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Objectives: This study evaluated the long-term efficacy of a standard antithrombotic strategy versus half-dose direct oral anticoagulation (DOAC) after Watchman implantation., Background: No consensus currently exists on the selection of the most effective antithrombotic strategy to prevent device-related thrombosis (DRT) in patients undergoing endocardial left atrial appendage closure., Methods: After successful left atrial appendage closure, consecutive patients were prescribed a standard antithrombotic strategy (SAT) or long-term half-dose DOAC (hdDOAC). The primary composite endpoint was DRT and thromboembolic (TE) and bleeding events., Results: Overall, 555 patients (mean age 75 ± 8 years, 63% male; median CHA 2 DS 2 -VASc [congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism, vascular disease, age 65-74 years, sex category] score 4 [interquartile range (IQR): 3-6]; median HAS-BLED [hypertension, abnormal renal or liver function, stroke, bleeding, labile international normalized ratio, elderly, drugs or alcohol] score 3 [IQR: 2-4]) were included. Patients were categorized into 2 groups (SAT: n = 357 vs hdDOAC: n = 198). Baseline clinical characteristics were similar between groups. The median follow-up duration was 13 months (IQR: 12-15 months). DRT occurred in 12 (2.1%) patients, all in the SAT group (3.4% vs 0.0%; log-rank P = 0.009). The risk of nonprocedural major bleeding was significantly more favorable in the hdDOAC group (0.5% vs. 3.9%; log-rank P = 0.018). The rate of the primary composite endpoint of DRT and TE and major bleeding events was 9.5% in SAT patients and 1.0% in hdDOAC patients (HR: 9.8; 95% CI: 2.3-40.7; P = 0.002)., Conclusions: After successful Watchman implantation, long-term half-dose DOAC significantly reduced the risk of the composite endpoint of DRT and TE and major bleeding events compared with a standard, antiplatelet-based, antithrombotic therapy., Competing Interests: Funding Support and Author Disclosures Dr Di Biase has served as a consultant for Biosense Webster, Boston Scientific, Stereotaxis, and St. Jude Medical; and has received speaker honoraria from Medtronic, Atricure, EPiEP, and Biotronik. Dr Burkhardt has served as a consultant for Biosense Webster and Stereotaxis. Dr Gibson has served as a consultant for Biosense Webster, Boston Scientific and Abbott. Dr Natale has received speaker honoraria from Boston Scientific, Biosense Webster, St. Jude Medical, Biotronik, and Medtronic; and has served as a consultant for Biosense Webster, St. Jude Medical, and Janssen. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021. Published by Elsevier Inc.)

EBV-positive and EBV-negative posttransplant lymphoproliferative disorders (PTLDs) arise in different immunovirological contexts and might have distinct pathophysiologies. To examine this hypothesis, we conducted a multicentric prospective study with 56 EBV-positive and 39 EBV-negative PTLD patients of the K-VIROGREF cohort, recruited at PTLD diagnosis and before treatment (2013-2019), and compared them to PTLD-free Transplant Controls (TC, n = 21). We measured absolute lymphocyte counts (n = 108), analyzed NK- and T cell phenotypes (n = 49 and 94), and performed EBV-specific functional assays (n = 16 and 42) by multiparameter flow cytometry and ELISpot-IFNγ assays (n = 50). EBV-negative PTLD patients, NK cells overexpressed Tim-3; the 2-year progression-free survival (PFS) was poorer in patients with a CD4 lymphopenia (CD4 + <300 cells/mm 3 , p <  .001). EBV-positive PTLD patients presented a profound NK-cell lymphopenia (median = 60 cells/mm 3 ) and a high proportion of NK cells expressing PD-1 (vs. TC, p = .029) and apoptosis markers (vs. TC, p < .001). EBV-specific T cells of EBV-positive PTLD patients circulated in low proportions, showed immune exhaustion (p = .013 vs. TC) and poorly recognized the N-terminal portion of EBNA-3A viral protein. Altogether, this broad comparison of EBV-positive and EBV-negative PTLDs highlight distinct patterns of immunopathological mechanisms between these two diseases and provide new clues for immunotherapeutic strategies and PTLD prognosis., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Substrate catheter ablation of scar-related ventricular tachycardia (VT) is a widely accepted therapeutic option for patients with ischemic cardiomyopathy (ICM)., Objective: