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Musculoskeletal disorders are the most common reason of chronic pain and disability representing worldwide an enormous socio-economic burden. In this review, new biomedical application fields for Raman spectroscopy (RS) technique related to skeletal tissues are discussed showing that it can provide a comprehensive profile of tissue composition in situ, in a rapid, label-free, and non-destructive manner. RS can be used as a tool to study tissue alterations associated to aging, pathologies, and disease treatments. The main advantage with respect to currently applied methods in clinics is its ability to provide specific information on molecular composition, which goes beyond other diagnostic tools. Being compatible with water, RS can be performed without pre-treatment on unfixed, hydrated tissue samples, without any labelling and chemical fixation used in histochemical methods. This review provides first the description of basic principles of RS as a biotechnology tool and introduces into the field of currently available RS based techniques, developed to enhance Raman signal. The main spectral processing statistical tools, fingerprint identification and available databases are mentioned. The recent literature has been analysed for such applications of RS as tendon and ligaments, cartilage, bone, and tissue engineered constructs for regenerative medicine. Several cases of proof-of-concept preclinical studies have been described. Finally, advantages, limitations, future perspectives, and challenges for translation of RS into clinical practice have been also discussed.

BACKGROUND Limited real-world data are available regarding the comparison about safety and efficacy of DOACs prescription in very elderly patients (≥85 years) with non-valvular atrial fibrillation (NVAF). Concern about the risk of bleeding with anticoagulation in very older patients still represents an important challenge for clinicians. OBJECTIVE To evaluate the different prevalence of major bleeding and thromboembolic events between very elderly NVAF patients (≥85 years) compared to those non very elderly (

Background Intracranial hemorrhage (ICH) represents the most serious complication of oral anticoagulant therapy (OAT) in patients with atrial fibrillation (AF), and AF patients with previous ICH are a challenge for clinicians. Left atrial appendage (LAA) occlusion has emerged as an alternative option for AF patients not suitable for OAT. Currently, few data are available on long term outcomes after LAA occlusion in this population. We evaluated the safety and efficacy of LAA occlusion in a cohort of patients with AF and previous ICH. Methods This is a multicenter, observational, retrospective study involving 5 LAA occlusion centers in Italy. It includes all consecutive patients (n = 120) with previous ICH who underwent LAA occlusion for nonvalvular AF and high thromboembolic risk. Procedural outcomes, post-procedural therapies and 12-months follow-up data were analyzed. Results The device was successfully implanted in 100% of cases, with a 6% of major peri-procedural complications. 59% had a prior ICH during OAT. The sample had a high risk of stroke (5.18%/year) and bleeding (6.62%/year). 30% were discharged on single and 54.2% on dual antiplatelet therapy. The expected annual risk for thromboembolism was 5.1%. Excluding periprocedural ischemic complications, the stroke annual rate was 1.8%. The expected annual risk of bleeding was 6.7%. The observed annual bleeding rate was 5.45%. Conclusions Percutaneous LAA occlusion is an effective option for AF patients and previous intracranial hemorrhage. After LAA occlusion, a single antiplatelet therapy strategy could be considered for patients with the highest risk of recurrent bleeding.

Background: Predicting an accessory pathway location is extremely important in pediatric patients. Aims: We designed a study to compare previously published algorithms by Arruda, Boersma, and Chiang. Methods: This multicenter study included patients who had undergone successful ablation of one accessory pathway. Analysis of resting 12-lead electrocardiograms was carried out. An aggregated prediction score was constructed on the basis of algorithm agreement, and a structured workflow approach was proposed. Results: The total population was 120 patients (mean age, 12.7 [± 3.6] years). The algorithm by Boersma had the highest accuracy (71.7%). The inter-rater agreement among the 3 reference algorithms, according to left-sided accessory pathway (AP) identification, was good between Boersma and Chiang (κ = 0.611; 95% confidence interval [CI], 0.468–0.753) but moderate between Arruda and Chiang and between Arruda and Boersma (κ = 0.566; 95% CI, 0.419–0.713 and κ = 0.582; 95% CI, 0.438–0.727, respectively). Regarding locations at risk of atrioventricular (AV) block, agreement was fair between Arruda and Chiang and between Boersma and Chiang (κ = 0.358; 95% CI, 0.195–0.520 and κ = 0.307; 95% CI, 0.192–0.422, respectively) but moderate between Arruda and Boersma (κ = 0.45; 95% CI, 0.304–0.597). On applying a first-step diagnostic evaluation, when concordance was achieved, we were able to correctly identify left-sided or non-left-sided ablation sites in 96.4% (n = 80) of cases. When concordance was achieved, correct prediction of risk/no risk of AV block was achieved in 92.2% (n = 59) of cases. Conclusions: An aggregated prediction score based on 3 reference algorithms proved able to predict an accessory pathway location very precisely and could be used to plan safely invasive procedures.

International audience; AimsDilated cardiomyopathy (DCM) is a complex disease where genetics interplay with extrinsic factors. This study aims to compare the phenotype, management, and outcome of familial DCM (FDCM) and non‐familial (sporadic) DCM (SDCM) across Europe.Methods and resultsPatients with DCM that were enrolled in the prospective ESC EORP Cardiomyopathy & Myocarditis Registry were included. Baseline characteristics, genetic testing, genetic yield, and outcome were analysed comparing FDCM and SDCM; 1260 adult patients were studied (238 FDCM, 707 SDCM, and 315 not disclosed). Patients with FDCM were younger (P < 0.01), had less severe disease phenotype at presentation (P < 0.02), more favourable baseline cardiovascular risk profiles (P ≤ 0.007), and less medication use (P ≤ 0.042). Outcome at 1 year was similar and predicted by NYHA class (HR 0.45; 95% CI [0.25–0.81]) and LVEF per % decrease (HR 1.05; 95% CI [1.02–1.08]. Throughout Europe, patients with FDCM received more genetic testing (47% vs. 8%, P < 0.01) and had higher genetic yield (55% vs. 22%, P < 0.01).ConclusionsWe observed that FDCM and SDCM have significant differences at baseline but similar short‐term prognosis. Whether modification of associated cardiovascular risk factors provide opportunities for treatment remains to be investigated. Our results also show a prevalent role of genetics in FDCM and a non‐marginal yield in SDCM although genetic testing is largely neglected in SDCM. Limited genetic testing and heterogeneity in panels provides a scaffold for improvement of guideline adherence.

Objectives The current reference standard for diagnosing LAA thrombi is transesophageal echocardiography (TEE), a semi-invasive technique. We aimed to devise an optimal protocol for cardiac computed tomography (CCT) in diagnosing left atrial appendage (LAA) thrombus in patients with atrial fibrillation (AF), using TEE as reference standard. Methods Two hundred sixty consecutive patients referred for radiofrequency ablation for AF were prospectively enrolled. All patients underwent CCT and TEE within 2 hours. The CCT protocol included one standard angiographic phase and three delayed acquisitions at 1-, 3-, and 6-min after contrast injection. Thrombi were defined as persisting defects at 6-min delayed acquisition. Results TEE demonstrated spontaneous contrast in 52 (20%) patients and thrombus in 10 (4%). In 63 patients (24%), CCT demonstrated LAA early filling defects at angiographic phase. Among them, 15 (6%) had a persistent defect at 1-min, 12 (5%) at 3-min, and 10 (4%) at 6-min. All 10 thrombi diagnosed on TEE were correctly identified by delayed CCT, without any false positives. For all phases, sensitivity and negative predictive were 100%. Specificity increased from 79% for the angiographic phase to 100% at 6-min. Positive predictive value increased from 16% to 100%. Estimated radiation exposure was 2.08 ± 0.76 mSv (mean ± standard deviation) for the angiographic phase and 0.45 ± 0.23 mSv for each delayed phase. Conclusion A CCT protocol adding a 6-min delayed phase to the angiographic phase can be considered optimized for the diagnosis of LAA thrombi, with a low radiation dose. Key Points • In patients with persistent atrial fibrillation referred for ablation procedures, a cardiac CT examination comprising an angiographic-phase acquisition and, in case of filling defects, a 6-min delayed phase may help reduce the need for transesophageal echocardiography. • Cardiac CT would provide morphological and volumetric data, along with the potential to exclude the presence of thrombi in the left atrial appendage.

