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Nicola Tarantino,1 Francesco Santoro,1,2 Luisa De Gennaro,3 Michele Correale,1 Francesca Guastafierro,1 Antonio Gaglione,1 Matteo Di Biase,1 Natale Daniele Brunetti1 1University of Foggia, Foggia, Italy; 2Asklepios Klinik – St Georg, Hamburg, Germany; 3Ospedale San Paolo, Bari, Italy Abstract: Lipids disorder is the principal cause of atherosclerosis and may present with several forms, according to blood lipoprotein prevalence. One of the most common forms is combined dyslipidemia, characterized by high levels of triglycerides and low level of high-density lipoprotein. Single lipid-lowering drugs may have very selective effect on lipoproteins; hence, the need to use multiple therapy against dyslipidemia. However, the risk of toxicity is a concerning issue. In this review, the effect and safety of an approved combination therapy with simvastatin plus fenofibrate are described, with an analysis of pros and cons resulting from randomized multicenter trials, meta-analyses, animal models, and case reports as well. Keywords: fibrates, simvastatin, fixed-dose combination, combined dyslipidemia, review

ABSTRACT Adolescents and young adults (young people) with HIV (YPWH) often struggle with treatment self-management. Many have symptoms due to HIV disease, medication side-effects, or comorbid conditions. Our study investigated the severity of HIV-related symptoms among YPWH aged 18-24 with detectable viral loads from an HIV clinic in Ghana ( N  = 60) and potential correlates of severity across a range of factors. Results indicated that YPWH currently experienced, on average, 13 symptoms (SD = 12.33). Six of the 10 most common symptoms were from two domains: fatigue and psychological. The most common symptoms were headaches (62%), weakness (53%), and fear/worries (52%). No differences were observed in number or severity of symptoms between youth based on HIV transmission status. Bivariate correlates of symptom severity were found with six that remained significant or approached significance in a multivariate model predicting severity: living with a parent/guardian, higher perceived access to HIV care, and higher treatment readiness were associated with lower severity while greater travel time to the HIV clinic, psychological distress, and more missed clinic appointments were associated with higher severity. Our findings suggest that interventions to address symptoms among YPWH should be multilevel and include strategies (e.g., telehealth, home care) to increase access to care.