The purpose of this study was to investigate whether concomitant amiodarone therapy affects procedural outcomes., Methods: A total of 134 consecutive patients (89% male; age 66 ± 10 years) with ICM undergoing catheter ablation of VT were included in the study. Patients were sorted by amiodarone therapy before ablation. In all patients, a substrate-based catheter ablation (endocardial ± epicardial) in sinus rhythm abolishing all "abnormal" electrograms within the scar was performed. The endpoint of the procedure was VT noninducibility. After the ablation procedure, all antiarrhythmic medications were discontinued. All patients had an implantable cardioverter-defibrillator, and recurrences were analyzed through the device., Results: In 84 patients (63%), the ablation was performed on amiodarone; the remaining 50 patients (37%) were off amiodarone. Patients had comparable baseline characteristics. Mean scar size area was 143.6 ± 44.9 cm 2 on amiodarone vs 139.2 ± 36.8 cm 2 off amiodarone (P = .56). More radiofrequency time was necessary to achieve noninducibility in the off-amiodarone group compared to the on-amiodarone group (68.1 ± 20.1 minutes vs 51.5 ± 19.7 minutes; P <.001). In addition, due to persistent VT inducibility, more patients in the off-amiodarone group required epicardial ablation than in the on-amiodarone group (13/50 [26%] vs 5/84 [6%], respectively; P <.001). During mean follow-up of 23.9 ± 11.6 months, recurrence of any ventricular arrhythmias off antiarrhythmic drugs was 44% (37/84) in the on-amiodarone group vs 22% (11/50) in the off-amiodarone group (P = .013)., Conclusion: Albeit, VT noninducibility after substrate catheter ablation for scar related VT was achieved faster, with less radiofrequency time and less need for epicardial ablation in patients taking amiodarone, these patients had significantly higher VT recurrence at long-term follow-up when this medication was discontinued., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Thromboembolic stroke is a rare but devastating consequence of atrial fibrillation (AF) ablation. Transesophageal echocardiography (TEE) is recommended to rule out left atrial appendage thrombus; however, its use is variable., Objective: The purpose of this study was to assess whether TEE is mandatory in patients undergoing AF ablation on uninterrupted direct oral anticoagulants (DOACs)., Methods: Data from our prospective multicenter registry of patients with AF undergoing radiofrequency catheter ablation on uninterrupted DOACs were analyzed. All the included patients were on anticoagulation for at least 4 weeks before ablation. All AF ablation procedures were performed under intracardiac echocardiography guidance. Before transseptal puncture, heparin bolus was administered, followed by continuous infusion, with a target activated clotting time of >300 seconds., Results: A total of 6186 patients (3180 on apixaban [51.4%], 2528 on rivaroxaban [40.9%], 404 on dabigatran [6.5%], and 74 on edoxaban [1.2%]) were analyzed. The mean age of the study population was 69.4 ± 10.3 years; 4194 patients (67.8%) were male, and 5120 patients (82.8%) had persistent and long-standing persistent AF. The mean CHA 2 DS 2 -VASc score was 2.86 ± 1.58; the mean CHADS 2 score was 1.65 ± 1.14. Intracardiac echocardiography ruled out left atrial appendage and left atrial thrombi in all patients and revealed "smoke" in 1672 patients (27.03%). Transient ischemic attack was noted in 1 patient with long-standing persistent AF in the setting of a missed dose of rivaroxaban before ablation., Conclusion: Our study showed that performing AF ablation in patients on uninterrupted DOACs without TEE is safe and feasible in high stroke risk patients. Elimination of routine preablation TEE would have significant economic and clinical implications., (Copyright © 2020 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Sympathergic hyperactivity is considered one of the main trigger precipitating takotsubo syndrome (TTS). Chromogranin-A (CgA), a prognostic biomarker of sympatho-adrenal activation, is markedly high in acute coronary syndrome (ACS) and heart failure (HF), but its role in TTS is unknown., Methods: CgA serum levels from patients with TTS and symptoms onset <24 hours were consecutively evaluated and compared with anterior ST-elevation myocardial infarction (STEMI) patients from November 2016 to December 2019. Short and