Background Limited real-world data are available regarding the outcome of patients treated with inappropriate dose of nonvitamin-K antagonist oral anticoagulants (NOACs). Objective To assess the prevalence and factors associated with inappropriate dose prescription of NOACs and to evaluate adverse events that come from this inappropriate prescription. Methods Single-center multidisciplinary registry including nonvalvular atrial fibrillation patients treated with NOACs. Based on guidelines criteria for dose reduction, two subcohorts were defined as treated with appropriate or inappropriate NOACs dose. Primary efficacy endpoint was 2-year rate of thromboembolic events. Primary safety endpoint was 2-year rate of major bleeding. Event-free survival curves among groups were compared using Cox-Mantel test. Results A total of 760 nonvalvular atrial fibrillation patients were included; 32% patients were treated with dabigatran, 34% with apixaban, 24% with rivaroxaban and 10% with edoxaban. An inappropriate dose was prescribed in 96 patients (12.6%), and in most cases (68%) it was too low. Rivaroxaban (15%) and apixaban (18.5%) were the most frequently prescribed with an inappropriate dose. Patients treated with an inappropriate dose were elderly people, with low-creatinine clearance value, who had experienced previous bleeding and with a high CHADS2 VASc score. In 2 years, a trend for higher numbers of thromboembolic events (5.2 vs. 3.3%, P = 0.348) and less major bleeding (2.1 vs. 4.2%, P = 0.316) has been observed in patients with inappropriate NOACs prescriptions. Conclusion Nearly 13% of patients were treated with an inappropriate dose of NOACs, in this single-center study. A trend for higher numbers of thromboembolic events was observed in these patients. The results should be considered as hypothesis generating.

Background To evaluate long-term efficacy of left atrial appendage occlusion with multiple devices. Methods All consecutive patients who underwent left atrial appendage occlusion (LAAO) with a follow-up of at least 4 years, were included in this single center, retrospective registry. No specific exclusion criteria were applied. LAA occlusion was performed with the Watchman, Watchman FLX, Amplatzer Cardiac plug or Amplatzer Amulet occluder devices. Results A total of 224 consecutive patients underwent LAAO occlusion. Mean age was 72.5 ± 9.0 years. A history of stroke was present in 29%, TIA in 8.5% and a previous episode of bleeding in 64.7% of patients. In 63% there was a contraindication to oral anticoagulants. The average CHADS-VASc was 4.0 ± 1.6 and the average HAS-BLED was 3.4 ± 1.3. There was a reduction of strokes of 72.9%, thromboembolic events of 59.7% and major bleeding events of 70.9% compared to historic data. During follow-up, 48.3% of the ischemic and major bleeding events occurred within the first year. The annual mortality rate of 7.5 deaths/ 100 patients years. There were no significant differences in terms of outcome between the devices used and there were no late events associated with any device. The main antithrombotic regimen in the long term was with single antiplatelet therapy and the second one was no therapy. Conclusion LAAO is a safe and effective procedure, that reduces ischemic and bleeding events in the long-term, regardless of the type of device used, in AF patients at high risk of ischemic stroke and major bleeding, without the need of anticoagulation.

Background The outcomes of patients presenting with acute myocarditis and life-threatening ventricular tachyarrhythmias (LT-VA) are unclear. The aim of this study was to assess incidence and predictors of recurrence of major arrhythmic events (MAEs) after hospital discharge in such patients. Methods and results We retrospectively analysed 156 patients (median age 44 years; 77% males) discharged with a diagnosis of acute myocarditis and LT-VA from 16 hospitals worldwide. Diagnosis of myocarditis was based on histology or on the combination of increased markers of cardiac injury and cardiac magnetic resonance (CMR) Lake Louise criteria. MAEs were defined as the relapse, after discharge, of sudden cardiac death (SCD) or ventricular fibrillation defibrillated successfully or sustained ventricular tachycardia (sVT) requiring implantable cardioverter-defibrillator therapy or synchronized external cardioversion. Median follow-up period was 23 months (first to third quartile [Q1-Q3] 7-60). Fifty-eight (37.2%) patients experienced MAEs after discharge, at a median time of 8 months (Q1-Q3 2.5-24.0 months; 60.3% of MAEs within the first year). At multivariable Cox analysis, variables independently associated to MAEs were presentation with sVT (hazard ratio [HR] 2.90, 95% confidence interval [CI] 1.38-6.11); late gadolinium enhancement (LGE) involving ≥2 myocardial segments (HR 4.51, 95% CI 2.39-8.53); and absence of positive short-tau inversion recovery (STIR) (HR 2.59, 95% CI 1.40-4.79) at first CMR. Conclusions Among patients discharged with the diagnosis of myocarditis and LT-VA, 37.2% had recurrences of MAEs during follow-up. Initial CMR pattern and sVT at presentation stratify the risk of arrhythmic recurrence.

Background Patients with non-valvular atrial fibrillation (nvAF) who experienced a cardioembolic (CE) event despite adequate oral anticoagulation (OAC) are at high risk of recurrence, and further prevention strategies are deemed necessary. The present study aimed to evaluate the safety and efficacy of off-label use of left atrial appendage closure (LAAC) in this subset of patients. Methods and results Seventy-five consecutive patients with nvAF who experienced a CE event despite adequate OAC therapy were retrospectively enrolled from two Italian centers. Patients were divided according to the treatment strategy following the index event: DOAC group (49 patients who continued OAC therapy with DOACs) and LAAC group (26 patients who underwent LAAC procedure). 1:1 propensity-score matching between the two groups was performed. LAAC group was made up of two subgroups according to the post-procedural pharmacological regimen: (a) dual antiplatelet therapy (DAPT) for 3 months followed by indefinite single antiplatelet therapy (LAAC+SAPT) or (b) aspirin plus DOAC for 3 months followed by indefinite DOAC therapy (LAAC+DOAC). The primary endpoint was a composite of CE event, major bleeding, or procedurerelated major complication. During a median follow-up of 3.4 years (IQR 2.0-5.3), LAAC was a predictor of primary endpoint-free survival (HR 0.28, 95%CI 0.08-0.97; p=0.044); within LAAC group, no procedure-related major complication occurred. Moreover, a trend toward a lower rate of both CE events and major bleedings was observed in LAAC group, particularly in the subgroup LAAC+DOAC. Conclusions LAAC is a reasonable therapeutic option in nvAF patients who suffered a CE event despite adequate OAC therapy.

Objective To outline the clinical, histological and prognostic features of systemic sclerosis (SSc) endomyocardial biopsy-proven myocarditis with respect to those of diverse endomyocardial biopsy-proven virus-negative myocarditis (VNM). Methods We retrospectively analysed data from three cohorts of endomyocardial biopsy-proven myocarditis: SSc-related VNM (SSc-VNM); isolated VNM (i-VNM); and VNM related to other systemic autoimmune diseases (a-VNM). The degree of myocardial fibrosis was expressed as relative percentage and fibrotic score (0–3). Clinical data, cardiac enzymes, echocardiogram, 24 h ECG Holter and cardiac magnetic resonance were obtained at baseline and during follow-up. Non-parametric tests were used. Results We enrolled 12 SSc-VNM [11 females, mean age 49.3 (14.2) years; seven diffuse-SSc, five early-SSc], 12 i-VNM [12 females, mean age 47.7 (10.8) years] and 10 a-VNM [four females, mean age 48.4 (16.3) years] patients. SSc patients had higher degrees of myocardial fibrosis as assessed by both percentage [SSc-VNM: 44.8 (18.8)%; a-VNM: 28.6 (16.5)%; i-VNM: 24.9 (10.3)%; P = 0.019] and score [SSc-VNM: 2.3 (0.8); a-VNM: 1.4 (1.1); i-VNM: 1.2 (0.7); P = 0.002]. Myocardial fibrosis directly correlated with skin score (r = 0.625, P = 0.03) and number of ventricular ectopic beats on 24 h ECG Holter in SSc patients (r = 0.756, P = 0.01). Dyspnoea class was higher at presentation in SSc-VNM patients (P = 0.041) and we found heart failure only in SSc patients (25%) (P = 0.05). At cardiac magnetic resonance, myocardial oedema was nearly undetectable in SSc-VNM patients compared with others (P = 0.02). All patients received immunosuppressive treatment. The number of patients who died during follow-up due to cardiac complications was significantly higher in SSc-VNM patients (50%), as compared with a-VNM (0%) and i-VNM (8.3%) patients (P = 0.006). Patients who died during follow-up had higher degrees of myocardial fibrosis [52.2 (11.6)% vs 27.5 (12.9)%, P = 0.024; fibrotic score: 2.83 (0.41) vs 1.4 (0.9), P Conclusion SSc has unique clinical and histological features, as it tends to present more frequently with heart failure and a higher dyspnoea class and to show higher degrees of myocardial fibrosis. These specific features are paralleled by a worse cardiac prognosis.

