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Liver regeneration is supported by hepatocytes and, in certain conditions, biliary epithelial cells (BECs). BECs are facultative liver stem cells that form organoids in culture and engraft in damaged livers. However, BEC heterogeneity in the homeostatic liver remains to be fully elucidated. Here, we exploit systemic lentiviral vector (LV) administration to achieve efficient and lifelong gene transfer to BECs in mice. We find that LV-marked BECs retain organoid formation potential and predominantly respond to liver damage; however, they are less clonogenic and display a hepatocyte-primed transcriptome compared to untransduced BECs. We thus identify a BEC subset committed to hepatocyte lineage in the absence of liver damage, characterized by a transcriptional network orchestrated by hepatocyte nuclear factor 4α. We also report in vivo targeting of such BECs in non-human primates. This work highlights intrinsic BEC heterogeneity and that in vivo LV gene transfer to the liver may persist following BEC-mediated repair of hepatic damage., Competing Interests: Declaration of interests L.N. and A.C. are inventors on patent applications submitted by Foundation Telethon and San Raffaele Scientific Institute on LV technology related to the work presented in this manuscript. M.H. is an inventor of several patents related to organoid technology., (Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The safety of subcutaneous implantable cardioverter defibrillator (S-ICD) recipients who lead active lifestyles and engage in recreational sports is unknown. We aimed to evaluate the association between lifestyle and recreational sports and the occurrence of arrhythmia- and device-related complications, appropriate and inappropriate shocks in S-ICD recipients., Methods: We assessed a cohort of young-adult (15-65 years) S-ICD patients, evaluated their physical activity with IPAQ (International Physical Activity Questionnaire), and assessed the association between lifestyle and recreational sports on S-ICD safety and shocks., Results: We enrolled 602 S-ICD recipients (77% males; age, 46±14 years). According to the IPAQ, patients were categorized as inactive subjects (26.4%), moderately active subjects (45.2%), or highly active subjects (28.4%). Among moderately/highly active subjects, 163 (27.1%) were recreational athletes. During follow-up (47.3 [interquartile range, 27.0-67.6] months), 23 patients (3.8%) reached the safety end point of arrhythmia- or device-related complications, with moderately and highly active subjects showing in multivariate analysis similar incidence compared with inactive subjects ( P =0.59 and P =0.83, respectively). Forty-four patients had 87 appropriate shocks. In multivariate analysis, moderately and highly active subjects showed a nonsignificantly lower incidence of appropriate shocks compared with inactive subjects ( P =0.12 and P =0.11, respectively). Consistently, there was a nonsignificant lower incidence of appropriate shocks in athletes versus nonathletes ( P =0.06). Thirty-nine patients had 46 inappropriate shocks. Moderately and highly active subjects had similar incidence of inappropriate shocks compared with inactive subjects ( P =0.92 and P =0.88, respectively)., Conclusions: Young S-ICD patients often lead active lifestyles and participate in sports. Higher activity levels were not associated with increased implantable cardioverter defibrillator-related complications or increased risk of implantable cardioverter defibrillator shocks.