Background: Uterus transplantation (UTx) is an emerging therapy for women with uterine infertility. However, critical questions remain with this procedure including the mechanisms involved in graft rejection., Methods: In this study, we analyzed the immune profile of ectocervical biopsies from 5 patients after UTx before and during their first episode of rejection using RNA sequencing, quantitative polymerase chain reaction, and imaging mass cytometry., Results: We identified 530 upregulated and 207 downregulated genes associated with graft rejection. Enrichment databases revealed abnormalities of skin-associated genes and the immune system, in particular activation of T and B lymphocytes, and macrophages. Imaging mass cytometry confirmed these observations; in cervical biopsies of 3 women, rejection was associated with the presence of B-cell structures linked to tertiary lymphoid structures, and 2 biopsies from 1 woman with severe rejection episodes and poor prognosis of graft function (repeated miscarriage and implantation failures) were associated with an accumulation of HLA-DR- macrophages, producing granzyme B at the surface of the epithelium., Conclusions: We showed that rejection of a UTx graft was associated with major alterations of immune markers including the involvement of tertiary lymphoid structures, the most organized of which may be a sign of chronic rejection, and with an increase in HLA-DR- macrophages expressing granzyme B in the case of grade 3 rejection episodes according Mölne's classification. We identified potential emerging biomarkers to predict or diagnose graft rejection (Keratin 1 granzyme B, IL1β). These findings could lead to development of improved strategies for the identification, prevention, and/or treatment of uterus graft rejection., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: In most cases, Zika virus (ZIKV) causes a self-limited acute illness in adults, characterized by mild clinical symptoms that resolve within a few days. Immune responses, both innate and adaptive, play a central role in controlling and eliminating virus-infected cells during the early stages of infection., Aim: To test the hypothesis that circulating T cells exhibit phenotypic and functional activation characteristics during the viremic phase of ZIKV infection., Methods: A comprehensive analysis using mass cytometry was performed on peripheral blood mononuclear cells obtained from patients with acute ZIKV infection (as confirmed by RT-PCR) and compared with that from healthy donors (HD). The frequency of IFN-γ-producing T cells in response to peptide pools covering immunogenic regions of structural and nonstructural ZIKV proteins was quantified using an ELISpot assay., Results: Circulating CD4+ and CD8+ T lymphocytes from ZIKV-infected patients expressed higher levels of IFN-γ and pSTAT-5, as well as cell surface markers associated with proliferation (Ki-67), activation ((HLA-DR, CD38) or exhaustion (PD1 and CTLA-4), compared to those from HD. Activation of CD4+ and CD8+ memory T cell subsets, including Transitional Memory T Cells (TTM), Effector Memory T cells (TEM), and Effector Memory T cells Re-expressing CD45RA (TEMRA), was prominent among CD4+ T cell subset of ZIKV-infected patients and was associated with increased levels of IFN-γ, pSTAT-5, Ki-67, CTLA-4, and PD1, as compared to HD. Additionally, approximately 30% of ZIKV-infected patients exhibited a T cell response primarily directed against the ZIKV NS5 protein., Conclusion: Circulating T lymphocytes spontaneously produce IFN-γ and express elevated levels of pSTAT-5 during the early phase of ZIKV infection whereas recognition of ZIKV antigen results in the generation of virus-specific IFN-γ-producing T cells., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Samri et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The very high-power short-duration (vHP-SD) ablation strategy is an alternative for pulmonary vein isolation (PVI) in patients with paroxysmal atrial fibrillation (PAF). However, the acute procedural biophysical behavior of successful lesion creation by means of this technique is still unexplored. We performed a retrospective case-control study aimed at evaluating the behavior of vHP-SD ablation parameters with the QDOT MICRO™ ablation catheter (Biosense Webster) compared with standard radiofrequency (RF) ablation with the THERMOCOOL SMARTTOUCH ® ablation catheter. Twenty consecutive cases of symptomatic PAF treated with the QDOT MICRO™ ablation catheter from December 2022 to March 2023 were compared with cases treated with the standard technique. The acute procedural success of PVI was obtained in all cases with 2192 RF applications, and no adverse events occurred. Compared with the controls, vHP-SD cases featured a significant reduction in procedural time (47 ± 10 vs. 56 ± 12 min, p = 0.023), total RF time (3.8 [CI 3.4-4.6] vs. 21.2 [CI 18.4-24.9] min, p < 0.001), ablation phase time (25 ± 5 vs. 39 ± 9 min, p < 0.001), and irrigation volume (165 [CI 139-185] vs. 404 [CI 336-472] ml, p < 0.001). In vHP-SD RF ablation, a contact force of 5 g minimum throughout the 4 s of RF application appeared to be statistically significant in terms of an impedance drop of at least 10 Ohm (OR 2.63 [CI 1.37; 5.07], p = 0.003). In contrast, in the control group, the impedance drop depended linearly on the contact force. This suggests a different biophysical behavior of vHP-SD ablation. A maximum temperature and minimum contact force of >5 g independently predicted an effective impedance drop in vHP-SD. Increasing the contact force over 5 g during 4 s of vHP RF application might not be necessary to achieve a successful lesion.

Background: The recommendation for transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR) in patients 65 to 80 years of age is equivocal, leaving patients with a difficult decision. We evaluated whether TAVR compared to SAVR is associated with reduced odds for loss of independent living in patients ≤65, 66 to 79, and ≥80 years of age. Further, we explored mechanisms of the association of TAVR and adverse discharge., Methods: Adult patients undergoing TAVR or SAVR within a large academic medical system who lived independently before the procedure were included. A multivariable logistic regression model, adjusting for a priori defined confounders including patient demographics, preoperative comorbidities, and a risk score for adverse discharge after cardiac surgery, was used to assess the primary association. We tested the interaction of patient age with the association between aortic valve replacement (AVR) procedure and loss of independent living. We further assessed whether the primary association was mediated (ie, percentage of the association that can be attributed to the mediator) by the procedural duration as prespecified mediator., Results: A total of 1751 patients (age median [quartiles; min-max], 76 [67, 84; 23-100]; sex, 56% female) were included. A total of 27% (222/812) of these patients undergoing SAVR and 20% (188/939) undergoing TAVR lost the ability to live independently. In our cohort, TAVR was associated with reduced odds for loss of independent living compared to SAVR (adjusted odds ratio [OR adj ] 0.19 [95% confidence interval {CI}, 0.14-0.26]; P < .001). This association was attenuated in patients ≤65 years of age (OR adj 0.63 [0.26-1.56]; P = .32) and between 66 and 79 years of age (OR adj 0.23 [0.15-0.35]; P < .001), and magnified in patients ≥80 years of age (OR adj 0.16 [0.10-0.25]; P < .001; P -for-interaction = .004). Among those >65 years of age, a shorter procedural duration mediated 50% (95% CI, 28-76; P < .001) of the beneficial association of TAVR and independent living., Conclusions: Patients >65 years of age undergoing TAVR compared to SAVR had reduced odds for loss of independent living. This association was partly mediated by shorter procedural duration. No association between AVR approach and the primary end point was found in patients ≤65 years of age., Competing Interests: Conflicts of Interest: See Disclosures at the end of this article., (Copyright © 2023 International Anesthesia Research Society.)

