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Background: Sacubitril-valsartan is a combination of a neprilysin inhibitor and an angiotensin II receptor blocker respectively. Sacubitril-valsartan has become a standard of care in the treatment of patients with Congestive Heart Failure (CHF) with reduced EF. During its clinical trials and upon review of U.S. Food and Drug Administration (FDA) approval, sacubitril-valsartan exhibited a side effect profile including hyperkalemia, hypotension, renal dysfunction, and angioedema. Recently, sacubitril-valsartan was also approved for the treatment of CHF patients with preserved EF. Objective: In view of new indications and increased usage, it is important to establish the updated safety profile of sacubitril-valsartan in the general population since the PARADIGM-HF trial. Methods: We explored reported Adverse Events (AEs) of sacubitril-valsartan using the FDA Adverse Event Reporting System. A total of 57,958 AEs were reported until August 2021. Total of 16,658 (28.7%) AEs were reported by HCPs, which were further analyzed. AEs were analyzed in men (56.7%) vs women (25.3%), and also in 3 age groups of 18-64, 65-85, >85. Results: Out of 16,658 AEs, the most frequently reported AE was hypotension (17.2%). Other commonly reported AEs were renal dysfunction (14.3%), allergic reactions including angioedema (10.8%), GI distress (8.8%), tachyarrhythmias (5.8%), hyperkalemia (4.5%), and cough (3.0%). Out of 16,658 AEs, 11,631 (69%) were deemed serious and 4,422 (26.5%) resulted in hospitalization. Deaths were attributed to 3,909 serious AEs (23.5%). In the age group of 18-64, events of atrial fibrillation were less among women compared to men (1% vs 3%), while total events of ventricular tachycardia were noted more among men compared to women (2% vs 0.5%). Conclusion: Most of the reported AEs were consistent with the observed AEs from PARADIGM-HF except for tachyarrhythmia. There are few reports documenting arrhythmias followed by the use of sacubitril-valsartan, however, the clear mechanism is unknown. Despite the wide use of sacubitril-valsartan, there is currently limited data on the safety profile. In future with the increasing use, further randomized controlled trials (RCTs) are needed to better understand the safety profile of the medication.

AbstractBackgroundPediatric brain tumor survivors are at risk for poor social outcomes. It remains unknown whether cognitive sparing with proton radiotherapy (PRT) supports better social outcomes relative to photon radiotherapy (XRT). We hypothesized that survivors treated with PRT would outperform those treated with XRT on measures of cognitive and social outcomes. Further, we hypothesized that cognitive performance would predict survivor social outcomes.ProcedureSurvivors who underwent PRT (n = 38) or XRT (n = 20) participated in a neurocognitive evaluation >1 year post radiotherapy. Group differences in cognitive and social functioning were assessed using analysis of covariance (ANCOVA). Regression analyses examined predictors of peer relations and social skills.ResultsAge at evaluation, radiation dose, tumor diameter, and sex did not differ between groups (all p > .05). XRT participants were younger at diagnosis (XRT M = 5.0 years, PRT M = 7.6 years) and further out from radiotherapy (XRT M = 8.7 years, PRT M = 4.6 years). The XRT group performed worse than the PRT group on measures of processing speed (p = .01) and verbal memory (p < .01); however, social outcomes did not differ by radiation type. The proportion of survivors with impairment in peer relations and social skills exceeded expectation; χ2(1) = 38.67, p < .001; χ2(1) = 5.63, p < .05. Household poverty predicted peer relation difficulties (t = 2.18, p < .05), and verbal memory approached significance (t = −1.99, p = .05). Tumor diameter predicted social skills (t = −2.07, p < .05).ConclusionsRegardless of radiation modality, survivors are at risk for social challenges. Deficits in verbal memory may place survivors at particular risk. Results support monitoring of cognitive and social functioning throughout survivorship, as well as consideration of sociodemographic risk factors.