This study evaluated the temporal association between atrial high-rate episodes (AHREs) and sustained ventricular arrhythmias (VAs) in a remotely monitored cohort with implantable cardioverter-defibrillators (ICD) with and/or without cardiac resynchronization therapy with a defibrillator (CRT-D).Clinical relevance of AHREs in terms of VA rate and survival has not been outlined yet.This study analyzed data of patients with ICDs and CRT-Ds from the nationwide Home Monitoring Expert Alliance network. The cohort included 2,435 patients with a median follow-up of 25 months (interquartile range: 13 to 42 months) and age 70 years (range 61 to 77 years); 19.7% were women, 51.4% had coronary artery disease, and 45.2% had a CRT-D. There were 3,410 appropriate VA episodes; 498 (14.6%) were preceded by AHREs within 48 h; in 85.5% of this group, AHREs were still ongoing at episode onset.In a longitudinal analysis, the odds ratios (ORs) of experiencing any VA in a 30-day interval with AHREs versus intervals without AHREs were 2.35 (95% confidence interval [CI]: 1.86 to 2.97; p 0.001) for ventricular tachycardia (VT), 3.06 (95% CI: 2.35 to 3.99; p 0.001) for fast VT, 1.84 (95% CI: 1.36 to 2.48; p 0.001) for self-extinguishing ventricular fibrillation (VF), and 2.31 (95% CI: 1.17 to 4.57; p = 0.01) for VF. ORs decreased with increasing AHRE burden. Patients with AHREs 48 h before VAs were more likely to experience VA recurrences (adjusted hazard ratio [HR]: 1.78; 95% CI: 1.41 to 2.24; p 0.001) and had higher overall mortality (HR: 2.67; 95% CI: 1.68 to 4.23; p 0.001).AHREs were not uncommon 48 h before VAs, which tended to be distributed around intervals with AHREs. Temporal connection between AHREs and VAs was a marker of increased risk of VA recurrence and a poorer prognosis.

To identify reliable predictors of periprocedural intensive care unit (ICU) admission after transvenous lead extraction (LE) in a high-volume center.Retrospective observational study.University tertiary-care hospital.All patients undergoing LE at San Raffaele Scientific Institute, Milan, Italy, from 2005 to 2015.LE procedures were performed in the electrophysiology laboratories with a cardiac operating room on standby between the end of the morning surgical case and before the start of the afternoon surgical case. Most procedures were conducted with the patient under procedural sedation and analgesia. After LE, patients were admitted either to the ward or to the ICU. Medical history and intraprocedural data were recorded.Of the 389 procedures performed during the study period, 50 patients (13%) were admitted to the ICU owing to persistent hemodynamic instability or intraoperative complications requiring endotracheal intubation. Complete procedural success was achieved in 370 patients (95%), and the clinical success rate was 98.4%. No deaths were recorded. Five complications requiring emergency surgery (1.3%) were reported. Preprocedural right ventricular dysfunction (odds ratio (OR) 7.41; confidence interval 1.85-29.7; p0.01) and the need for general anesthesia (OR 12; confidence interval 1.49-97.06; p = 0.019) were independent predictors of ICU admission.Preoperative identification of patients who need ICU admission after LE is crucial to increase patient safety and decrease hospital costs. Severe right ventricular dysfunction and need for general anesthesia identify patients with low cardiac reserve who are at increased risk for ICU admission after the procedure.

Permanent pacemaker implantation (PPI) represents a rare complication after cardiac surgery, with no uniform agreement on timing and no information on follow-up. A multi-center retrospective study was designed to assess pacemaker dependency (PMD) and long-term mortality after cardiac surgery procedures. Between 2004 and 2016, PPI-patients from 18 centers were followed. Time-to-event data were evaluated with semiparametric regression Cox models and semiparametric Fine and Gray model for competing risk framework. Of 859 (0.90%) PPI-patients, 30% were pacemaker independent (PMI) at 6 months. PMD showed higher mortality compared with PMI (10-year survival 80.1% +/- 2.6% and 92.2% +2.4%, respectively, log-rank p-value < 0.001) with an unadjusted hazard ratio for death of 0.36 (95% CI 0.20 to 0.65, p< 0.001 favoring PMI) and an adjusted hazard ratio of 0.19 (95% CI 0.08 to 0.45, p< 0.001 with PMD as reference). Crude cumulative incidence function of restored PMI rhythm at follow-up at 6 months, 1 year and 12 years were 30.5% (95% CI 27.3% to 33.7%), 33.7% (95% CI 30.4% to 36.9%) and 37.2% (95% CI 33.8% to 40.6%) respectively. PMI was favored by preoperative sinus rhythm with normal conduction (SR) (HR 2.37, 95% CI 1.65 to 3.40, p< 0.001), whereas coronary artery bypass grafting and aortic valve replacement were independently associated with PMD (HR 0.63, 95% CI 0.45 to 0.88, p = 0.006 and HR 0.807, 95% CI 0.65 to 0.99, p = 0.047 respectively). Time-to-implantation was not associated with increased rate of PMI. Although 30% of PPI-patients are PMI after 6 months, PMD is associated with higher mortality at long term. (C) 2020 The Author(s). Published by Elsevier Inc.

Background Interest has grown in recent years in bipolar radiofrequency ablation (B-RFA). However, indications and outcome in patients with ventricular tachycardia (VT) are still to be defined. Objective The purpose of this study was to describe patient selection, safety and effectiveness of B-RFA, in a pilot cohort study of patients with nonischemic dilated cardiomyopathy (NIDCM) and drug-refractory VT. Methods We enrolled 21 patients with NIDCM (mean age 66±10 years; 18/21 (86%) men; left ventricular ejection fraction 35%±14%; 100% redo procedures) scheduled for a B-RFA procedure because of drug-refractory VT of suspected septal (interventricular septum [IVS]) origin. After electroanatomic mapping by using the CARTO®3 system, B-RFA was performed in all patients. Short- and long-term outcomes, including procedural success, major complications, and occurrence of major ventricular arrhythmias (MVAs), were evaluated at 25±8 months of follow-up (FU). Results Endocardial mapping showed IVS scar in all patients and extra-IVS in 7 patients (33%). B-RFA was performed at an average power of 33 W, for 60–90 seconds, over a 4.1 cm2 area, with 13±3 mm distance between catheters tips. The impedance drop was 27±4 Ω. The primary end point of noninducibility of the target clinical VT was obtained in 20 patients (95%). During FU, MVAs were documented in 7 patients (33%). FU MVAs occurred in all (100%) patients with extra-IVS localizations (7 of 7) or inflammatory nonischemic cardiomyopathy etiology (2 of 2). IVS thinning (tip-to-tip catheter distance Conclusion B-RFA is feasible in patients with NIDCM and drug-refractory VT of septal origin. Extra-IVS substrate and inflammatory NIDCM etiology were associated with an adverse outcome.

Aims Contemporary data from prospective multicentre registries on catheter ablation in pediatric patients are sparse. Aim of the European Pediatric Catheter Ablation Registry EUROPA was to contribute data to fill this gap of knowledge. Methods and results From July 2012 to June 2017, data on catheter ablation in pediatric patients (≤18 years of age) including a 1-year follow-up from five European pediatric EP centres were collected prospectively. A total of 683 patients (mean age 12.4 ± 3.9 years, mean body weight 50.2 ± 19 kg) were enrolled. Target tachycardia was WPW/atrioventricular-nodal re-entrant tachycardia (AVRT) in 380 (55.7%) patients, AVNRT in 230 (33.8%) patients, ventricular tachycardia (VT) in 24 (3.5) patients, focal atrial tachycardia (FAT) in 20 (2.9%) patients, IART in 14 (2%) patients, and junctional ectopic tachycardia in 3 (0.45) patients. Overall procedural success was 95.6%. Compared with all other substrates, success was significantly lower in FAT patients (80%, n = 16, P = 0.001). Mean procedure duration was 136 ± 67 min and mean fluoroscopy time was 4.9 ± 6.8 min. Major complications occurred in 0.7% of the patients. No persisting AV block requiring permanent pacing was reported. At 1-year follow-up (605/683 patients, 95%), tachycardia recurrence was reported in 7.8% of patients. Recurrence after VT ablation (33%) was significantly higher (P = 0.001) than after ablation of all other substrates. Conclusion The present study proves overall high efficacy and safety of catheter ablation of various tachycardia substrates in pediatric patients. Of note, complication rate was exceptionally low. Long-term success was high except for patients after VT ablation.