Aims: The subcutaneous implantable cardioverter defibrillator (S-ICD) is an alternative to traditional ICDs. The PRAETORIAN score, based on chest radiographs, has been validated to predict the probability of successful S-ICD defibrillation testing by assessing factors like fat thickness between the coil and sternum and generator placement. This study evaluated the correlation between the PRAETORIAN score and clinical characteristics, as well as implantation variables., Methods and Results: We retrospectively analysed data from 1253 patients who had undergone implantation of an S-ICD across 33 centres. The intermuscular positioning of the pulse generator was adopted in all patients. Post-implantation posterior-anterior and lateral chest radiographs were analysed to calculate the PRAETORIAN score. A total of 95.7% of patients had a PRAETORIAN score < 90, indicative of a low risk of conversion failure. Body mass index (BMI) was the only independent predictor of a score ≥ 90, and all patients with BMI < 25 kg/m2 (normal weight or underweight) had a score < 90. The intermuscular positioning technique resulted in optimal posterior placement of the device in all patients and significant sub-generator fat in only 3% of cases. A shock impedance value > 88 Ohm enabled to detect a PRAETORIAN score ≥ 90 with 98% (95% CI 97-99%) negative predictive value., Conclusion: In contemporary practice, the PRAETORIAN score can be simplified. By adopting an intermuscular approach, two of the three steps of the score-evaluating the adequate posterior positioning of the generator and measuring the sub-generator fat-become superfluous, and impedance may serve as a reliable surrogate of sub-coil fat thickness. Furthermore, our data suggest that for non-obese patients, a favourable PRAETORIAN score is assured, making the score evaluation potentially unnecessary., Clinical Trial Registration: URL: http://clinicaltrials.gov/ Identifier: NCT02275637., Competing Interests: Conflict of interest: This was an independent study. No external funding was received for this project. M.Z. receives speaker’s fees and educational grant from Abbott, Boston Scientific, Biotronik, and Edwards Lifesciences. L.O. is consultant for Boston Scientific. P.F. received speaker’s fees and educational grants from Boston Scientific and research grants from Abbott. G.B. received speaker’s fee from Abbott, Biotronik, Boston Scientific, Medtronic, and Microport; R.R. received speaker’s fees from Abbot and Boston Scientific. M.L. and S.Va. are employees of Boston Scientific. The other authors report no conflicts., (© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background/Objectives : Right ventricular pacing (RVP), leadless pacing (LL), and conduction system pacing (CSP) are treatment options for atrioventricular block (AVB), each with distinct characteristics. However, the long-term outcomes of these pacing strategies remain insufficiently compared. This study evaluates clinical and echocardiographic outcomes of patients with AVB treated with dual chamber RVP, His bundle pacing (HBP), or LL. Methods : This single-center observational registry study included 22 consecutive patients receiving LL with atrioventricular resynchronization functionality (October 2020 to October 2022), matched with 66 control patients receiving either RVP (33 patients) or HBP (33 patients) using propensity score matching (2:3:3 ratio). Primary and secondary endpoints included all-cause mortality, cardiovascular mortality, heart failure, and echocardiographic outcomes. Atrioventricular synchrony in the LL group was assessed. Results : At two years, all-cause mortality was significantly higher in the LL group compared to RVP (36.4% vs. 6.1%, p = 0.002) and HBP (36.4% vs. 12.1%, p = 0.03), but LL had a more severe clinical profile. Cardiovascular mortality and heart failure incidence showed no significant differences. Patients receiving RVP showed a significant decrease in left ventricular ejection fraction and an increase in ventricular volumes. In contrast, HBP patients exhibited favorable cardiac remodeling. Stratification based on atrial sensing showed that LL patients with >66% AV synchrony had a lower mortality ( p = 0.02). Conclusions : CSP offers superior results compared to other pacing methods in terms of ventricular function owing to a physiological ventricular activation and maintenance of AV synchrony. However, LL may be a viable alternative for frail and high-risk patients, as the suboptimal AV synchrony is traded off with lesser ventricular dyssynchrony.

