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Aims: The third-generation laser balloon (LB3) is an established ablation device for pulmonary vein isolation (PVI) that allows direct visualization of the anatomical target. Equipped with an automatic circumferential laser delivery modality, it aims at continuous circumferential PVI, improving both acute and clinical outcomes. We sought to evaluate the clinical efficacy of LB3 ablation using an anatomical-based approach without verifying electrical isolation., Methods and Results: Among 257 paroxysmal AF patients undergoing LB3 ablation across four Italian centres, 204 (72% male, mean age 60.4 ± 11.1 years) were included. The primary endpoint was freedom from any atrial tachyarrhythmia (ATa) recurrence after the blanking period (BP), assessed with implantable cardiac monitors (ICMs). All pulmonary veins (PVs) were targeted using the LB3, with the RAPID mode used on an average of 96 ± 8, 86 ± 19, 98 ± 11, and 84 ± 15% for the left superior, left inferior, right superior, right inferior PV, and left common ostium, respectively. Freedom from arrhythmia recurrences was 84.8% at 1, 80.4% at 2, and 76.0% at 3 years. An ATa burden ≥ 5% was documented in 2.5, 4.4, and 5.4% at 1, 2, and 3 years, respectively. Relapses during the BP [hazard ratio (HR) = 2.182, P = 0.032] and left atrial dilation (HR = 1.964, P = 0.048) were independent predictors of recurrences., Conclusion: Anatomical-guided LB3 ablation for paroxysmal AF is a safe and effective approach, providing excellent clinical outcomes as assessed by ICM over nearly 3 years of follow-up., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Competing Interests: Conflict of interest: C.T. is a member of Boston Scientific and Medtronic Inc. advisory board. L.D.B. is a consultant for Biosense Webster, Boston Scientific, Stereotaxis, and St. Jude Medical and has received speaker honoraria from Medtronic, AtriCure, EPiEP, and Biotronik. A.N. is a consultant for Biosense Webster, Stereotaxis, and Abbott Medical and has received speaker honoraria/travel from Medtronic, AtriCure, Biotronik, and Janssen. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Aims: Pulsed-field ablation (PFA) is a novel, myocardial-selective, non-thermal ablation modality used to target cardiac arrhythmias. Although prompt electrogram (EGM) signal disappearance is observed immediately after PFA application in the pulmonary veins, whether this finding results in adequate transmural lesions is unknown. The aim of this study is to check whether application repetition and catheter-tissue contact impact lesion formation during PFA., Methods and Results: A circular loop PFA catheter was used to deliver repeated energy applications with various levels of contact force. A benchtop vegetal potato model and a beating heart ventricular myocardial model were utilized to evaluate the impact of application repetition, contact force, and catheter repositioning on contiguity and lesion depth. Lesion development occurred over 18 h in the vegetal model and over 6 h in the porcine model. Lesion formation was found to be dependent on application repetition and contact. In porcine ventricles, single and multiple stacked applications led to a lesion depth of 3.5 ± 0.7 and 4.4 ± 1.3 mm, respectively (P = 0.002). Furthermore, the greater the catheter-tissue contact, the more contiguous and deeper the lesions in the vegetal model (1.0 ± 0.9 mm with no contact vs. 5.4 ± 1.4 mm with 30 g of force; P = 0.0001)., Conclusion: Pulsed-field ablation delivered via a circular catheter showed that both repetition and catheter contact led independently to deeper lesion formation. These findings indicate that endpoints for effective PFA are related more to PFA biophysics than to mere EGM attenuation., Competing Interests: Conflict of interest: L.D.B. is a consultant for Stereotaxis, Biosense Webster, Boston Scientific, Abbott Medical, I-Rhythm, Siemens Medtronic, AtriCure, Biotronik, and Zoll. T.G., E.B., and V.G. are employees of Biosense Webster, Inc., a Johnson & Johnson company. All remaining authors have declared no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Competing Interests: Conflict of interest: The authors do no report disclosures regarding this article.