Purpose To describe how a referral center for cardiac electrophysiology (EP) rapidly changed to comply with the ongoing COVID-19 healthcare emergency. Methods We present retrospective data about the modification of daily activities at our EP unit, following the pandemic outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Italy. In particular, in the context of a pre-existing “hub-and-spoke” network, we describe how procedure types and volumes have changed in the last 3 months. Results Since our institution was selected as a COVID-19 referral center, the entire in-hospital activity was reorganized to assist more than 1000 COVID-positive cases. Only urgent EP procedures, including ventricular tachycardia ablation and extraction of infected devices, were both maintained and optimized to meet the needs of external hospitals. In addition, most of the non-urgent EP procedures were postponed. Finally, following prompt internal reorganization, both outpatient clinics and on-call services underwent significant modification, by integrating telemedicine support whenever applicable. Conclusion We presented the fast reorganization of an EP referral center during the ongoing COVID-19 healthcare emergency. Our hub-and-spoke model may be useful for other centers, aiming at a cost-effective management of resources in the context of a global crisis.

Aim The aim of this study is to assess the safety and efficacy of the new bidirectional rotational mechanical sheath TightRail™ (Spectranetics) for lead extraction. Methods and results This is a bicentric prospective study that included patients who underwent a transvenous lead extraction (TLE) in two Italian centers (San Raffaele Hospital and Humanitas Gavazzeni Hospital). From November 2016 to December 2018, 26 patients underwent a TLE procedure in which the TightRail™ was used. The new TightRail Sub‐C was used in 20 (76%) patients to overcome the fibrosis between the vessel and the first rib. Median age was 69 (IQR 60.7‐79.5) years. The indication for TLE were infection (57.7%) or lead dysfunction (42.3%). A total of 57 leads (range 1‐4), 40 of which using the TightRail (range 1‐4), were extracted. Overall mean implant duration was 98.2.0 ± 66.5 months. Mean age of the lead extracted with the TightRail sheath was 99.1 ± 70.2 months and was higher compared to that of the leads extracted manually (84.4 ± 60.3 months, P = .001). The overall clinical success was 100% and complete procedural success without the use of a snare was achieved in 98.3%. There were no cases of death or major complications and only two minor complications occurred. All patients were event‐free at 6‐month follow‐up. Conclusion This initial experience using the TightRail™ suggests a high safety and efficacy profile for extractions in a wide range of lead age., The bidirectional rotational mechanical sheath TightRail™ (Spectranetics) is a novel tool for transvenous lead extraction (TLE). This is the first multicentric study evaluating the safety and efficacy of this new extraction system. This is the first experience with the new TightRail Sub‐C sheath to overcome the fibrous between the vessel and the first rib.

Background Left atrial appendage (LAA) thrombosis increases the risk of stroke and its management has to be assessed. The aim of the present study is to evaluate short and long-term safety and efficacy of a standardized approach of percutaneous left atrial appendage closure (LAAC) routinely using a cerebral protection device (CPD) in patients with LAA thrombosis or sludge (LAAT). Methods we prospectively enrolled 14 consecutive patients with atrial fibrillation complicated by LAAT presenting in a high-volume tertiary center. In seven patients (50%) LAAT was found after anticoagulant withdrawal for severe bleedings and in the remaining half LAAT was found despite appropriate anticoagulant therapy. All patients were treated with a standardized interventional approach of LAAC routinely using a CPD and guided by transoesophageal echocardiography. Results Mean age was 68±14 years and 9 patients (64%) were male. Mean CHA2 DS2 -VASc and HAS-BLED scores were 3.3±1.6 and 2.3±1.1, respectively. Six patients (42.8%) presented organized thrombi while 8 LAA sludge (57.1%). In 13 patients (92.8%) CPD was positioned through a right radial arterial access. Procedural success was achieved in all patients. In one patient we assisted to embolization of the thrombus during deployment of the device in the absence of neurological consequences. During a mean follow up of 426±307 days, one patient died for non-cardiac cause while no embolic event or major bleeding were reported. Conclusion in an unselected cohort, LAAC with the systematic use of CPD was a feasible, safe and effective therapeutic option for LAAT both acutely and after long-term follow-up. This article is protected by copyright. All rights reserved.

Background: Limited clinical data exist describing the use of direct oral anticoagulants (DOACs) in patient with extreme body weight. Thus, the International Society of Thrombosis and Haemostasis (ISTH) recommends avoiding DOACs in patients with weight >120Kg, and on the contrary, no restrictions exist for underweight patients. Objective: To evaluate the effects of extreme body weight on DOAC activity and to compare the clinical outcomes of patients with an extreme body weight versus patients with a normal weight (61-119Kg) treated with DOACs. Methods: Single tertiary care Italian centre multidisciplinary registry including nonvalvular atrial fibrillation (NVAF) patients treated with DOACs. Based on weight, three subcohorts were defined: (i) underweight patients (≤60Kg); (ii) patients with a normal weight (61-119Kg, as control group); and (iii) overweight patients (≥120Kg). Primary efficacy endpoint was 2-year rate of thromboembolic events. Primary safety endpoint was 2-year rate of major bleeding. Event-free survival curves among groups were compared using Cox-Mantel test. Results: 812 NVAF patients were included, 108 patients weighed ≤60Kg (13%, underweight), 688 weighed between 61 and 119Kg (85%, normal weight), and 16 weighed ≥120Kg (2%, overweight). In particular, among underweight patients, dabigatran was prescribed in 26% patients, apixaban in 27%, rivaroxaban in 28% and edoxaban in 22% ones. Instead, among overweight patients, 44% were treated with dabigatran, 25% with apixaban, 25% with rivaroxaban and 4% with edoxaban. Underweight patients were older, more frequently women, with lower creatinine clearance and a history of previous strokes, resulting in higher CHA2DS2-VASc score than in both remaining groups. Up to 2years, no statistically significant difference was observed between the three groups of weight for thromboembolic events (P=.765) and for overall bleeding (P=.125), but a trend towards decreased overall bleeding rates was noticed as weight increased (24.1% vs 16.7% vs 12.5%, respectively). Conclusion: In this tertiary care centre registry, 15% of patients treated with DOACs presented an extreme weight. Compared to patients with a normal weight, no significant rates of thromboembolic events were observed for underweight or overweight patients. A trend towards decreased overall bleeding frequency as weight increased was highlighted up to 2years. The present results should be considered as preliminary and hypothesis generating.

Background: Myxomatous mitral valve prolapse (MVP) and mitral-annular disjunction (Barlow disease) are at-risk for ventricular arrhythmias (VA). Fibrosis involving the papillary muscles and/or the infero-basal left ventricular (LV) wall was reported at autopsy in sudden cardiac death (SCD) patients with MVP. Objectives: We investigated the electrophysiological substrate subtending VA in MVP patients with Barlow disease phenotype. Methods: Twenty-three patients with VA were enrolled, including five with syncope and four with a history of SCD. Unipolar (Uni < 8.3 mV) and bipolar (Bi < 1.5 mV) low-voltage areas were analyzed with electro-anatomical mapping (EAM), and VA inducibility was evaluated with programmed ventricular stimulation (PES). Electrophysiological parameters were correlated with VA patterns, electrocardiogram (ECG) inferior negative T wave (nTW), and late gadolinium enhancement (LGE) assessed by cardiac magnetic resonance. Results: Premature ventricular complex (PVC) burden was 12 061.9 ± 12 994.6/24 h with a papillary-muscle type (PM-PVC) in 18 patients (68%). Twelve-lead ECG showed nTW in 12 patients (43.5%). A large Uni less than 8.3 mV area (62.4 ± 45.5 cm2) was detected in the basal infero-lateral LV region in 12 (73%) patients, and in the papillary muscles (2.2 ± 2.9 cm2) in 5 (30%) of 15 patients undergoing EAM. A concomitant Bi less than 1.5 mV area (5.0 ± 1.0 cm2) was identified in two patients. A history of SCD, and the presence of nTW, and LGE were associated with a greater Uni less than 8.3 mV extension: (32.8 ± 3.1 cm2 vs. 9.2 ± 8.7 cm2), nTW (20.1 ± 11.0 vs. 4.1 ± 3.8 cm2), and LGE (19.2 ± 11.7 cm2 vs. 1.0 ± 2.0 cm2, p =.013), respectively. All patients with PM-PVC had a Uni less than 8.3 mV area. Sustained VA (ventricular tachycardia 2 and VF 2) were induced by PES only in four patients (one with resuscitated SCD). Conclusions: Low unipolar low voltage areas can be identified with EAM in the basal inferolateral LV region and in the papillary muscles as a potential electrophysiological substrate for VA and SCD in patients with MVP and Barlow disease phenotype.