Abstract Purpose: In a post hoc analysis of the CATNON trial (NCT00626990), we explored whether adding temozolomide to radiotherapy improves outcome in patients with IDH1/2 wildtype (wt) anaplastic astrocytomas with molecular features of glioblastoma [redesignated as glioblastoma, isocitrate dehydrogenase–wildtype (IDH-wt) in the 2021 World Health Organization (WHO) classification of central nervous system tumors]. Patients and Methods: From the randomized phase III CATNON study examining the addition of adjuvant and concurrent temozolomide to radiotherapy in anaplastic astrocytomas, we selected a subgroup of IDH1/2wt and H3F3Awt tumors with presence of TERT promoter mutations and/or EGFR amplifications and/or combined gain of chromosome 7 and loss of chromosome 10. Molecular abnormalities including MGMT promoter methylation status were determined by next-generation sequencing, DNA methylation profiling, and SNaPshot analysis. Results: Of the 751 patients entered in the CATNON study, 670 had fully molecularly characterized tumors. A total of 159 of these tumors met the WHO 2021 molecular criteria for glioblastoma, IDH-wt. Of these patients, 47 received radiotherapy only and 112 received a combination of radiotherapy and temozolomide. There was no added effect of temozolomide on either overall survival [HR, 1.19; 95% confidence interval (CI), 0.82–1.71] or progression-free survival (HR, 0.87; 95% CI, 0.61–1.24). MGMT promoter methylation was prognostic for overall survival, but was not predictive for outcome to temozolomide treatment either with respect to overall survival or progression-free survival. Conclusions: In this cohort of patients with glioblastoma, IDH-wt temozolomide treatment did not add benefit beyond that observed from radiotherapy, regardless of MGMT promoter status. These findings require a new well-powered prospective clinical study to explore the efficacy of temozolomide treatment in this patient population.

Background: There are limited data on uninsured patients presenting with acute myocardial infarction-cardiogenic shock (AMI-CS). This study sought to compare the management and outcomes of AMI-CS between uninsured and privately insured individuals. Methods: Using the National Inpatient Sample (2000–2016), a retrospective cohort of adult (≥18 years) uninsured admissions (primary payer—self-pay or no charge) were compared with privately insured individuals. Interhospital transfers were excluded. Outcomes of interest included in-hospital mortality, temporal trends in admissions, use of cardiac procedures, do-not-resuscitate status, palliative care referrals, and resource utilization. Results: Of 402 182 AMI-CS admissions, 21 966 (5.4%) and 93 814 (23.3%) were uninsured and privately insured. Compared with private insured individuals, uninsured admissions were younger, male, from a lower socioeconomic status, had lower comorbidity, higher rates of acute organ failure, ST-segment elevation AMI-CS (77.3% versus 76.4%), and concomitant cardiac arrest (33.8% versus 31.9%; all P <0.001). Compared with 2000, in 2016, there were more uninsured (adjusted odds ratio, 1.15 [95% CI, 1.13–1.17]; P <0.001) and less privately insured admissions (adjusted odds ratio, 0.85 [95% CI, 0.83–0.87]; P <0.001). Uninsured individuals received less frequent coronary angiography (79.5% versus 81.0%), percutaneous coronary intervention (60.8% versus 62.2%), mechanical circulatory support (54% versus 55.5%), and had higher palliative care (3.8% versus 3.2%) and do-not-resuscitate status use (4.4% versus 3.2%; all P <0.001). Uninsured admissions had higher in-hospital mortality (adjusted odds ratio, 1.62 [95% CI, 1.55–1.68]; P <0.001) and resource utilization. Conclusions: Uninsured individuals have higher in-hospital mortality and lower use of guideline-directed therapies in AMI-CS compared with privately insured individuals.