Aims: Women have been historically underrepresented in implantable cardioverter-defibrillator (ICD) trials. No data on sex differences regarding subcutaneous ICDs (S-ICD) carriers have been described. Aim of our study was to investigate sex-related differences among unselected S-ICD recipients., Methods and Results: Consecutive patients enrolled in the multicentre, international i-SUSI registry were analysed. Comparisons between sexes were performed using a 1:1 propensity matching adjusted analysis for age, body mass index (BMI), left ventricular function, and substrate. The primary outcome was the rate of appropriate shocks during follow-up. Inappropriate shocks and other device-related complications were deemed secondary outcomes. A total of 1698 patients were extracted from the i-SUSI registry; 399 (23.5%) were females. After propensity matching, two cohorts of 374 patients presenting similar baseline characteristics were analysed. Despite similar periprocedural characteristics and a matched BMI, women resulted at lower risk of conversion failure as per PRAETORIAN score (73.4% vs. 81.3%, P = 0.049). Over a median follow-up time of 26.5 [12.7-42.5] months, appropriate shocks were more common in the male cohort (rate/year 3.4% vs. 1.7%; log-rank P = 0.049), while no significant differences in device-related complications (rate/year: 6.3% vs. 5.8%; log-rank P = 0.595) and inappropriate shocks (rate/year: 4.3% vs. 3.1%; log-rank P = 0.375) were observed. After controlling for confounders, sex remained significantly associated with the primary outcome (aHR 1.648; CI 0.999-2.655, P = 0.048), while not resulting predictor of inappropriate shocks and device-related complications., Conclusion: In a propensity-matched cohort of S-ICD recipients, women are less likely to experience appropriate ICD therapy, while not showing higher risk of device-related complications., Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT0473876., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Catheter ablation (CA) of ventricular tachycardia (VT) has become an important tool to improve clinical outcomes in patients with appropriate transvenous implantable cardioverter defibrillator (ICD) shocks. The aim of our analysis was to test whether VT ablation (VTA) impacts long-term clinical outcomes even in subcutaneous ICD (S-ICD) carriers., Methods and Results: International Subcutaneous Implantable Cardioverter Defibrillator (iSUSI) registry patients who experienced either an ICD shock or a hospitalization for monomorphic VT were included in this analysis. Based on an eventual VTA after the index event, patients were divided into VTA+ vs. VTA- cohorts. Primary outcome of the study was the occurrence of a combination of device-related appropriate shocks, monomorphic VTs, and cardiovascular mortality. Secondary outcomes were addressed individually. Among n = 1661 iSUSI patients, n = 211 were included: n = 177 experiencing ICD shocks and n = 34 hospitalized for VT. No significant differences in baseline characteristics were observed. Both the crude and the yearly event rate of the primary outcome (5/59 and 3.8% yearly event rate VTA+ vs. 41/152 and 16.4% yearly event rate in the VTA-; log-rank: P value = 0.0013) and the cardiovascular mortality (1/59 and 0.7% yearly event rate VTA+ vs. 13/152 and 4.7% yearly event rate VTA-; log-rank P = 0.043) were significantly lower in the VTA + cohort. At multivariate analysis, VTA was the only variable remaining associated with a lower incidence of the primary outcome [adjusted hazard ratio 0.262 (0.100-0.681), P = 0.006]., Conclusion: In a real-world registry of S-ICD carriers, the combined study endpoint of arrhythmic events and cardiovascular mortality was lower in the patient cohort undergoing VTA at long-term follow-up., Clinicaltrials.gov Identifier: NCT0473876., Competing Interests: Conflict of interest: A.D.R. is a consultant for Abbott. M.C. has received speaker honoraria from Abbott and Biosense Webster. L.K. worked as a proctor for Boston Scientific. R.T. is a consultant for Boston Scientific, Biotronik, Biosense Webster, Abbott Medical, and he received speaker’s honoraria from Boston Scientific, Biotronik, Biosense Webster, Abbott Medical, and LifeTech and research grants from Abbott, Biosense Webster, and LifeTech. A.B. has received consultant and/or speaker fees from Abbott, Bayer Healthcare, Biosense Webster, Biotronik, Boston Scientific, Bristol Myers Squibb, Cook Medical, Daiichi Sankyo, Medtronic, Pfizer, and Spectranetics/Philips., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Pulsed field ablation (PFA) is a non-thermal ablative approach in which cardiomyocyte death is obtained through irreversible electroporation (IRE). Data correlating the biophysical characteristics of IRE and lesion characteristics are limited. The aim of this study was to assess the effect of different procedural parameters [voltage, number of cycles (NoCs), and contact] on lesion characteristics in a vegetal and animal model for IRE., Methods and Results: Two hundred and four Russet potatoes were used. Pulsed field ablation lesions were delivered on 3 cm cored potato specimens using a multi-electrode circular catheter with its dedicated IRE generator. Different voltage (from 300 to 1200 V) and NoC (from 1 to 5×) protocols were used. The impact of 0.5 and 1 mm catheter-to-specimen