long-term follow-up data were recorded., Results: Eleven women with TTS and 10 subjects with anterior STEMI were analyzed and compared; differences were not significant in terms of age, gender and cardiovascular risk factors. NT-pro-BNP levels were similar (9,887 ± 12,170 vs 8,969 ± 15,053 pg/ml, p = .88), while troponin-I levels were higher in patients with STEMI (4 ± 3.2 vs 13.3 ± 10 ng/dl, p = .03). CgA admission levels were significantly lower in TTS patients (2.2 ± 1.5 vs 7.3 ± 6.2 nMol/l, p = .017), even after multivariable correction for principal bias. CgA levels correlated with NTproBNP levels (p = .02) and were higher in subjects with in-hospital events (3.7 ± 1.1 vs 1.6 ± 1.2 nMol/l, p = .03), even after multivariable forward stepwise analysis (p < .01). CgA levels <3.25 nMol/l (AUC 0.754, 95% C.I. 0.54-0.968) were able to discriminate TTS from anterior STEMI (negative predictive power of 99%)., Conclusions: Systemic CgA levels in the acute phase of TTS are lower than in anterior STEMI, possibly indicating a greater myocardial catecholamine release rather than adrenal., Competing Interests: Declaration of competing interest None to disclose., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Aims: Systemic inflammatory activation can be observed in both Takotsubo cardiomyopathy (TTC) and acute coronary syndrome (ACS). The aim of this study was therefore to compare circulating cytokine levels during the acute and subacute phase of TTC and ACS., Methods: One hundred thirty-six consecutive patients were enrolled in the study; after a propensity score matching, 32 TTC patients were compared with 32 subjects with ACS. Clinical baseline features and circulating levels of interleukin(IL)-1β, IL-1α, IL-2, IL-4, IL-6, IL-8, IL-10, IFN-γ, MCP1, EGF, VEGF, TNFα were obtained at admission (t 0 ) and after 120 h (t 1 )., Results: At t 0 , several circulating IL levels were higher in subjects with TTC (IL-2 2 vs. 0.5 pg/ml, IL-4 1.5 vs. 0.82 pg/ml, IL-10 3.34 vs. 1.62 pg/ml, TNF-α 5 vs. 2.3 pg/ml, IFN-γ 0.92 vs. 0.32 pg/ml, EGF 84.8 vs. 10.7 pg/ml, p < 0.05 in all cases), while IL-6 levels were higher in patients with ACS (25.4 vs. 12.4 pg/ml p = 0.03). At t 1, IL-2 and EGF levels were still higher in patients with TTC vs. those with ACS (IL-2 4.6 vs. 0.72 pg/ml, p = 0.01; EGF 36.3 vs. 18.5 pg/ml, p = 0.03), while IL-6 serum levels were higher in ACS patients (19.6 vs. 7.35 pg/ml, p = 0.02)., Conclusions: Different inflammatory patterns can be observed during the acute and subacute phase of TTC when compared to ACS. Increased levels of anti-inflammatory interleukins can be found during the acute phase of TTC while ACS is featured by higher levels of IL-6 during the acute and sub-acute phase., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Potential predictors of clinical complications of Takotsubo syndrome (TTS) are poorly known. Persistent ST-segment elevation (PSTE) may have an impact on outcome similar as previously reported in acute coronary syndrome. The aim of this study was to assess the prevalence and prognostic relevance of PSTE in patients with TTS., Methods: Two-hundred-sixty-nine consecutive patients were enrolled in an international multicenter registry. PSTE was defined as the documentation of ST-elevation at least for the first 48h of hospitalization. Long-term mortality was evaluated in median 1.9years after the acute event., Results: PSTE was found in 52 TTS patients (19%). Patients with PSTE were characterized by higher admission levels of troponin-I (23±12 vs 8±49ng/L, p<0.001), experienced a longer hospitalization (10±5 vs 8±3days, p=0.02) and a higher rate of in-hospital complications (31% vs 17% p=0.03). At multivariate analysis including PSTE, age, male sex, admission ejection fraction, PSTE (odds ratio [OR] 4.2; 95% confidence interval [CI] 1.4-13; p=0.01), age (OR 1.05; 95%CI 1.00-1.10; p=0.03) and admission ejection fraction (OR 0.93; 95%CI 0.87-0.99; p=0.02) were independent predictors of in-hospital complications. At long-term follow-up no significant differences in terms of mortality were observed between patients with and without PSTE (19% vs 15%; p=0.5). However, PSTE was a predictor of major cardiac adverse events (MACE) at follow-up (HR 2.32, 95% CI 1.02-5.31, p 0.045)., Conclusions: In TTS patients, PSTE is a common finding, represents an independent predictor of in-hospital complications and could be associated