Background: Optimal antithrombotic therapy after left atrial appendage (LAA) occlusion is still not clear. The aim of this study was to investigate the role of different antithrombotic regimens after the procedure. Methods and Results: We retrospectively analyzed data of 260 patients who underwent LAA occlusion and divided them into four groups according to therapy at discharge: dual antiplatelet therapy (group A, 71.5%), oral anticoagulants (group B, 19%), “minimal” antithrombotic therapy (single antiplatelet agent or without any antithrombotic therapy, group C, 4.5%) and other therapeutic regimens (such as a combination of antiplatelets and anticoagulants, group D, 4.5%). We analyzed baseline characteristics, procedural data, and clinical and transesophageal follow-up for each group. The incidence of adverse events was low in the whole population and had a similar distribution among groups. The majority of bleeding events was registered during the first 3 months after the procedure (34 out of 46, 70%). Ischemic events (2%), as well as silent left atrial thrombosis, were rare and not significantly higher in the population discharged with “minimal” antithrombotic therapy. Conclusion: Our experience seems to suggest that LAA occlusion was associated with a low incidence of adverse events, regardless of antithrombotic therapy. A “minimal” drug regimen may be feasible without losing efficacy on embolic prevention for patients with high bleeding risk.

Aims In arrhythmogenic cardiomyopathy (ACM), sustained ventricular tachycardia (VT) typically displays a left bundle branch block (LBBB) morphology while a right bundle branch block (RBBB) morphology is rare. The present study assesses the VT morphology in ACM patients with sustained VT and their clinical and genetic characteristics. Methods and results Twenty-six centres from 11 European countries provided information on 954 ACM patients who had ≥1 episode of sustained VT spontaneously documented during patients’ clinical course. Arrhythmogenic cardiomyopathy was defined according to the 2010 Task Force Criteria, and VT morphology according to the QRS pattern in V1. Overall, 882 (92.5%) patients displayed LBBB-VT alone and 72 (7.5%) RBBB-VT [alone in 42 (4.4%) or in combination with LBBB-VT in 30 (3.1%)]. Male sex prevalence was 79.3%, 88.1%, and 56.7% in the LBBB-VT, RBBB-VT, and LBBB + RBBB-VT groups, respectively (P = 0.007). First RBBB-VT occurred 5 years after the first LBBB-VT (46.5 ± 14.4 vs 41.1 ± 15.8 years, P = 0.011). An implanted cardioverter-defibrillator was more frequently implanted in the RBBB-VT (92.9%) and the LBBB + RBBB-VT groups (90%) than in the LBBB-VT group (68.1%) (P Conclusion RBBB-VT accounts for a significant proportion of sustained VTs in ACM. Sex and type of pathogenic mutations were associated with VT type, female sex with LBBB + RBBB-VT, and DSP mutation with RBBB-VT.

Background: Ventricular arrhythmias (VAs) are rare in pediatric patients, especially in absence of structural heart disease (SHD). Few data are available regarding the invasive VAs treatment with catheter ablation (CA) in pediatric patients and predictors of outcomes have not been fully investigated. Objective: To describe the clinical presentation, procedural characteristics, and outcomes in pediatric patients undergoing CA for VAs. Methods: Eighty-one consecutive pediatric patients (58 male [72%], 15.5 ± 2.2 years) treated by CA for ventricular tachycardia (VT) or premature ventricular beats (PVBs) were retrospectively evaluated. Study endpoints were VAs recurrence and mortality for any cause. Results: Ninety-five procedures were performed in 81 patients, 52 (55%) PVBs and 43 (45%) VT ablations. During a follow-up of 35.0 months (interquartile range = 13.0–71.0), 14 patients (14.7%) had a VA recurrence: 11 (33.3%) patients treated with CA for VT and 3 (6.2%) patients treated for PVBs (p

International audience; Human Vδ2 cells are innate-like γδ T effectors performing potent immune surveillance against tumors. The constitutive expression of NKG2A identifies a subset of Vδ2 T cells licensed with an intrinsic hyper-responsiveness against cancer. Indeed, the transcriptomic profiles of NKG2A+ and NKG2A- cells characterize two distinct "intralineages" of Vδ2 T lymphocytes that appear early during development, keep their phenotypes, and show self-renewal capabilities in adult life. The hyper-responsiveness of NKG2A+ Vδ2 T cells is counterbalanced by the inhibitory signaling delivered by human leukocyte antigen E (HLA-E) expressed on malignant cells as a tumor-escape mechanism. However, either masking or knocking out NKG2A restores the capacity of Vδ2 T cells to exert the highest effector functions even against HLA-E+ tumors. This is highly relevant in the clinic, as the different degrees of engagement of the NKG2A-HLA-E checkpoint in hepatocellular carcinoma, glioblastoma, and non-small cell lung cancer directly impact patients' overall survival. These findings open avenues for developing combined cellular and immunologic anticancer therapies.

Background: the neoplastic B cells of the Helicobacter pylori-related low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma proliferate in response to H. pylori, however, the nature of the H. pylori antigen responsible for proliferation is still unknown. The purpose of the study was to dissect whether CagY might be the H. pylori antigen able to drive B cell proliferation. Methods: the B cells and the clonal progeny of T cells from the gastric mucosa of five patients with MALT lymphoma were compared with those of T cell clones obtained from five H. pylori–infected patients with chronic gastritis. The T cell clones were assessed for their specificity to H. pylori CagY, cytokine profile and helper function for B cell proliferation. Results: 22 of 158 CD4+ (13.9%) gastric clones from MALT lymphoma and three of 179 CD4+ (1.7%) clones from chronic gastritis recognized CagY. CagY predominantly drives Interferon-gamma (IFN-γ) and Interleukin-17 (IL-17) secretion by gastric CD4+ T cells from H. pylori-infected patients with low-grade gastric MALT lymphoma. All MALT lymphoma-derived clones dose dependently increased their B cell help, whereas clones from chronic gastritis lost helper activity at T-to-B-cell ratios greater than 1. Conclusion: the results obtained indicate that CagY drives both B cell proliferation and T cell activation in gastric MALT lymphomas.

OBJECTIVES To assess by a continuous implantable rhythm monitoring (ILR) the mid-term outcomes of a staged-hybrid approach for patients with persistent/long-standing persistent atrial fibrillation (AF) and dilated atria. METHODS Fifty patients [age 57 (standard deviation, SD: 8.3), previous catheter ablation 66%, AF history 6.5 (2–12) years, left ventricular ejection fraction 56 (SD: 7.9)%, left atrial volume index 44 (38–56) ml/m2] with persistent (44%) or long-standing persistent (56%) AF, underwent a 2-staged hybrid ablation (thoracoscopic epicardial procedure with Cobra-Fusion system and transcatheter Rhythmia mapping with endocardial touch-up of gaps). All patients received an ILR. RESULTS No hospital deaths and no stroke occurred. Follow-up was 98% complete [median 22 (11–34) months]. The 2-year arrhythmia-free survival off class I–III antiarrhythmic drugs/electrical cardioversion/redo catheter ablation and the arrhythmia control (maintenance of sinus rhythm with or without antiarrhythmic drugs/electrical cardioversion) were 65 (SD: 7.1)% and 82 (SD: 5.8)%, respectively. The occurrence of AF in the blanking period was identified as an independent predictor of AF recurrence (odds ratio 26.6, 95% confidence interval 5.3, 132.3; P CONCLUSIONS A staged hybrid approach yields promising results in selected patients with persistent/long-standing persistent AF and dilated left atrium who are at very high risk of AF recurrence. The use of ILR in this setting should become a standard to optimize patient management.