Aims: Intracardiac echocardiography (ICE) is a useful but operator-dependent tool for left atrial (LA) anatomical rendering during atrial fibrillation (AF) ablation. The CARTOSOUND FAM Module, a new deep learning (DL) imaging algorithm, has the potential to overcome this limitation. This study aims to evaluate feasibility of the algorithm compared to cardiac computed tomography (CT) in patients undergoing AF ablation., Methods and Results: In 28 patients undergoing AF ablation, baseline patient information was recorded, and three-dimensional (3D) shells of LA body and anatomical structures [LA appendage/left superior pulmonary vein/left inferior pulmonary vein/right superior pulmonary vein/right inferior pulmonary vein (RIPV)] were reconstructed using the DL algorithm. The selected ultrasound frames were gated to end-expiration and max LA volume. Ostial diameters of these structures and carina-to-carina distance between left and right pulmonary veins were measured and compared with CT measurements. Anatomical accuracy of the DL algorithm was evaluated by three independent electrophysiologists using a three-anchor scale for LA anatomical structures and a five-anchor scale for LA body. Ablation-related characteristics were summarized. The algorithm generated 3D reconstruction of LA anatomies, and two-dimensional contours overlaid on ultrasound input frames. Average calculation time for LA reconstruction was 65 s. Mean ostial diameters and carina-to-carina distance were all comparable to CT without statistical significance. Ostial diameters and carina-to-carina distance also showed moderate to high correlation (r = 0.52-0.75) except for RIPV (r = 0.20). Qualitative ratings showed good agreement without between-rater differences. Average procedure time was 143.7 ± 43.7 min, with average radiofrequency time 31.6 ± 10.2 min. All patients achieved ablation success, and no immediate complications were observed., Conclusion: DL algorithm integration with ICE demonstrated considerable accuracy compared to CT and qualitative physician assessment. The feasibility of ICE with this algorithm can potentially further streamline AF ablation workflow., Competing Interests: Conflict of interest: L.D.B. is a consultant for Stereotaxis, Biosense Webster, Boston Scientific, Abbott Medical; has received speaker honoraria/travel from Medtronic, Atricure, Biotronik, Baylis Medical, and Zoll. G.H., D.H., R.A.M., J.A., G.C., and R.U. are employees of Biosense Webster, Inc. The remaining authors report no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Several commercially available and newly synthesized riluzole analogs were evaluated in vitro as voltage-gated skeletal muscle sodium-channel blockers. Data obtained from the patch-clamp technique demonstrated that potency is well correlated with lipophilicity and the introduction of a protonatable amino function in the benzothiazole 2-position enhances the use-dependent behavior. The most interesting compound, the 2-piperazine analog of riluzole ( 14 ), although slightly less potent than the parent compound in the patch-clamp assay as well as in an in vitro model of myotonia, showed greater use-dependent Nav1.4 blocking activity. Docking studies allowed the identification of the key interactions that 14 makes with the amino acids of the local anesthetic binding site within the pore of the channel. The reported results pave the way for the identification of novel compounds useful in the treatment of cell excitability disorders., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