distances was tested. A swine animal model was then used to validate the results observed in the vegetable model. The association between voltage, the NoCs, distance, and lesion depth was assessed through linear regression. An almost perfect linear association between lesion depth and voltage was observed (R2 = 0.95; P < 0.001). A similarly linear relationship was observed between the NoCs and the lesion depth (R2 = 0.73; P < 0.001). Compared with controls at full contact, a significant dampening on lesion depth was observed at 0.5 mm distance (1000 V 2×: 2.11 ± 0.12 vs. 0.36 ± 0.04, P < 0.001; 2.63 ± 0.10 vs. 0.43 ± 0.08, P < 0.001). No lesions were observed at 1.0 mm distance., Conclusion: In a vegetal and animal model for IRE assessment, PFA lesion characteristics were found to be strongly dependent on voltage settings and the NoCs, with a quasi-linear relationship. The lack of catheter contact was associated with a dampening in lesion depth., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Cardiac resynchronization therapy (CRT) via biventricular pacing (BVP) is a well-established therapy for patients with heart failure with reduced ejection fraction and left bundle branch block, who remain symptomatic despite optimal medical therapy. Despite the long-standing clinical evidence, as well as the familiarity of cardiac electrophysiologists with the implantation technique, CRT via BVP cannot be achieved or may result ineffective in up to one-third of the patients. Therefore, new alternative techniques, such as conduction system pacing and left ventricular pacing, are emerging as potential alternatives to this technique, not only in case of BVP failure, but also as a stand-alone first choice due to several potential advantages over traditional CRT. Specifically, due to its procedural characteristics, left bundle branch area pacing appears to be the most convincing technique, showing comparable efficacy outcomes when compared with traditional CRT, not increasing short-term device-related complications, as well as improving procedural times. However, transvenous leads remain a major limitation of all these pacing modalities. To overcome this limit, a leadless left ventricular endocardial pacing has been developed as an additional tool to achieve a left endocardial activation, although being still associated with non-negligible pitfalls, limiting its current use in clinical practice. This article focuses on the current state and latest progresses in cardiac resynchronization therapy., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Context: Children with congenital hypothyroidism (CH) are at risk for suboptimal neurodevelopment., Objectives: To evaluate neurocognitive function and white matter microstructure in children with permanent or transient CH and to correlate these findings with disease severity., Design, Participants and Methods: A retrospective and prospective observational study was conducted in 39 children with permanent or transient CH, and in 39 healthy children. Cognitive function was assessed by Wechsler Intelligence Scale, Fourth Edition, and by other tests; the white matter microstructure was investigated by 3 Tesla magnetic resonance imaging., Results: Children with permanent CH have lower cognitive scores at a median age of 9.5 years than those with transient CH and controls. An IQ score between 71 and 84 was found in 28.6% of permanent CH and of <70 (P = 0.06) in 10.7%. The Processing Speed Index (PSI; P = 0.004), sustained visual attention (P = 0.02), reading speed (P = 0.0001), written calculations (P = 0.002), and numerical knowledge (P = 0.0001) were significantly lower than controls. Children born to mothers with Hashimoto's thyroiditis have significantly lower IQ values (P = 0.02), Working Memory Index (P = 0.03), and PSI (P = 0.02). Significantly lower IQ and Verbal Comprehension Index values were found in children with a family history of thyroid disorders (P = 0.004 and P = 0.009, respectively). In children with permanent CH, significant correlations between abnormalities in white matter microstructural, clinical, and cognitive measures were documented., Conclusions: These findings indicate that children with CH are at risk of neurocognitive impairment and white matter abnormalities despite timely and adequate treatment. The association between offspring cognitive vulnerability and maternal thyroid disorders requires careful consideration., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: Balloon-based technologies have been developed to simplify catheter ablation of atrial fibrillation (AF), to improve the clinical outcome of the procedure and to achieve durable pulmonary vein isolation (PVI). The objective of this study is to evaluate the safety and efficacy of second-generation laser balloon (LB2) ablation in the treatment of AF using a continuous cardiac rhythm monitoring strategy. Atrial tachyarrhythmias (ATas) recurrences were assessed with implantable cardiac monitors (ICMs) or devices., Methods and Results: All patients underwent LB2 ablation procedure. The primary endpoint was the first recurrence of any, >5.5 and >24 h duration ATas after the blanking period (90 days). In-hospital visits were performed at 3, 6, and 12 months. Seventy-three patients (68% male, mean age 59.8 ± 11.3) were included in the study. The average procedure, fluoroscopy, and