Background: The subcutaneous implantable cardioverter-defibrillator (S-ICD) has emerged as an alternative to transvenous systems for prevention of sudden cardiac death. However, concerns have been raised regarding its efficacy and safety in obese individuals., Objective: The purpose of this study was to perform a meta-analysis to evaluate the efficacy and safety of the S-ICD in patients with obesity by assessing the relationship between body mass index (BMI) and clinical outcomes., Methods: A comprehensive search of multiple databases was conducted for English-language peer-reviewed studies reporting clinical outcomes in S-ICD recipients with (BMI ≥30 kg/m 2 ) and without obesity (BMI <30 kg/m 2 ). Data on preimplantation screening failure, defibrillation testing, complications, appropriate and inappropriate shocks, and survival were analyzed using standard, random-effects, meta-analytical techniques., Results: Twenty-nine studies involving 20,486 patients were included. There was no statistically significant difference in mean BMI values of patients with failed or successful preimplantation screening (mean difference -0.60 kg/m 2 ; 95% confidence interval [CI] -2.06 to 0.86). Obesity was associated with higher rates of failed defibrillation testing at ≤65 J (odds ratio [OR] 2.16; 95% CI 1.39-3.35), and malpositioning/suboptimal positioning occurred more frequently in obese compared to nonobese patients (OR 3.37; 95% CI 1.76-6.44). Increased BMI as a continuous variable (per increase in 1 kg/m 2 BMI) was associated with elevated defibrillation thresholds (OR 1.05; 95% CI 1.03-1.08); higher risk of complications (hazard ratio [HR] 1.04; 95% CI 1.02-1.05); a trend toward an increased number of appropriate shocks (HR 1.02; 95% CI 1.00-1.04); and no significant increase in the risk of inappropriate shocks (HR 1.01; 95% CI 0.99-1.03)., Conclusion: This meta-analysis underscores the importance of considering obesity in S-ICD implantation decisions. Although S-ICD remains effective in obese patients, attention to potential technical challenges and higher complication rates is warranted., Competing Interests: Disclosures Dr Vamos reports educational activity and advisory relationship with Biotronik, and educational activity on behalf of Medtronic, Novo Nordisk, and Pfizer. Dr Biffi reports educational activity on behalf of Biotronik and Philips. Dr Szili-Torok reports educational activity/advisory relationship with Biotronik; and until 2022 he was in educational/advisory/product development relationships with Ablacon Inc., Abbott, Acutus Medical, Biosense Webster, and Stereotaxis. Dr Ziacchi reports educational activity on behalf of Abbott, Biotronik, and Boston Scientific. Dr Benz reports speaker fees from Bristol-Myers Squibb and AstraZeneca; and participation in an educational program supported by Boston Scientific (“Fellowship Herzrhythmus”). Dr Spittler reports a travel grant to attend a scientific meeting from Johnson & Johnson. All other authors have no conflicts of interest to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Limited data are available on leadless pacemaker (LPM) outcomes according to different stages of chronic kidney disease (CKD)., Objective: The purpose of this study was to investigate differences in the safety and efficacy of LPMs among patients stratified per different stages of renal function., Methods: Consecutive patients enrolled in the multicenter international i-LEAPER registry (International LEAdless PacemakEr Registry) were analyzed. Patients were divided into 3 groups according to CKD stage. The primary end point was the comparison of LPM-related major complication rate at implantation and during follow-up. Differences in electrical performance were deemed secondary outcomes., Results: Of the 1748 patients enrolled, 33% were in CKD stage G3a/G3b and 9.4% were in CKD stage G4/G5. Patients with CKD presented cardiovascular comorbidities more frequently. During a median follow-up of 39 months (interquartile range [IQR] 18-59 months), major complication rate did not differ between groups (normal kidney function [NKF] group 1.8% vs CKD stage G3a/G3b group 2.9% vs CKD stage G4/G5 group 2.4%; P = .418). All-cause mortality resulted higher in the CKD stage G4/G5 group than in the NKF group (19.5% vs 9.8%; adjusted hazard ratio 1.9; 95% confidence interval 1.25-2.89; P = .003). LPM electrical performance was comparable between groups, except for patients with CKD who showed a slightly higher pacing threshold during 1-month follow-up (NKF group 0.50 V [IQR 0.35-0.70 