte growth factor by 338%, insulin-like growth factor by 200%, interleukin-4 by 200%, vascular endothelial cell growth factor by 192%, placental growth factor by 150%, interleukin-10 by 150% and angiogenin by 121%. H2O2 increased myocyte JNK activation by 237% and p38 activation by 60%, decreased myocyte viability by 38% and increased necrosis by 34% (all P < 0.01). hUCBC paracrine factors increased in myocytes with H2O2 Akt activation by ≥ 25%, decreased JNK and p38 activation by > 35%, increased viability by > 22% and decreased apoptosis by > 33% (all P < 0.05). Akt inhibitor API-1 prevented the effects of hUCBC and enhanced H2O2 decrease of myocyte viability. Addition of JNK inhibitor SP600125 or p38 inhibitor SB203580 to myocytes plus H2O2 prevented H2O2 decrease in viability and increased hUCBC beneficial effects. CONCLUSIONS: During free radical stress, hUCBC paracrine factors activate myocyte Akt, which increases myocyte viability by decreasing activation of death-promoting protein kinases JNK and p38.

Loss of Kmt2c or Kmt2d drives brain metastasis via KDM6A-dependent upregulation of MMP3.

KMT2C and KMT2D, encoding histone H3 lysine 4 methyltransferases, are among the most commonly mutated genes in triple-negative breast cancer (TNBC). However, how these mutations may shape epigenomic and transcriptomic landscapes to promote tumorigenesis is largely unknown. Here we describe that deletion of Kmt2c or Kmt2d in non-metastatic murine models of TNBC drives metastasis, especially to the brain. Global chromatin profiling and chromatin immunoprecipitation followed by sequencing revealed altered H3K4me1, H3K27ac and H3K27me3 chromatin marks in knockout cells and demonstrated enhanced binding of the H3K27me3 lysine demethylase KDM6A, which significantly correlated with gene expression. We identified Mmp3 as being commonly upregulated via epigenetic mechanisms in both knockout models. Consistent with these findings, samples from patients with KMT2C-mutant TNBC have higher MMP3 levels. Downregulation or pharmacological inhibition of KDM6A diminished Mmp3 upregulation induced by the loss of histone-lysine N-methyltransferase 2 (KMT2) and prevented brain metastasis similar to direct downregulation of Mmp3. Taken together, we identified the KDM6A-matrix metalloproteinase 3 axis as a key mediator of KMT2C/D loss-driven metastasis in TNBC.

Coronary artery bypass grafting after acute ST-elevation myocardial infarction.

OBJECTIVES: The study objectives were to describe the trends and outcomes of isolated coronary artery bypass grafting after ST-elevation myocardial infarction using a nationwide database. METHODS: We queried the 2002-2016 National Inpatient Sample database for hospitalized patients with ST-elevation myocardial infarction who underwent isolated coronary artery bypass grafting. We report temporal trends, predictors, and outcomes of coronary artery bypass grafting in the early (2002-2010) and recent (2011-2016) cohorts. RESULTS: Of 3,347,470 patients hospitalized for ST-elevation myocardial infarction, 7.7% underwent isolated coronary artery bypass grafting. The incidence of isolated coronary artery bypass grafting after ST-elevation myocardial infarction decreased over time (9.2% in 2002 vs 5.5% in 2016, Ptrend < .001), whereas perioperative crude in-hospital mortality did not change (5.1% in 2002 vs 4.2% in 2016, Ptrend = .66), coinciding with an increase in the burden of comorbidities. There was an increase in performing isolated coronary artery bypass grafting on hospitalization day 3 or more, as well as an increase in the use of mechanical support devices and precoronary artery bypass grafting percutaneous coronary intervention. In the early cohort, isolated coronary artery bypass grafting on days 1 and 2 was associated with higher in-hospital mortality. In the recent cohort, coronary artery bypass grafting on day 2 had similar in-hospital mortality compared with day 3 or more and lower rates of acute kidney injury, ischemic stroke, ventricular arrhythmia, and length of hospital stay. CONCLUSIONS: In this nationwide analysis, there has been a decline in the use of isolated coronary artery bypass grafting after ST-elevation myocardial infarction. Isolated coronary artery bypass grafting on day 1 was performed in sicker patients and was associated with higher in-hospital mortality than coronary artery bypass grafting performed on day 3 or more. In the recent cohort, isolated coronary artery bypass grafting on day 2 had similar in-hospital mortality compared with day 3 or more.