laser ablation times were 81.5 ± 30.1, 21.5 ± 12.4, and 33.8 ± 9.7, respectively. All PVs were isolated using the LB2 with no need of touch-up using focal catheters. No major complications occurred during or after the procedures. The one-year freedom from recurrences was 66.9% (95% CI: 57.0-76.7%), 81.0% (69.5-88.5%), and 86.8% (76.1-92.9%) considering any, 5.5-h and 24-h cut-off duration, respectively. At 3, 6, and 12 months, any ATas was recorded in 22%, 32%, and 25% of patients, with a ≥5% arrhythmic burden documented in 4%, 5%, and 3%, respectively. Few patients reported AF-related symptoms (7%, 8%, and 5%)., Conclusion: LB2 ablation is a safe and effective procedure, showing a high freedom from recurrences and low arrhythmic burden as documented by a continuous rhythm monitoring strategy., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Aims: The aim of the study was to describe ECG modifications and arrhythmic events in COVID-19 patients undergoing hydroxychloroquine (HCQ) therapy in different clinical settings., Methods and Results: COVID-19 patients at seven institutions receiving HCQ therapy from whom a baseline and at least one ECG at 48+ h were available were enrolled in the study. QT/QTc prolongation, QT-associated and QT-independent arrhythmic events, arrhythmic mortality, and overall mortality during HCQ therapy were assessed. A total of 649 COVID-19 patients (61.9 ± 18.7 years, 46.1% males) were enrolled. HCQ therapy was administrated as a home therapy regimen in 126 (19.4%) patients, and as an in-hospital-treatment to 495 (76.3%) hospitalized and 28 (4.3%) intensive care unit (ICU) patients. At 36-72 and at 96+ h after the first HCQ dose, 358 and 404 ECGs were obtained, respectively. A significant QT/QTc interval prolongation was observed (P < 0.001), but the magnitude of the increase was modest [+13 (9-16) ms]. Baseline QT/QTc length and presence of fever (P = 0.001) at admission represented the most important determinants of QT/QTc prolongation. No arrhythmic-related deaths were reported. The overall major ventricular arrhythmia rate was low (1.1%), with all events found not to be related to QT or HCQ therapy at a centralized event evaluation. No differences in QT/QTc prolongation and QT-related arrhythmias were observed across different clinical settings, with non-QT-related arrhythmias being more common in the intensive care setting., Conclusion: HCQ administration is safe for a short-term treatment for patients with COVID-19 infection regardless of the clinical setting of delivery, causing only modest QTc prolongation and no directly attributable arrhythmic deaths., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Context: The etiology of central diabetes insipidus (CDI) in children is often unknown. Clinical and radiological features at disease onset do not allow discrimination between idiopathic forms and other conditions or to predict anterior pituitary dysfunction., Objective: To evaluate the evolution of pituitary stalk (PS) thickening and the pattern of contrast-enhancement in relation with etiological diagnosis and pituitary function., Methods: We enrolled 39 children with CDI, 29 idiopathic and 10 with Langerhans cell histiocytosis (LCH). Brain magnetic resonance images taken at admission and during follow-up (332 studies) were examined, focusing on PS thickness, contrast-enhancement pattern, and pituitary gland size; T2-DRIVE and postcontrast T1-weighted images were analyzed., Results: Seventeen of 29 patients (58.6%) with idiopathic CDI displayed "mismatch pattern," consisting in a discrepancy between PS thickness in T2-DRIVE and postcontrast T1-weighted images; neuroimaging findings became stable after its appearance, while "mismatch" appeared in LCH patients after chemotherapy. Patients with larger PS displayed mismatch more frequently (P = 0.003); in these patients, reduction of proximal and middle PS size was documented over time (P = 0.045 and P = 0.006). The pituitary gland was smaller in patients with mismatch (P < 0.0001). Patients with mismatch presented more frequently with at least one pituitary hormone defect, more often growth hormone deficiency (P = 0.033)., Conclusions: The PS mismatch pattern characterizes patients with CDI, reduced pituitary gland size, and anterior pituitary dysfunction. The association of mismatch pattern with specific underlying conditions needs further investigation. As patients with mismatch show stabilization of PS size, we assume a prognostic role of this peculiar pattern, which could be used to lead follow-up., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: There is little information on cognitive function in Silver-Russell syndrome (SRS), and no neuroimaging studies are available so far., Objective: To assess cognitive function and brain volumes in patients with SRS., Design/setting: Wechsler Intelligence Scale and brain magnetic resonance on a 3-Tesla scanner with Voxel-based morphometry analysis were performed between 2016 and 2018 in a single tertiary university center., Partecipants: 38 white subjects with clinical diagnosis of SRS confirmed by molecular analysis: 30 of these patients (mean age 12.6 ± 10 years) were enrolled for cognitive assessment; 23 of the 30 performed neuroimaging sequences. A control group of 33 school-aged children performed cognitive assessment while 65 age and