AIMS: The aim of this study was to evaluate the sensitivity of right ventricular endomyocardial biopsy (EMB) in myocarditis patients with cardiac magnetic resonance (CMR) and electroanatomical mapping (EAM) showing left ventricular abnormalities. METHODS: We performed right ventricular EMB in 144 consecutive patients (66% men, age 43 ± 15 years) with acute symptoms and CMR-proved diagnosis of left ventricular myocarditis. Right ventricular EMB sensitivity has been evaluated in patients with different localization and extension of abnormal substrate at both CMR and -- when performed -- EAM. Abnormal substrate was defined, respectively, by late gadolinium enhancement (LGE) and low-voltage areas (LVAs). RESULTS: Globally, right ventricular EMB sensitivity was 87.5%. EMB-negative cases had significantly smaller fragment sizes (cumulative area 2.8 ± 1.7 vs. 3.8 ± 1.8 mm2, P = 0.023), and lower LGE surface extension (24.7 ± 14.2 vs. 38.5 ± 20.2%, P = 0.006) and transmurality (32.0 ± 26.1 vs. 49.3 ± 22.6, P = 0.003). Right ventricular EMB sensitivity in patients with LGE involving both right ventricular and interventricular septum (IVS), isolated right ventricular or IVS, and remote left ventricular areas (n = 10, 49 and 67 cases) was 83.3, 84.4 and 90.5%, respectively (P = 0.522). Overall, 34 patients (23.6%) underwent EAM. On the basis of EAM, right ventricular EMB sensitivity was 85.3%: in detail, it was 50.0, 88.2 and 86.7% in patients with both right ventricular and IVS, isolated right ventricular/IVS and distant left ventricular involvement (n = 2, 17 and 15, respectively, P > 0.05). Sample size area was the only factor associated with right ventricular EMB sensitivity (hazard ratio = 1.6/mm2, 95% confidence interval 1.1-2.4, P = 0.013). CONCLUSION: Right ventricular EMB is still an accurate technique to confirm diagnosis in patients with CMR-proved left ventricular myocarditis. In particular, provided there is an adequate sample size, its sensitivity is comparable among patients with heterogeneous LGE or LVA localization.

Background. Myocarditis lacks systematic characterization in COVID-19 patients. Methods. We enrolled consecutive patients with newly diagnosed myocarditis in the context of COVID-19 infection. Diagnostic and treatment strategies were driven by a dedicated multidisciplinary disease unit for myocarditis. Multimodal outcomes were assessed during prospective follow-up. Results. Seven consecutive patients (57% males, age 51 ± 9 y) with acute COVID-19 infection received a de novo diagnosis of myocarditis. Endomyocardial biopsy was of choice in hemodynamically unstable patients (n = 4, mean left ventricular ejection fraction (LVEF) 25 ± 9%), whereas cardiac magnetic resonance constituted the first exam in stable patients (n = 3, mean LVEF 48 ± 10%). Polymerase chain reaction (PCR) analysis revealed an intra-myocardial SARS-CoV-2 genome in one of the six cases undergoing biopsy: in the remaining patients, myocarditis was either due to other viruses (n = 2) or virus-negative (n = 3). Hemodynamic support was needed for four unstable patients (57%), whereas a cardiac device implant was chosen in two of four cases showing ventricular arrhythmias. Medical treatment included immunosuppression (43%) and biological therapy (29%). By the 6-month median follow-up, no patient died or experienced malignant arrhythmias. However, two cases (29%) were screened for heart transplantation. Conclusions. Myocarditis associated with acute COVID-19 infection is a spectrum of clinical manifestations and underlying etiologies. A multidisciplinary approach is the cornerstone for tailored management.

Purpose Systemic inflammation has been associated with corrected QT (QTc) interval prolongation. The role of inflammation on QTc prolongation in COVID-19 patients was investigated. Methods Patients with a laboratory-confirmed SARS-CoV-2 infection admitted to IRCCS San Raffaele Scientific Institute (Milan, Italy) between March 14, 2020, and March 30, 2020 were included. QTc-I was defined as the QTc interval by Bazett formula in the first ECG performed during the hospitalization, before any new drug treatment; QTc-II was the QTc in the ECG performed after the initiation of hydroxychloroquine drug treatment. Results QTc-I was long in 45 patients (45%) and normal in 55 patients (55%). Patients with long QTc-I were older and more frequently males. C-Reactive protein (CRP) and white blood cell (WBC) count at hospitalization were higher in patients with long QTc-I and long QTc-II. QTc-I was significantly correlated with CRP levels at hospitalization. After a median follow-up of 83 days, 14 patients (14%) died. There were no deaths attributed to ventricular arrhythmias. Patients with long QTc-I and long QTc-II had a shorter survival, compared with normal QTc-I and QTc-II patients, respectively. In Cox multivariate analysis, independent predictors of mortality were age (HR = 1.1, CI 95% 1.04–1.18, p = 0.002) and CRP at ECG II (HR 1.1, CI 95% 1.0–1.1, p = 0.02). Conclusions QTc at hospitalization is a simple risk marker of mortality risk in COVID-19 patients and reflects the myocardial inflammatory status.

Kaposi's sarcoma (KS) is a lymphangioproliferative disorder associated with Human herpesvirus 8 (HHV8) infection. Four clinical subtypes are recognized: classic, endemic, epidemic (HIV-related) and iatrogenic. KS diagnosis is based on clinical features, histopathological assessment, and HHV8 serology. Classic KS is usually skin-limited and has a chronic course, while the iatrogenic variant may show mucosal, nodal or visceral involvement. Clinical staging is fundamental to guide the management. Localized disease may be treated with different local therapies, even if there are no randomized trials comparing these different modalities. Aggressive, disseminated KS and cases with visceral involvement usually require systemic chemotherapy, most commonly vinblastine, bleomycin or paclitaxel. Iatrogenic KS needs immunosuppression tapering/ withdrawal and, if possible, switch to m-TOR inhibitors in post-transplant KS. The present work by a panel of Italian experts provides guidelines on KS diagnosis and management based on a critical review of the literature and a long and extensive personal experience.

Background: Novel Coronavirus SARS-CoV-2 pandemic is spreading around the world. At the end of February, the outburst of the pandemic has hit hard on northern Italian's hospitals. As of today, no data have been published regarding the severity of respiratory failure of patients presenting to the Emergency Departments. Moreover, the outcome the patients forced to undergo Continuous Positive Airway Pressure (CPAP) or Non-Invasive Positive Pressure Ventilation (NIPPV) due to lack of Intensive Care resources is unknown. “Papa Giovanni XXIII” hospital (HPG23) of Bergamo is one of the largest hospitals in the Country, with an Emergency Department (ED) managing over 100,000 patients per year. Methods: This is a retrospective observational study based on chart review of patients presenting to the Emergency Department of HPG23 from 29/02/2020 to 10/03/2020 with a clinical condition highly suspicious for COVID-19 infection. Registration of admission rates, severity of respiratory failure (ARDS classification), need of respiratory support, SARS-CoV-2 PCR test and outcome of patients treated with a ventilatory support were registered on 10th of May 2020. Findings: From 29/02 to 10/03 611 patients with a suspected diagnosis of COVID-19 infection were evaluated in our ED; 320 (52%) met the criteria for hospital admission and 99 (31%) needed to be immediately started on ventilatory support (81% CPAP, 7% NIPPV, 12% Invasive Mechanical Ventilation). Eighty-five (86%) of the 99 patients needing a ventilatory support eventually had SARS-CoV-2 infection confirmed by PCR test on nasal-pharyngeal swab. Their median PO2/FiO2 ratio was 128 (IQR 85–168), with 23 patients (29.5%) classified as severe ARDS. Mortality rate as of 10th of May was 76.5%, ranging from 44.4% within patients