V] vs G3a/G3b group 0.56 V [IQR 0.38-0.81 V] vs G4/G5 group 0.51 V [0.38-0.84 V] @ 0.24 ms; P < .001)., Conclusion: In a real-world setting, patients with advanced CKD who underwent LPM implantation were underrepresented. Although all-cause mortality was higher in end-stage CKD, periprocedural complications and LPM performance were overall comparable between NKF and different stages of CKD, except for higher values of pacing threshold in patients with CKD up to first-month follow-up., Competing Interests: Disclosures Dr Tondo is a member of an advisory board of Medtronic. Other authors do not report disclosures regarding this article., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Substernal lead placement of the extravascular implantable cardioverter defibrillator (EV ICD) permits both defibrillation at thresholds similar to those seen with transvenous implantable cardioverter defibrillators and effective anti-tachycardia pacing (ATP) while avoiding the vasculature and associated complications. The global Pivotal study has shown the EV ICD system to be safe and effective through 6 months, but long-term experience has yet to be published. Our aim was to report the performance and safety of the EV ICD system throughout the study., Methods: The EV ICD Pivotal study was a prospective, global, single-arm, premarket clinical study. Individuals with a Class I or IIa indication for a single-chamber implantable cardioverter defibrillator per guidelines were enrolled. Freedom from major system- or procedure-related complications and appropriate and inappropriate therapy rates were assessed through 3 years with the Kaplan-Meier method. ATP success was calculated from simple proportions., Results: An implantation was attempted in 316 patients (25.3% female; 53.8±13.1 years of age; 81.6% primary prevention; left ventricular ejection fraction, 38.9±15.4%). Of 299 patients with a successful implantation, 24 experienced 82 spontaneous arrhythmic episodes that were appropriately treated with ATP only (38, 46.3%), shock only (34, 41.5%), or both (10, 12.2%) for a Kaplan-Meier-estimated rate of first any appropriate therapy of 9.2% at 3 years. ATP was successful in 77.1% (37/48) of episodes, and ATP use significantly increased from discharge to last follow-up visit ( P <0.0001). Shock therapy was successful in 100% (27/27) of discrete, spontaneous ventricular arrhythmias. The inappropriate shock rates at 1 and 3 years were 9.8% and 17.5%, respectively, with P-wave oversensing the predominant cause. No major intraprocedural complications were reported, and the estimated freedom from system- or procedure-related major complications was 91.9% at 1 year and 89.0% at 3 years. The most common major complications were lead dislodgement (10 events; n=9 patients, 2.8%), postoperative wound or device pocket infection (n=8, 2.5%), and device inappropriate shock delivery (n=4, 1.3%). Twenty-four system revisions were performed as a result of major complications related to the EV ICD system or procedure., Conclusions: From implantation to study completion, the EV ICD Pivotal study demonstrated that a single integrated system with an extravascular lead placed in the substernal space maintains high ATP success, effective defibrillation, and a consistent safety profile., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04060680., Competing Interests: Dr Friedman reports receiving EV ICD Pivotal study participation support, paid to their institution, from Medtronic; licenses and patents with Anumana, Eko Health, Alive Cor, and Marani Health; advisory board participation at Anumana; a leadership position with xAI.health and MediCool; steering committee participation and advisory group participation at Boston Scientific, funds paid to their institution; and stock from MediCool, Marani Health, and xAI.health. Dr Murgatroyd reports receiving EV ICD Pivotal study participation support, paid to their institution, from Medtronic; consulting fees from Medtronic for advisory board and steering committee participation, consulting fees from Boston Scientific for steering committee participation; and speaker fees from Medtronic. Dr Boersma reports receiving EV ICD Pivotal study participation support, paid to their institution, from Medtronic and consulting fees from Medtronic and Adagio, paid to the cardiology department at their institution. Dr Manlucu reports receiving EV ICD Pivotal study participation support, paid to their institution, from Medtronic; consulting fees from Medtronic for advisory board and steering committee