Evaluation of genetic alterations in hereditary cancer susceptibility genes in the Ashkenazi Jewish women community of Mexico.

Background: Individuals of Ashkenazi Jewish ancestry have been identified as having higher prevalence of specific pathogenic variants associated with susceptibility to specific rare and chronic diseases. In Mexico, the prevalence and composition of rare cancer predisposing germline variants in Ashkenazi Jewish individuals has not been evaluated. Aim and methods: We aimed to evaluate the prevalence of pathogenic variants by massive parallel sequencing in a panel of 143 cancer-predisposing genes in 341 women from the Ashkenazi Jewish community of Mexico, who were contacted and invited to participate in the study through the ALMA Foundation for Cancer Reconstruction. Pre- and posttest genetic counseling was given and a questionnaire on personal, gyneco-obstetric, demographic and lifestyle variables was conducted. From peripheral blood DNA, the complete coding region, and splicing sites of a panel of 143 cancer susceptibility genes, including 21 clinically relevant genes, were sequenced. The Mexican founder mutation BRCA1 ex9-12del [NC_000017.10(NM_007294):c. (825+1-826-1)_(4,589+1-4,590-1)del] was also evaluated. Results: Among study participants (mean age ±standard deviation: 47 ± 14) 15% reported a personal history of cancer (50/341). Fourteen percent of participants (48/341) were carriers of pathogenic and likely pathogenic variants distributed among seven high-risk genes (APC, CHEK2, MSH2, BMPR1A, MEN1, MLH1, and MSH6), whereas 18.2% (62/341) had variants of uncertain clinical significance in genes associated with breast and ovarian cancer susceptibility (list of genes with VUS). Pathogenic and likely pathogenic variants in 16 susceptibility genes with ambiguous or non-well-established risk association for cancer were detected in 17.6% (60/341) of participants. Sixty four percent of participants reported current alcohol consumption compared with the 39 percent prevalence of alcohol consumption in Mexican women. None of the participants carried the recurrent Ashkenazi and Mexican founder mutations in BRCA1 or BRCA2, but 2% (7/341) had pathogenic Ashkenazi Jewish founder variants in BLM. Conclusion: Our findings show a diverse pathogenic variant composition among the recruited individuals of Ashkenazi Jewish ancestry in Mexico consistent with being a high-risk population for genetic diseases, which warrants further investigation to adequately assess the burden of hereditary breast cancer in this group and implement appropriate preventative programs.

Production of nanometer-size GaAs nanocristals by nanosecond laser ablation in liquid.

This paper reports the formation and characterization of spherical GaAs quantum dots obtained by nanosecond pulsed laser ablation in a liquid (ethanol or methanol). The produced bare GaAs nanoparticles demonstrate rather narrow size distribution which depends on the applied laser power density (from 4.25 to 13.9 J/cm2 in our experiments) and is as low as 2.5 nm for the highest power used. The absolute value of the average diameter also decreases significantly, from 13.7 to 8.7 nm, as the laser power increases in this interval. Due to the narrow nanoparticle size dispersion achieved at the highest laser powers two absorption band edges are clearly distinguishable at about 1.72 and 3.15 eV which are ascribed to E0 and E1 effective optical transitions, respectively. A comparison of the energies with those known for bulk GaAs allows one to conclude that an average diameter of the investigated GaAs nanoparticles is close to 10 nm, i.e., they are quantum dots. High resolution transmission electron microscopy (HRTEM) images show that the bare GaAs nanoparticles are nanocrystalline, but many of them exhibit single/multiple twin boundary defects or even polycrystallinity. The formation of the GaAs crystalline core capped with a SiO2 shell was demonstrated by HRTEM and energy dispersive X-ray (EDX) spectroscopy. Effective band edges can be better distinguished in SiO2 capped nanoparticles than in bare ones, In both cases the band edges are correlated with size quantum confinement effect.

Low left ventricular ejection fraction, complication rescue, and long-term survival after coronary artery bypass grafting.