with MACE at follow-up., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Background: Takotsubo syndrome (TTS) is associated with a considerable risk of complications during the acute phase and substantial long-term mortality rates. Concomitant atrial fibrillation may have an impact on outcome in these patients. Aim of this study was to assess the prevalence and prognostic relevance of atrial fibrillation in TTS., Methods: We performed an international, multicenter study including 387 TTS patients consecutively enrolled at 3 centers. Atrial fibrillation was defined as known history before admission or documented episodes during hospital stay. Long-term mortality was evaluated in median 2.9years after the acute event., Results: Atrial fibrillation was found in 97 TTS patients (25.1%) and was associated with older age (p<0.01), less emotional triggers (p=0.03), higher incidence of cardiogenic shock (p<0.01), lower left ventricular ejection fraction (p<0.01), and a prolonged hospital stay (p<0.01). Determinants of atrial fibrillation at admission (n=34 patients; 9.0%) in multivariate logistic regression analysis were age (p=0.001) and cardiogenic shock (p=0.013). Long-term mortality was significantly higher in TTS patients with as compared to patients without atrial fibrillation (35.2% versus 15.3%; hazard ratio 3.02, 95% confidence interval 1.90-4.78; p<0.001). In multivariate Cox regression analysis atrial fibrillation was identified as an independent determinant of outcome even after adjustment for clinical variables, left ventricular functional parameters (ballooning pattern, ejection fraction), and cardiogenic shock., Conclusions: In TTS patients, atrial fibrillation is frequent and associated with increased long-term mortality rates. Furthermore, our study identifies atrial fibrillation as an independent predictor of outcome and a potential tool for risk stratification in TTS., (Copyright © 2017. Published by Elsevier B.V.)

Background and Aims: Systemic inflammation has been hypothesized as a possible mechanism of Takotsubo cardiomyopathy (TTC). Aim of the study was to assess the role of interleukin (IL)-6 and IL-10 in subjects with an episode of TTC., Methods: Fifty-six consecutive subjects with TTC were prospectively enrolled in the study and followed for a mean of 178 days. Circulating levels of IL-6, IL-10, clinical condition and left ventricular ejection fraction were evaluated at admission. Incidence of death, re-hospitalization and recurrence of TTC during follow-up was also recorded., Results: 23% of patients experienced in-hospital complications while 20% of patients had adverse events at follow-up. IL-6 and IL-10 serum levels at admission were higher in subjects with adverse events at follow-up (120 ± 294 vs. 22 ± 40 pg/ml, p<0.05; 13 ± 35 vs. 2 ± 3 pg/ml, p=0.05, respectively). Increased serum levels of IL-6 and IL-10 were associated with higher adverse events rates at follow-up (Log-Rank p<0.001, <0.05, hazard ratio 8.6, 5.1, respectively) and mortality rates (Log-Rank p<0.001, p<0.05, hazard ratio 20.8, 7.1, respectively). Subjects with both increased IL-6 and IL-10 levels were characterized by an increased risk of adverse events when compared to subjects with only IL-6 or IL-10 increased levels or with values below cutoff values (Log-Rank p<0.01 for any event, <0.001 for death; hazard ratio 1.20 for any event, 1.31 for death), even after correction for age, LVEF and NTproBNP levels in multivariable Cox analysis., Conclusions: Serum IL-6 and IL-10 admission levels are associated with higher risk of adverse events during follow-up., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

P100, which is encoded by NF-kappa B2, inhibits Rel dimers. It can also be processed into p52, one of the DNA binding sub-units of NF-kappa B/Rel factors. Several p100 C-terminal truncations that result from gene rearrangements are associated with lymphomagenesis. Here, we characterized a new p100 mutant that we termed p100HB. It originates from a point-mutation that generates a premature stop-codon, and thus the protein lacks the last 125 amino acids. We have detected p100HB in several human tumor cell lines. The truncated protein is mainly unprocessed, and although it still binds Rel dimers, it has reduced inhibitory potency compared to p100 and translocates into the nucleus. Thus, p100HB may be associated with deregulated NF-kappa B/Rel functions.