participation; and speaker fees from Medtronic. Dr Knight reports receiving EV ICD Pivotal study participation support, paid to their institution, from Medtronic; consulting fees from Medtronic for advisory board and steering committee participation; consulting fees from Boston Scientific for advisory board participation; and speaker fees from Medtronic and Boston Scientific. Dr Clémenty reports receiving consulting fees, honoraria fees, travel support, and advisory board participation from Medtronic. Dr Leclercq reports receiving consulting fees and honoraria from Medtronic, Boston Scientific, and Abbott for steering committee participation and speaker fees from Medtronic. Dr Amin reports receiving EV ICD Pivotal study participation support from Medtronic; an institutional grant from Biosense Webster; consulting fees from Medtronic, Boston Scientific, Biosense Webster, Atricure, and Philips; honoraria from Medtronic, Boston Scientific, Biosense Webster, Atricure, and Philips; travel support from Boston Scientific, Medtronic, and Philips; and advisory board participation at Boston Scientific, Medtronic, Atricure, and Philips. Dr Merkely reports receiving institutional grants from Medtronic and Boston Scientific and lecture fees from Medtronic, Biotronik, and Abbott. Dr Birgersdotter-Green reports receiving honoraria from Medtronic, Boston Scientific, Abbott, and Biotronik; advisory board participation at Biotronik; and stock ownership in Vektor Medical. Dr Chan reports receiving honoraria for lectures from Medtronic. Dr Biffi receiving EV ICD Pivotal study participation support, paid to their institution, from Medtronic and grants from Medtronic, paid to their institution. Dr Knops reports receiving EV ICD Pivotal study participation support from Medtronic for trial funding; grants from Boston Scientific and Abbott for trial funding; institutional and private consulting fees from Abbott and Boston Scientific; honoraria from Medtronic, Boston Scientific, and Abbott; advisory board participation at Boston Scientific, Atacor, and Kestra; participation on the ESC pacing guideline committee; and stock ownership from Atacor. Dr Engel reports consulting fees from Medtronic. Dr Epstein reports institutional support for the EV ICD Pivotal study, consulting fees from Medtronic, and honoraria from Medtronic. Dr Johansen reports honoraria paid to their institution from Merit Medical, Education course and advisory board participation at Medtronic and Biotronik. Dr Sterliński reports receiving EV ICD Pivotal study participation support, paid to their institution, from Medtronic; grants from Biotronik and HammerMed; consulting fees from Abbott, Biotronik, HammerMed, and Medtronic; honoraria from Abbott, Biotronik, Medtronic, and Zoll; and advisory board participation at Medtronic. Dr Hounshell reports consulting fees from Medtronic, lecture fees from Medtronic, and advisory board participation at Medtronic. Dr Abben reports consulting fees and honoraria from Medtronic. A. Thompson, Y. Zhang, Dr Wiggenhorn, and S. Willey report employment by Medtronic. Dr Crozier reports receiving research funding for the EV ICD Pivotal study from Medtronic, grants from Medtronic for fellowship funding, and consulting fees from Medtronic. The other authors report no conflicts.

Studies show that propolis has antimicrobial, antifungal, antiviral, anti-inflammatory, antioxidant, antitumor, and immunomodulatory properties, and may protect against diseases such as diabetes, cardiovascular disease, and cancer. We aimed to extract compounds of brown propolis with hydroalcoholic solvents and evaluate their cytotoxic activity on tumor and non-tumor cells by MTT test. We tested the solute:solvent ratio (ethanol:water) and extraction time in a Shaker incubator (710 rpm) before conducting a central composite rotational design (CCRD) to optimize time and solvent mixture. We found that a temperature of 80 °C and a solvent concentration of 90:10 were the best extraction conditions for phenolic compounds, especially pinocembrin and cinnamic acid. The extract showed antioxidant capacity, acid characteristics, low humidity, and the presence of ash, lipids, and soluble solids. The cytotoxicity test with normal kidney cells of Macaca mullata (LLC-MK2) and human lung tumor cells (A549) showed no statistical difference from the negative control. For liver tumor cells (HuH7.5), different concentrations showed cytotoxic/antiproliferative activity. Thus, the data indicate that this product deserves prominence in the search for new applications.