OBJECTIVES: To evaluate the association between low left ventricular ejection fraction (LVEF), complication rescue, and long-term survival after isolated coronary artery bypass grafting. METHODS: National cohort study of patients who underwent isolated coronary artery bypass grafting (2000-2016) using Veterans Affairs Surgical Quality Improvement Program data. Left ventricular ejection fraction was categorized as ≥35% (n = 55,877), 25%-34% (n = 3893), or <25% (n = 1707). Patients were also categorized as having had no complications, 1 complication, or more than 1 complication. The association between LVEF, complication rescue, and risk of death was evaluated with multivariable Cox regression. RESULTS: Among 61,477 patients, 6586 (10.7%) had a perioperative complication and 2056 (3.3%) had multiple complications. Relative to LVEF ≥35%, decreasing ejection fraction was associated with greater odds of complications (25%-34%, odds ratio, 1.30 [1.18-1.42]; <25%, odds ratio, 1.65 [1.43-1.92]). There was a dose-response relationship between decreasing LVEF and overall risk of death (≥35% [ref]; 25%-35%, hazard ratio, 1.46 [1.37-1.55]; <25%, hazard ratio, 1.68 [1.58-1.79]). Among patients who were rescued from complications, there were decreases in 10-year survival, regardless of LVEF. Among those rescued after multiple complications, LVEF was no longer associated with risk of death. CONCLUSIONS: While decreasing LVEF is associated with post-coronary artery bypass grafting complications, patients rescued from complications have worse long-term survival, regardless of left ventricular function. Prevention and timely treatment of complications should remain a focus of quality improvement initiatives, and future work is needed to mitigate their long-term detrimental impact on survival.

Decongestion Models and Metrics in Acute Heart Failure: ESCAPE Data in the Age of the Implantable Cardiac Pressure Monitor.

The United States Food and Drug Administration restricts the use of implantable cardiac pressure monitors to patients with New York Heart Association (NYHA) class III heart failure (HF). We investigated whether single-pressure monitoring could predict survival in HF patients as part of a model constructed using data from the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) trial. We validated survival models in 204 patients, using all-cause 180-day mortality. Two levels of model complexity were tested: 1) a simplified 1-pressure model based on pulmonary artery mean pressure ([PAM]1P) (information obtainable from an implanted intracardiac monitor alone), and 2) a pair of 5-variable risk score models based on right atrial pressure (RAP) + pulmonary capillary wedge pressure (PCWP) ([RAP+PCWP]5V) and on RAP + PAM ([RAP+PAM]5V). The more complex models used 5 dichotomous variables: a congestion index above a certain threshold value, baseline systolic blood pressure of <100 mmHg, baseline blood urea nitrogen level of ≥ 34 mg/dL, need for cardiopulmonary resuscitation or mechanical ventilation, and posttreatment NYHA class IV status. The congestion index was defined as posttreatment RAP+PCWP or posttreatment RAP+PAM, with congestion thresholds of 34 and 42 mmHg, respectively (median pulmonary catheter indwelling time, 1.9 d). The 5-variable models predicted survival with areas under the curve of 0.868 for the (RAP+PCWP)5V model and 0.827 for the (RAP+PAM)5V model, whereas the 1-pressure model predicted survival with an area under the curve of 0.718. We conclude that decongestion as determined by hemodynamic assessment predicts survival in HF patients and that it may be the final pathway for treatment benefit despite improvements in pharmacologic intervention since the ESCAPE trial.

Left Ventricle Mass Regression After Surgical or Transcatheter Aortic Valve Replacement in Veterans.

BACKGROUND: Differences in left ventricular mass regression (LVMR) between transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR) have not been studied. We present clinical and echocardiographic data from veterans who underwent TAVR and SAVR, evaluating the degree of LVMR and its association with survival. METHODS: We retrospectively reviewed TAVR (n = 194) and SAVR (n = 365) procedures performed in veterans from 2011 to 2019. After 1:1 propensity matching, we evaluated mortality and secondary outcomes. Echocardiographic data (median follow-up 957 days, interquartile range 483-1652 days) were used to evaluate LVMR, its association with survival, and predictors of LVMR. RESULTS: There was no difference between SAVR and TAVR patients in mortality (for up to 8 years), stroke at 30 days, myocardial infarction, renal failure, prolonged ventilation, reoperation, or structural valve deterioration. SAVR patients (67.3% [101 of 150]) were more likely to have LVMR than TAVR patients (55.7% [44 of 79], P = .11). The magnitude of LVMR was greater for the SAVR patients (median, -23.3%) than for the TAVR patients (median, -17.8%, P = .062). SAVR patients with LVMR had a survival advantage over SAVR patients without LVMR (P = .016). However, LVMR was not associated with greater survival in TAVR patients (P = .248). CONCLUSIONS: SAVR patients were more likely to have LVMR and had a greater magnitude of LVMR than TAVR patients. LVMR was associated with better survival in SAVR patients, but not in TAVR patients.