AbstractBackgroundReal‐world data on atrial fibrillation (AF) ablation outcomes in obese populations have remained scarce, especially the relationship between obesity and in‐hospital AF ablation outcome.HypothesisObesity is associated with higher complication rates and higher admission trend for AF ablation.MethodsWe drew data from the US National Inpatient Sample to identify patients who underwent AF ablation between 2005 and 2018. Sociodemographic and patients' characteristics data were collected, and the trend, incidence of catheter ablation complications and mortality were analyzed, and further stratified by obesity classification.ResultsA total of 153 429 patients who were hospitalized for AF ablation were estimated. Among these, 11 876 obese patients (95% confidence interval [CI]: 11 422–12 330) and 10 635 morbid obese patients (95% CI: 10 200–11 069) were observed. There was a substantial uptrend admission, up to fivefold, for AF ablation in all obese patients from 2005 to 2018 (p < .001). Morbidly obese patients were statistically younger, while coexisting comorbidities were substantially higher than both obese and nonobese patients (p < .01) Both obesity and morbid obesity were significantly associated with an increased risk of total bleeding, and vascular complications (p < .05). Only morbid obesity was significantly associated with an increased risk of ablation‐related complications, total infection, and pulmonary complications (p < .01). No difference in‐hospital mortality was observed among obese, morbidly obese, and nonobese patients.ConclusionOur study observed an uptrend in the admission of obese patients undergoing AF ablation from 2005 through 2018. Obesity was associated with higher ablation‐related complications, particularly those who were morbidly obese.

AbstractBackgroundThere is a paucity of data regarding the sex‐related differences in the trends and outcomes of trans‐septal transcatheter mitral valve replacement (TS‐TMVR).MethodsThe Nationwide Readmissions Database (2015–2018) was queried for admissions for TS‐TMVR. Propensity matched analysis was conducted to compare outcomes with hospitalizations for TS‐TMVR among women versus men. The main study outcome was in‐hospital mortality.ResultsOur final analysis included 2063 hospitalizations for TS‐TMVR; of whom, 58.1% were women. The proportion of women among those undergoing TS‐TMVR increased from 50% in 2015 to 60.2% in 2018 (Ptrend = 0.04). Compared with men, women undergoing TS‐TMVR were slightly younger, and had a distinct profile of comorbidities. After matching, there was no significant difference in in‐hospital mortality among women versus men undergoing TS‐TMVR (7.8% vs. 6.1%, OR = 1.30; 95% CI: 0.79–2.13). Subgroup analyzes showed an interaction toward higher mortality with women versus men among patients with CKD (Pinteraction = 0.07). There were no significant differences between women and men in in‐hospital complications or length of stay after TS‐TMVR. Compared with men, women undergoing TS‐TMVR were more likely to be discharged to a nursing facility (17.7% vs. 11.5%, p = 0.01) and had higher rates of 30‐day readmissions (22.4% vs. 13.6%, p = 0.01).ConclusionThis nationwide analysis showed an increase in the proportion of women among patients undergoing TS‐TMVR during the study years. There were no differences in in‐hospital mortality, in‐hospital complications, or length of stay between both sexes following TS‐TMVR. Women were more likely to be discharged to nursing facilities and had higher rates of readmission at 30 days even after propensity matching.