All authors: Andrea Cossarizza Hyun‐Dong Chang Andreas Radbruch Andreas Acs Dieter Adam Sabine Adam‐Klages William W. Agace Nima Aghaeepour Mübeccel Akdis Matthieu Allez Larissa Nogueira Almeida Giorgia Alvisi Graham Anderson Immanuel Andrä Francesco Annunziato Achille Anselmo Petra Bacher Cosima T. Baldari Sudipto Bari Vincenzo Barnaba Joana Barros‐Martins Luca Battistini Wolfgang Bauer Sabine Baumgart Nicole Baumgarth Dirk Baumjohann Bianka Baying Mary Bebawy Burkhard Becher Wolfgang Beisker Vladimir Benes Rudi Beyaert Alfonso Blanco Dominic A. Boardman Christian Bogdan Jessica G. Borger Giovanna Borsellino Philip E. Boulais Jolene A. Bradford Dirk Brenner Ryan R. Brinkman Anna E. S. Brooks Dirk H. Busch Martin Büscher Timothy P. Bushnell Federica Calzetti Garth Cameron Ilenia Cammarata Xuetao Cao Susanna L. Cardell Stefano Casola Marco A. Cassatella Andrea Cavani Antonio Celada Lucienne Chatenoud Pratip K. Chattopadhyay Sue Chow Eleni Christakou Luka Čičin‐Šain Mario Clerici Federico S. Colombo Laura Cook Anne Cooke Andrea M. Cooper Alexandra J. Corbett Antonio Cosma Lorenzo Cosmi Pierre G. Coulie Ana Cumano Ljiljana Cvetkovic Van Duc Dang Chantip Dang‐Heine Martin S. Davey Derek Davies Sara De Biasi Genny Del Zotto Gelo Victoriano Dela Cruz Michael Delacher Silvia Della Bella Paolo Dellabona Günnur Deniz Mark Dessing James P. Di Santo Andreas Diefenbach Francesco Dieli Andreas Dolf Thomas Dörner Regine J. Dress Diana Dudziak Michael Dustin Charles‐Antoine Dutertre Friederike Ebner Sidonia B. G. Eckle Matthias Edinger Pascale Eede Götz R.A. Ehrhardt Marcus Eich Pablo Engel Britta Engelhardt Anna Erdei Charlotte Esser Bart Everts Maximilien Evrard Christine S. Falk Todd A. Fehniger Mar Felipo‐Benavent Helen Ferry Markus Feuerer Andrew Filby Kata Filkor Simon Fillatreau Marie Follo Irmgard Förster John Foster Gemma A. Foulds Britta Frehse Paul S. Frenette Stefan Frischbutter Wolfgang Fritzsche David W. Galbraith Anastasia Gangaev Natalio Garbi Brice Gaudilliere Ricardo T. Gazzinelli Jens Geginat Wilhelm Gerner Nicholas A. Gherardin Kamran Ghoreschi Lara Gibellini Florent Ginhoux Keisuke Goda Dale I. Godfrey Christoph Goettlinger Jose M. González‐Navajas Carl S. Goodyear Andrea Gori Jane L. Grogan Daryl Grummitt Andreas Grützkau Claudia Haftmann Jonas Hahn Hamida Hammad Günter Hämmerling Leo Hansmann Goran Hansson Christopher M. Harpur Susanne Hartmann Andrea Hauser Anja E. Hauser David L. Haviland David Hedley Daniela C. Hernández Guadalupe Herrera Martin Herrmann Christoph Hess Thomas Höfer Petra Hoffmann Kristin Hogquist Tristan Holland Thomas Höllt Rikard Holmdahl Pleun Hombrink Jessica P. Houston Bimba F. Hoyer Bo Huang Fang‐Ping Huang Johanna E. Huber Jochen Huehn Michael Hundemer Christopher A. Hunter William Y. K. Hwang Anna Iannone Florian Ingelfinger Sabine M Ivison Hans‐Martin Jäck Peter K. Jani Beatriz Jávega Stipan Jonjic Toralf Kaiser Tomas Kalina Thomas Kamradt Stefan H. E. Kaufmann Baerbel Keller Steven L. C. Ketelaars Ahad Khalilnezhad Srijit Khan Jan Kisielow Paul Klenerman Jasmin Knopf Hui‐Fern Koay Katja Kobow Jay K. Kolls Wan Ting Kong Manfred Kopf Thomas Korn Katharina Kriegsmann Hendy Kristyanto Thomas Kroneis Andreas Krueger Jenny Kühne Christian Kukat Désirée Kunkel Heike Kunze‐Schumacher Tomohiro Kurosaki Christian Kurts Pia Kvistborg Immanuel Kwok Jonathan Landry Olivier Lantz Paola Lanuti Francesca LaRosa Agnès Lehuen Salomé LeibundGut‐Landmann Michael D. Leipold Leslie Y.T. Leung Megan K. Levings Andreia C. Lino Francesco Liotta Virginia Litwin Yanling Liu Hans‐Gustaf Ljunggren Michael Lohoff Giovanna Lombardi Lilly Lopez Miguel López‐Botet Amy E. Lovett‐Racke Erik Lubberts Herve Luche Burkhard Ludewig Enrico Lugli Sebastian Lunemann Holden T. Maecker Laura Maggi Orla Maguire Florian Mair Kerstin H. Mair Alberto Mantovani Rudolf A. Manz Aaron J. Marshall Alicia Martínez‐Romero Glòria Martrus Ivana Marventano Wlodzimierz Maslinski Giuseppe Matarese Anna Vittoria Mattioli Christian Maueröder Alessio Mazzoni James McCluskey Mairi McGrath Helen M. McGuire Iain B. McInnes Henrik E. Mei Fritz Melchers Susanne Melzer Dirk Mielenz Stephen D. Miller Kingston H.G. Mills Hans Minderman Jenny Mjösberg Jonni Moore Barry Moran Lorenzo Moretta Tim R. Mosmann Susann Müller Gabriele Multhoff Luis Enrique Muñoz Christian Münz Toshinori Nakayama Milena Nasi Katrin Neumann Lai Guan Ng Antonia Niedobitek Sussan Nourshargh Gabriel Núñez José‐Enrique O'Connor Aaron Ochel Anna Oja Diana Ordonez Alberto Orfao Eva Orlowski‐Oliver Wenjun Ouyang Annette Oxenius Raghavendra Palankar Isabel Panse Kovit Pattanapanyasat Malte Paulsen Dinko Pavlinic Livius Penter Pärt Peterson Christian Peth Jordi Petriz Federica Piancone Winfried F. Pickl Silvia Piconese Marcello Pinti A. Graham Pockley Malgorzata Justyna Podolska Zhiyong Poon Katharina Pracht Immo Prinz Carlo E. M. Pucillo Sally A. Quataert Linda Quatrini Kylie M. Quinn Helena Radbruch Tim R. D. J. Radstake Susann Rahmig Hans‐Peter Rahn Bartek Rajwa Gevitha Ravichandran Yotam Raz Jonathan A. Rebhahn Diether Recktenwald Dorothea Reimer Caetano Reis e Sousa Ester B.M. Remmerswaal Lisa Richter Laura G. Rico Andy Riddell Aja M. Rieger J. Paul Robinson Chiara Romagnani Anna Rubartelli Jürgen Ruland Armin Saalmüller Yvan Saeys Takashi Saito Shimon Sakaguchi Francisco Sala‐de‐Oyanguren Yvonne Samstag Sharon Sanderson Inga Sandrock Angela Santoni Ramon Bellmàs Sanz Marina Saresella Catherine Sautes‐Fridman Birgit Sawitzki Linda Schadt Alexander Scheffold Hans U. Scherer Matthias Schiemann Frank A. Schildberg Esther Schimisky Andreas Schlitzer Josephine Schlosser Stephan Schmid Steffen Schmitt Kilian Schober Daniel Schraivogel Wolfgang Schuh Thomas Schüler Reiner Schulte Axel Ronald Schulz Sebastian R. Schulz Cristiano Scottá Daniel Scott‐Algara David P. Sester T. Vincent Shankey Bruno Silva‐Santos Anna Katharina Simon Katarzyna M. Sitnik Silvano Sozzani Daniel E. Speiser Josef Spidlen Anders Stahlberg Alan M. Stall Natalie Stanley Regina Stark Christina Stehle Tobit Steinmetz Hannes Stockinger Yousuke Takahama Kiyoshi Takeda Leonard Tan Attila Tárnok Gisa Tiegs Gergely Toldi Julia Tornack Elisabetta Traggiai Mohamed Trebak Timothy I.M. Tree Joe Trotter John Trowsdale Maria Tsoumakidou Henning Ulrich Sophia Urbanczyk Willem van de Veen Maries van den Broek Edwin van der Pol Sofie Van Gassen Gert Van Isterdael René A.W. van Lier Marc Veldhoen Salvador Vento‐Asturias Paulo Vieira David Voehringer Hans‐Dieter Volk Anouk von Borstel Konrad von Volkmann Ari Waisman Rachael V. Walker Paul K. Wallace Sa A. Wang Xin M. Wang Michael D. Ward Kirsten A Ward‐Hartstonge Klaus Warnatz Gary Warnes Sarah Warth Claudia Waskow James V. Watson Carsten Watzl Leonie Wegener Thomas Weisenburger Annika Wiedemann Jürgen Wienands Anneke Wilharm Robert John Wilkinson Gerald Willimsky James B. Wing Rieke Winkelmann Thomas H. Winkler Oliver F. Wirz Alicia Wong Peter Wurst Jennie H. M. Yang Juhao Yang Maria Yazdanbakhsh Liping Yu Alice Yue Hanlin Zhang Yi Zhao Susanne Maria Ziegler Christina Zielinski Jakob Zimmermann Arturo Zychlinsky., These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer‐reviewed by leading experts in the field, making this an essential research companion., This work was supported by the Netherlands Organisation for Scientific Research – Domain Applied and Engineering Sciences (NWO-TTW), research program VENI 15924. This work was funded by the Deutsche Forschungsgemeinschaft. European Union Innovative Medicines Initiative - Joint Undertaking - RTCure Grant Agreement 777357 and innovation program (Grant Agreement 695551).