Outcomes of Transcatheter Versus Surgical Aortic Valve Replacement in Patients <60 Years of Age.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is an alternative therapeutic modality to surgical aortic valve replacement (SAVR) in patients with severe aortic stenosis (AS). In the current analysis, we compare the characteristics and outcomes of AVR procedures in patients <60 years of age. METHODS: We queried the Nationwide Readmissions Database for all AVR hospitalizations in patients 18-59 years of age between January 2012 and December 2017. We performed a propensity score matching analysis (1:1) and compared baseline characteristics, procedural complications, and outcomes between TAVR and SAVR patients. RESULTS: A total of 72,356 hospitalizations for AVR were identified in patients <60 years of age. Compared to their SAVR counterparts, TAVR patients were older (52.5 ± 7.6) vs. 48.8 ± 9.6, p < 0.001), more likely to be women (37.9% vs. 28.0%, p < 0.001), and have history of prior radiation (8.3% vs. 0.7%, p < 0.001). After propensity score matching, TAVR patients had lower procedural complications, but a similar mortality rate compared to SAVR patients (2.9% vs. 3.0%, p = 0.77). TAVR was associated with a shorter length of hospital stay [4 [2-9] vs. 6 [5-11], p < 0.001), but no significant difference in the 30-day readmission rate was noted (16.2% vs. 16.8%, p-value = 0.49). CONCLUSION: Our study demonstrates favorable short-term outcomes in younger patients undergoing TAVR, which improved over time. Further investigation of long-term outcomes in TAVR performed younger patients is warranted to draw a comprehensive picture of TAVR safety and efficacy in low-risk patients.

Demographic Landscape of Cardiothoracic Surgeons and Residents at United States Training Programs.

BACKGROUND: Recruiting and promoting women and racial/ethnic minorities could help enhance diversity and inclusion in the academic cardiothoracic (CT) surgery workforce. However, the demographics of trainees and faculty at US training programs have not yet been studied. METHODS: Traditional, integrated (I-6), and fast-track (4+3) programs listed in the Accreditation Council for Graduate Medical Education (ACGME) public database were analyzed. Demographics of trainees and surgeons, including gender, race/ethnicity, subspecialty, and academic appointment (if applicable), were obtained from ACGME Data Resource Books, institutional websites, and public profiles. Chi-square and Cochran-Armitage trend tests were performed. RESULTS: In July 2020, 78 institutions had at least 1 CT surgery training program; 40 (51%) had only a traditional program, 20 (26%) traditional and I-6, 6 (8%) all 3 types of program, and 4 (5%) only I-6. The proportion of female trainees increased significantly from 2011 to 2019 (19% vs 24%, P < .001), with female I-6 trainees outnumbering female traditional trainees since 2018. Significant increases by race/ethnicity were observed overall and by program type, notably for Asian and Hispanic individuals in I-6 programs and Black individuals in traditional programs. Finally, of the 1175 CT surgeons identified, 633 (54%) were adult cardiac surgeons, 360 (37%) assistant professors, 116 (10%) women, and 33 (3%) Black. CONCLUSIONS: The demographic landscape of CT surgery trainees and faculty across multiple training pathways reflects increasing representation by gender and race/ethnicity. However, we must continue to work toward equitable representation in the workforce to benefit the diverse patients we treat.

Hypervirulence and Multiresistance to Antibiotics in Klebsiella pneumoniae Strains Isolated from Patients with Hospital- and Community-Acquired Infections in a Mexican Medical Center.