OBJECTIVES: Mixed cardiogenic-septic shock is common and associated with high mortality. There are limited contemporary data on concomitant sepsis in acute myocardial infarction complicated by cardiogenic shock (AMI-CS). DESIGN: Observational study. SETTING: Twenty percent stratified sample of all community hospitals (2000–2014) in the United States. PARTICIPANTS: Adults (> 18 yr) with AMI-CS with and without concomitant sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Outcomes of interest included inhospital mortality, development of noncardiac organ failure, complications, utilization of guideline-directed procedures, length of stay, and hospitalization costs. Over 15 years, 444,253 AMI-CS admissions were identified, of which 27,057 (6%) included sepsis. The sepsis cohort had more comorbidities and had higher rates of noncardiac multiple organ failure (92% vs 69%) (all p < 0.001). In 2014, compared with 2000, the prevalence of sepsis increased from 0.5% versus 11.5% with an adjusted odds ratio (aOR) 11.71 (95% CI, 9.7–14.0) in ST-segment elevation myocardial infarction and 24.6 (CI, 16.4–36.7) (all p < 0.001) in non-ST segment elevation myocardial infarction. The sepsis cohort received fewer cardiac interventions (coronary angiography [65% vs 68%], percutaneous coronary intervention [43% vs 48%]) and had greater use of mechanical circulatory support (48% vs 45%) and noncardiac support (invasive mechanical ventilation [65% vs 41%] and acute hemodialysis [12% vs 3%]) (p < 0.001). The sepsis cohort had higher inhospital mortality (44.3% vs 38.1%; aOR, 1.21; 95% CI, 1.18–1.25; p < 0.001), longer length of stay (14.0 d [7–24 d] vs 7.0 d [3–12 d]), greater hospitalization costs (×1,000 U.S. dollars) ($176.0 [$85–$331] vs $77.0 [$36–$147]), fewer discharges to home (22% vs 44%) and more discharges to skilled nursing facilities (51% vs 28%) (all p < 0.001). CONCLUSIONS: In AMI-CS, concomitant sepsis is associated with higher mortality and morbidity highlighting the need for early recognition and integrated management of mixed shock.

Background. This single-arm, multicenter, phase 2 study evaluated the safety and antitumor activity of pazopanib in patients with unresectable, pulmonary metastatic osteosarcoma. Patients and Methods. Patients with pulmonary metastatic osteosarcoma unresponsive to chemotherapy were eligible. Patients who received prior tyrosine kinase inhibitor therapy were excluded. Pazopanib at 800 mg once daily was administered for 28-day cycles. Tumor responses were evaluated by local radiology assessment 1 month prior to and after initiation of treatment to calculate tumor doubling time and after every even numbered cycle. The primary endpoints were progression-free survival at 4 months, concomitant with a demonstrated 30% increase in tumor doubling time relative to the pretreatment growth rate. Results. 12 patients (7 female) were enrolled. The study was terminated prematurely due to withdrawal of financial support by the sponsor. 8 subjects were eligible for the primary analysis, whereas 4 patients were in a predefined exploratory “slow-growing” cohort. In the “fast-growing” cohort, 3 of the 8 patients (37.5%) eligible for first-stage analysis were deemed “success” by the preplanned criteria, adequate to proceed to second-stage accrual. In addition, 1 of the 4 patients in the “slow-growing” cohort experienced a partial remission. Grade 1-2 diarrhea was the most common adverse event, and grade 3 events were infrequent. Conclusion. This study illustrates a novel method of demonstrating positive drug activity in osteosarcoma by increasing tumor doubling time, and this is further supported by a partial response in a patient with “slow-growing” disease. This trial is registered with NCT01759303.

AbstractIntroductionReal‐world data on atrial fibrillation (AF) ablation among moderate and advanced chronic kidney disease (CKD) patients have so far remained scarce, especially in‐hospital AF ablation outcomes.MethodsWe drew data from the US National Inpatient Sample to identify hospitalized patients who underwent AF ablation between 2005 and 2018, and further stratified by CKD classification. We assessed the trend of AF ablation, as well as its complications.ResultsA total of 152 630 patients who were primarily hospitalized for AF and underwent ablation were estimated. Among these, CKD patients were found in a total of 1509 participants, with 978, 206, and 325 under CKD3, CKD4, and CKD5/ESKD, respectively. There was a significant increment in admission rates for AF ablation in the CKD population across all CKD classifications (p < .001). All CKD patients were statistically older, with higher coexisting comorbidities, while hypertension was found substantially lower than non‐CKD patients (p ≤ .001). Importantly, CKD, especially CKD3 and CKD5/ESKD, was significantly associated with an increased risk of total complications, and total bleeding, Neurological complications were found statistically lower in CKD patients (p = .029), and no mortality rates were significantly different (p = .287).ConclusionOur study observed an increase in admission trends for AF ablation among moderate and advanced CKD patients from 2005 to 2018. CKD was strongly associated with higher procedure‐related complications and bleeding, but neurological safety profiles and mortalities rates were nonsignificantly different.