Objective: To evaluate the safety and effectiveness of a zonal-progressive multifocal silicone intraocular lens (IOL)., Design: Prospective, nonrandomized, fellow eye comparative trial., Participants: Four hundred fifty-six subjects were enrolled at 14 investigational sites in the United States; 400 subjects achieved 1-year follow-up. A subset of 123 subjects (102 at 1 year) were enrolled in a monofocal fellow eye control substudy; subjects were implanted with the multifocal IOL in one eye and a comparable monofocal IOL in the fellow eye., Methods: Cataract extraction and implantation of a zonal-progressive multifocal silicone IOL was performed using the surgeon's standard technique. Subjects were followed at six postoperative examination intervals through 1 year., Main Outcome Measures: The key efficacy measures were mean uncorrected and corrected distance and near visual acuity at 1 year after surgery., Results: In the monofocal fellow eye control substudy, the multifocal eyes showed a mean 2-line increase over monofocal eyes for uncorrected and distance-corrected near visual acuity (P < 0.0001). Mean uncorrected distance visual acuity was similar between multifocal and monofocal eyes (P = 0.116). A significantly higher proportion of bilateral multifocal subjects reported that they could function comfortably without glasses at near (81%, 96 of 118) compared with multifocal/monofocal subjects (56%; 93 of 165; P < 0.001) and unilateral multifocal subjects (58%; 56 of 97; P < 0.001). Low-contrast visual acuity was reduced in multifocal eyes by approximately 1 Snellen line. However, no perceived disadvantages attributable to the reduction in low-contrast acuity were found. Although the perception of halos and glare increased in the multifocal eyes, good visual function remained, and nearly all subjects were satisfied with the results of their surgery., Conclusions: In a large study that included a subset of subjects with paired eye compared with those with monofocal lenses, this zonal-progressive multifocal lens provided a high level of uncorrected and corrected distance vision, improved uncorrected and distance-corrected near vision, reduced spectacle dependency, and a high level of patient satisfaction despite some loss of low-contrast visual acuity and increased reports of halos and glare.

Objective: The authors measured functional status after bilateral implantation of a multifocal versus a monofocal intraocular lens (IOL)., Methods: A retrospective, case-control study was done on 100 subjects implanted bilaterally with a silicone-optic foldable zonal progressive IOL under United States Food and Drug Administration Investigational Device Exemption protocol and 103 control subjects implanted bilaterally with a monofocal IOL of similar design who were matched on age and postoperative corrected distance acuity. The Cataract TyPE specification, a 17-item functional status instrument, was modified, validated, and administered via telephone interview. The measures of vision, functional status, and quality of life were compared between patients and controls., Results: The instrument was valid (Cronbach's alpha = 0.94) and correlated moderately (Pearson's r= 0.34) with Snellen acuity. Multifocal subjects were more likely than monofocal controls to never wear spectacles (41% vs. 11.7%; P < 0.001). Multifocal subjects rated their vision without spectacles significantly better than those with monofocal IOLs (9.0 vs. 7.9; P < 0.001). The difference was most significant in rating of near vision without spectacles (7.8 vs. 5.0; P < 0.001). Multifocal subjects reported less limitation in specific visual tasks without spectacles (0.3 vs. 0.8; P < 0.001, where 1.0 represents "slightly" limited). This difference was consistently observed in subscales related to distance vision activities (0.1 vs. 0.4; P < 0.001), near vision activities (0.6 vs. 1.4; P < 0.001), and social activities (0.1 vs. 0.6; P < 0.001)., Conclusions: In this study, subjects with bilateral multifocal IOLs reported better overall vision, less limitation in visual function, and less spectacle usage than monofocal controls.

NF-kB is a eukaryotic transcription regulatory factor. In T cells and T cell lines, NF-kB is bound to a cytoplasmic proteic inhibitor, the IkB. Treatment of T cells with mitogens (phorbol esters) or cytokines (TNF alpha) induces NF-kB nuclear translocation and the subsequent expression of NF-kB dependent T cell genes. Here we examined the activation of NF-kB in human T cell thymic progenitors. We report differences in (Ca2+)i requirement for NF-kB activation in thymocytes as compared to mature T cells. Furthermore, our results indicated that thymocytes have a constitutively active form of NF-kB, suggesting that they are activated in vivo.