Cardiac laminopathies, associated with mutations in the LMNA gene, encompass a wide spectrum of clinical manifestations, involving electrical and mechanical alterations of cardiomyocytes. Thus, dilated cardiomyopathy, bradyarrhythmias and atrial or ventricular tachyarrhythmias may occur in a number of combined phenotypes. Nowadays, some attempt has been made to identify clinical predictors for the most life-threatening complications of LMNA-associated heart disease, i.e. sudden cardiac death and end-stage heart failure. The goal of this manuscript is to combine the most recent evidences in an updated review to show the state-of-the-art of such a complex disease group. This is supposed to be the starting point to collect more data and design new ad hoc studies to identify clinically useful predictors to stratify risk in mutation carriers, including probands and their asymptomatic relatives.

Background CHA2DS2-VASc is a validated score for predicting stroke in patients with atrial fibrillation (AF). Objective The purpose of this study was to assess whether the CHA2DS2-VASc score can predict new-onset AF in a cohort of patients with a cardiac implantable electronic device (CIED) followed with remote monitoring. Methods Using the database of the Home Monitoring Expert Alliance project, we selected 2410 patients with no documented AF who had received a CIED with diagnostics on atrial high rate episodes (AHREs). The primary endpoint was time to first day with cumulative AHRE burden ≥15 minutes, 5 hours, 24 hours, and ≥7 consecutive days. Results During a median duration of 24.1(11.5–42.9) months, the incidence of AHRE increased with increasing CHA2DS2-VASc. At 6 years, occurrence of ≥15-minute AHRE was 80.2% (CHA2DS2-VASc ≤1) vs 93.7% (CHA2DS2-VASc ≥5), whereas ≥5-hour AHRE incidence was 68.4% (CHA2DS2-VASc ≤1) vs 92.5% (CHA2DS2-VASc ≥5). Occurrence of ≥24-hour and ≥7-day AHREs also increased with increasing CHA2DS2-VASc: 9.1% and 3.9% (CHA2DS2-VASc ≤1) vs 40.4% and 28.7% (CHA2DS2-VASc ≥5), respectively. Adjusted hazard ratio for unitary CHA2DS2-VASc increase ranged from 1.09 (confidence interval 1.04–1.14; P

Background Immunotherapeutic early-phase clinical trials (ieCTs) increasingly adopt large expansion cohorts exploring novel agents across different tumor types. High-grade glioma (HGG) patients are usually excluded from these trials. Methods Data of patients with recurrent HGGs treated within multicohort ieCTs between February 2014 and August 2019 (experimental group, EG) at our Phase I Unit were retrospectively reviewed and compared to a matched control group (CG) of patients treated with standard therapies. We retrospectively evaluated clinical, laboratory, and molecular parameters through univariate and multivariate analysis. A prospective characterization of circulating leukocyte subpopulations was performed in the latest twenty patients enrolled in the EG, with a statistical significance cutoff of P < .1. Results Thirty HGG patients were treated into six ieCTs. Fifteen patients received monotherapies (anti-PD-1, anti-CSF-1R, anti-TGFβ, anti-cereblon), fifteen patients combination regimens (anti-PD-L1 + anti-CD38, anti-PD-1 + anti-CSF-1R). In the EG, median progression-free survival and overall survival (OS) from treatment initiation were 1.8 and 8.6 months; twelve patients survived more than 12 months, and two of them more than 6 years. Univariate analysis identified O6-methylguanine DNA methyltransferase (MGMT) promoter methylation and total protein value at six weeks as significantly correlated with a better outcome. Decreased circulating neutrophils and increased conventional dendritic cells levels lead to significantly better OS. Conclusions A subgroup of EG patients achieved remarkably durable disease control. MGMT promoter methylation identifies patients who benefit more from immunotherapy. Monitoring dynamic changes of innate immune cell populations may help to predict clinical outcomes.

Background: both myocarditis and mitral valve prolapse (MVP) are known uncommon causes of ventricular arrhythmias in young patients. Aim: to report the first clinical case of endomyocardial biopsy (EMB)-proven autoimmune myocarditis and associated arrhythmogenic MVP in a patient with recurrent ventricular fibrillation (VF) episodes. Methods: myocarditis was diagnosed both by cardiac magnetic resonance (CMR) and EMB. Arrhythmogenic MVP was documented by transthoracic echocardiogram, CMR, and electroanatomical mapping of the trigger premature ventricular contractions (PVCs). Results: a 22-year-old woman underwent immunosuppressive therapy after EMB-proven diagnosis of autoimmune myocarditis with VF onset and early implantable cardioverter defibrillator (ICD) placement. Three years later, she experienced two VF recurrences and persistent PVCs, despite no signs of myocarditis recurrence. An echocardiogram revealed bileaflet MVP with high arrhythmic risk features. Finally, electroanatomical mapping and ablation of the trigger PVC were successfully performed. Conclusion: in patients with recurrent VF episodes despite evidence-based medical treatment for myocarditis, MVP should be considered as an alternative arrhythmogenic substrate, and warrants early ICD implant and PVC-targeted therapy.

Background Although potentially life-threatening, arrhythmias in myocarditis are under-reported. Purpose To assess diagnostic yield and clinical impact of continuous arrhythmia monitoring (CAM) in patients with arrhythmic myocarditis. Methods We enrolled consecutive adult patients (n=104; 71% males, age 47±11y, mean LVEF 50±13%) with biopsy-proven active myocarditis and de novo ventricular arrhythmias (VA). All patients underwent prospective monitoring by both sequential 24-hour Holter ECGs (4/y in the first year; 2/y in years 2–5; 1/y later) and CAM, including either ICD (n=62; 60%) or loop recorder (n=42; 40%). Results By 3.7±1.6 y follow-up, 45 patients (43%) had VT, 67 (64%) NSVT, and 102 (98%) premature ventricular complexes (PVC). As compared to Holter ECG (average 9.5 exams per patient), CAM identified more patients with VA (VT: 45 vs. 4; NSVT: 64 vs. 45; both p Conclusion In patients with arrhythmic myocarditis, CAM allowed accurate arrhythmia detection and showed a considerable clinical impact. As a complementary exam, VA characterization and PVC burden were better assed by repeated Holter ECGs. Funding Acknowledgement Type of funding sources: None.

Background Arrhythmic risk of patients with left ventricular arrhythmogenic cardiomyopathy (LVAC) is unpredictable. Purpose To identify risk facors associated with major ventricular tachyarrhythmias (VTA) in clinically-suspected LVAC patients. Methods We enrolled 127 consecutive patients (69% males, age 46±13 y, LVEF 54±7%) with clinically-suspected LVAC. All patients presented with either major (VT, VF) or minor VTA (NSVT, frequent VEB), and underwent extensive diagnostic workup to rule-out alternative diagnoses. Medical treatment and ICD implant were clinically-driven. Prospective follow-up was obtained via sequential 24h-Holter ECG (2–4/y) with or without continuous arrhythmia monitoring (ICD or implantable loop recorders, ILR). The primary endpoint was occurrence of major VTA (VT/VF/ICD therapy) by 24-month follow-up. Results At presentation, 56 (44%) and 71 patients (56%) had, respectively, major and minor VTA. Variants in desmosomal genes were identified in 7 of the 9 patients with clinically-indicated genetic test. Delayed gadolinium enhancement (DGE, average 23±12% of the LV mass) had anteroseptal distribution in 43 cases (34%). Monitoring strategy included ICD (n=64), ILR (n=33), or sequential Holer ECGs (n=30). By 24-month follow-up, major VTA occurred in 32 patients (25%). At univariable anlysis, major VTA onset (HR 16.8, 95% CI 5.4–52.2, p Conclusion Our preliminary experience suggests that, in patients with clinically-suspected LVAC, major VTA onset and anteroseptal DGE are relevant risk factors for major arrhythmic events by 24-month follow-up. Funding Acknowledgement Type of funding sources: None.