Klebsiella pneumoniae is a pathogenic bacterium associated with different infectious diseases. This study aimed to establish the different association profiles of virulence genes related to the hypermucoviscous phenotype (HM), capsular serotypes, biofilm formation, and multidrug resistance in K. pneumoniae strains from patients with hospital- and community-acquired infections. K. pneumoniae virulence genes and capsular serotypes were identified by PCR, antibiotic susceptibility by the Kirby-Bauer method, HM by the string test, and biofilm formation by measurement in polystyrene microtiter plates. Of a total of 150 strains from patients with hospital- (n = 25) and community-acquired infections (n = 125), 53.3% (80/150) were HM-positive and 46.7% (70/150) were HM-negative. HM-positive (68/80) and HM-negative (67/70) strains were biofilm-forming. Moreover, 58.7% (47/80) HM-positive and 57.1% (40/70) HM-negative strains were multidrug-resistant. Among HM-positive, HM-negative, and serotypes K1 (25/150), K2 (48/150), and non-K1/K2 strains, (77/150) the frequently detected adhesion genes were fimH, mrkD, ycfM, and kpn; entB, irp2, irp1, and ybtS, for iron acquisition; and rmpA for protectins. The gene association pattern fimH/kpn/mrkD/ycfM/entB/irp1/irp2/ybtS/fyuA (18/150) was frequent among the strains. K. pneumoniae strains from patients with hospital- and community-acquired infections demonstrated a wide diversity of virulence gene profiles related to phenotype (hypermucoviscosity, multidrug resistance, and biofilm formation) and serotypes.

Insights into Immune Escape During Tumor Evolution and Response to Immunotherapy Using a Rat Model of Breast Cancer.

Animal models are critical for the preclinical validation of cancer immunotherapies. Unfortunately, mouse breast cancer models do not faithfully reproduce the molecular subtypes and immune environment of the human disease. In particular, there are no good murine models of estrogen receptor-positive (ER+) breast cancer, the predominant subtype in patients. Here, we show that Nitroso-N-methylurea-induced mammary tumors in outbred Sprague-Dawley rats recapitulate the heterogeneity for mutational profiles, ER expression, and immune evasive mechanisms observed in human breast cancer. We demonstrate the utility of this model for preclinical studies by dissecting mechanisms of response to immunotherapy using combination TGFBR inhibition and PD-L1 blockade. Short-term treatment of early-stage tumors induced durable responses. Gene expression profiling and spatial mapping classified tumors as inflammatory and noninflammatory, and identified IFNγ, T-cell receptor (TCR), and B-cell receptor (BCR) signaling, CD74/MHC II, and epithelium-interacting CD8+ T cells as markers of response, whereas the complement system, M2 macrophage phenotype, and translation in mitochondria were associated with resistance. We found that the expression of CD74 correlated with leukocyte fraction and TCR diversity in human breast cancer. We identified a subset of rat ER+ tumors marked by expression of antigen-processing genes that had an active immune environment and responded to treatment. A gene signature characteristic of these tumors predicted disease-free survival in patients with ER+ Luminal A breast cancer and overall survival in patients with metastatic breast cancer receiving anti-PD-L1 therapy. We demonstrate the usefulness of this preclinical model for immunotherapy and suggest examination to expand immunotherapy to a subset of patients with ER+ disease. See related Spotlight by Roussos Torres, p. 672.

Breast cancer prevention by short-term inhibition of TGFß signaling.

Cancer prevention has a profound impact on cancer-associated mortality and morbidity. We previously identified TGFß signaling as a candidate regulator of mammary epithelial cells associated with breast cancer risk. Here, we show that short-term TGFBR inhibitor (TGFBRi) treatment of peripubertal ACI inbred and Sprague Dawley outbred rats induces lasting changes and prevents estrogen- and carcinogen-induced mammary tumors, respectively. We identify TGFBRi-responsive cell populations by single cell RNA-sequencing, including a unique epithelial subpopulation designated secretory basal cells (SBCs) with progenitor features. We detect SBCs in normal human breast tissues and find them to be associated with breast cancer risk. Interactome analysis identifies SBCs as the most interactive cell population and the main source of insulin-IGF signaling. Accordingly, inhibition of TGFBR and IGF1R decrease proliferation of organoid cultures. Our results reveal a critical role for TGFß in regulating mammary epithelial cells relevant to breast cancer and serve as a proof-of-principle cancer prevention strategy.