sex-matched volunteers were included for the neuroradiological assessment., Main Outcomes: Intelligence quotient, Verbal Comprehension Index (VCI), Perceptual Reasoning Index (PRI), Working Memory Index (WMI), Processing Speed Index, and brain volume., Results: The mean overall IQ score was 87.2 ± 17, and it was significantly lower in the maternal uniparental disomy of chromosome 7 (mUPD7) group at the age of 6 to 16 years compared to loss of methylation on chromosome 11p15 (11p15 LOM) group and to controls. VCI, PRI, and WMI were significantly higher in 11p15 LOM group and in control group than in mUPD7 group at the age of 6 to 16 years. There were no significant differences in cognitive scores between 11p15 LOM school-aged patients and the control group. SRS patients showed lower brain volume compared to controls at the frontal/temporal poles and globi pallidi., Conclusions: Patients with mUPD7 had an impaired cognitive profile. The brain volume at the frontal/temporal lobes and at the globi pallidi was reduced in patients with SRS., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The Saccharomyces cerevisiae cell surface is endowed with some relevant technological properties, notably antimicrobial and biosorption activities. For these purposes, yeasts are usually processed and packaged in an 'autolysed/dried' formula, which may have some impacts on cell surface properties. In this report, we showed using a combination of biochemical, biophysical and molecular methods that the composition of the cell wall of two wine yeast strains was not altered by the autolysis process. In contrast, this process altered the nanomechanical properties as shown by a 2- to 4-fold increased surface roughness and to a higher adhesion to the atomic force microscope tips of the autolysed cells as compared to live yeast cells. Besides, we found that the two strains harboured differences in biomechanical properties that could be due in part to higher levels of mannan in one of them, and to the fact that the surface of this mannan-enriched strain is decorated with highly adhesive patches forming nanodomains. The presence of these nanodomains could be correlated with the upregulation of flocculin encoding FLO11 as well as to higher expression of few other genes encoding cell wall mannoproteins in this mannan-enriched strain as compared to the other strain., (© FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

A reliable method to determine cell wall polysaccharides composition in yeast is presented, which combines acid and enzymatic hydrolysis. Sulphuric acid treatment is used to determine mannans, whereas specific hydrolytic enzymes are employed in a two sequential steps to quantify chitin and the proportion of β-(1,3) and β-(1,6)-glucan in the total β-glucan of the cell wall. In the first step, chitin and β-(1,3)-glucan were hydrolysed into their corresponding monomers N-acetylglucosamine and glucose, respectively, by the combined action of a chitinase from Streptomyces griseus and a pure preparation of endo/exo-β-(1,3)-glucanase from Trichoderma species. This step was followed by addition of recombinant endo-β-(1,6)-glucanase from Trichoderma harzianum with β-glucosidase from Aspergillus niger to hydrolyse the remaining β-glucan. This latter component corresponded to a highly branched β-(1,6)-glucan that contained about 75-80% of linear β-(1,6)-glucose linked units as deduced from periodate oxidation. We validated this novel method by showing that the content of β-(1,3), β-(1,6)-glucan or chitin was dramatically decreased in yeast mutants defective in the biosynthesis of these cell wall components. Moreover, we found that heat shock at 42 °C in Saccharomyces cerevisiae and treatment of this yeast species and Candida albicans with the antifungal drug caspofungin resulted in 2- to 3-fold increase of chitin and in a reduction of β-(1,3)-glucan accompanied by an increase of β-(1,6)-glucan, whereas ethanol stress had apparently no effect on yeast cell wall composition., (© 2014 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.)

Bruton's tyrosine kinase (Btk) is required for B-cell development. Btk deficiency causes X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (Xid) in mice. Btk lacks a negative regulatory domain and may rely on cytoplasmic proteins to regulate its activity. Consistently, we identified an inhibitor of Btk, IBtk, which binds to the PH domain of Btk and down-regulates the Btk kinase activity. IBtk is an evolutionary conserved protein encoded by a single genomic sequence at 6q14.1 cytogenetic location, a region of recurrent chromosomal aberrations in lymphoproliferative disorders; however, the physical and functional organization of IBTK is unknown. Here, we report that the human IBTK locus includes three distinct mRNAs arising from complete intron splicing, an additional polyadenylation signal and a second transcription start site that utilizes a specific ATG for protein translation. By northern blot, 5'RACE and 3'RACE we identified three IBTKalpha, IBTKbeta and IBTKgamma mRNAs, whose transcription is driven by two distinct promoter regions; the corresponding IBtk proteins were detected in human cells and mouse tissues by specific antibodies. These results provide the first characterization of the human IBTK locus and may assist in understanding the in vivo function of IBtk.