Introduction: Increasing evidence has shown that coronavirus disease 19 (COVID-19) severity is driven by a dysregulated immunological response. Previous studies have demonstrated that natural killer (NK) cell dysfunction underpins severe illness in COVID-19 patients, but have lacked an in-depth analysis of NK cell markers as a driver of death in the most critically ill patients., Methods: We enrolled 50 non-vaccinated hospitalized patients infected with the initial virus or the alpha variant of SARS-CoV-2 with moderate or severe illness, to evaluate phenotypic and functional features of NK cells., Results: Here, we show that, consistent with previous studies, evolution NK cells from COVID-19 patients are more activated, with the decreased activation of natural cytotoxicity receptors and impaired cytotoxicity and IFN-γ production, in association with disease regardless of the SARS-CoV-2 strain. Fatality was observed in 6 of 17 patients with severe disease; NK cells from all of these patients displayed a peculiar phenotype of an activated memory-like phenotype associated with massive TNF-α production., Discussion: These data suggest that fatal COVID-19 infection is driven by an uncoordinated inflammatory response in part mediated by a specific subset of activated NK cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tarantino, Litvinova, Samri, Soulié, Morin, Rousseau, Dorgham, Parizot, Bonduelle, Beurton, Miyara, Ghillani, Mayaux, Lhote, Lacorte, Marcelin, Amoura, Luyt, Gorochov, Guihot and Vieillard.)

The brief symptom inventory (BSI), a 53-item measure that assesses psychological distress, is a popular tool for measuring mental health symptoms among youth living with HIV (YLH) in the United States (US); however, it has been used inconsistently with this population. This scoping review summarizes discrepancies in the use of the BSI to identify opportunities to improve systematism and make recommendations for clinicians and researchers, and highlights correlates of psychological distress among YLH as measured by the BSI. Databases searched included PsycINFO, PubMed, and CENTRAL. Eligible studies that assessed psychological distress using the BSI among YLH, were conducted in the US, and were written in English. Of the 237 articles identified, 57 were selected for inclusion. Studies investigated associations between BSI scores and several variables, including pre- versus post-highly active antiretroviral therapy (ART) era, ART adherence, sexual risk behavior, substance use, stigma, social support, self-efficacy, mode of HIV infection, and sexual orientation. There was variation in BSI elements used as outcome measures, sample age ranges, and reporting of mean scores and cutoff t-scores. 89.5% (n = 51) of studies did not report which BSI norms were used in their data analysis, and 68.4% of studies (n = 39) did not report the cut-off t-score value used. Variability in study objectives restricted this study to a scoping review rather than a meta-analysis. Generalizability to non-US settings is another limitation. More consistency in how the BSI is used among YLH is needed to accurately identify distress among YLH and provide tailored interventions to address their unique challenges., (Copyright: © 2023 Permanyer.)

Skeletal muscle tissue has the important function of supporting and defending the organism. It is the largest apparatus in the human body, and its function is important for contraction and movements. In addition, it is involved in the regulation of protein synthesis and degradation. In fact, inhibition of protein synthesis and/or activation of catabolism determines a pathological condition called muscle atrophy. Muscle atrophy is a reduction in muscle mass resulting in a partial or complete loss of function. It has been established that many physiopathological conditions can cause a reduction in muscle mass. Nevertheless, it is not well known the molecular mechanisms and signaling processes causing this dramatic event. There are multiple concomitant processes involved in muscle atrophy. In fact, the gene transcription of some factors, oxidative stress mechanisms, and the alteration of ion transport through specific ion channels may contribute to muscle function impairment. In this review, we focused on the molecular mechanisms responsible for muscle damage and potential drugs to be used to alleviate this disabling condition.

The COVID-19 pandemic has occurred due to infection caused by the SARS-CoV-2 coronavirus, which impacts gestation and pregnancy. In SARS-CoV-2 infection, only very rare cases of vertical transmission have been reported, suggesting that fetal immune imprinting due to a maternal infection is probably a result of changes in maternal immunity. Natural killer (NK) cells are the leading maternal immune cells that act as a natural defense system to fight infections. They also play a pivotal role in the establishment and maintenance of pregnancy. While peripheral NK cells display specific features in patients infected with SARS-CoV-2 in the general population, information remains elusive in pregnant mothers and neonates. In the present study, we analyzed the characteristics of NK cells isolated from both neonatal umbilical cord blood and maternal peripheral blood close to the time of delivery. Phenotype and functions were compared in 18 healthy pregnant women and 34 COVID-19 patients during pregnancy within an ongoing infection (PCR + ; N = 15) or after recovery (IgG + PCR - ; N = 19). The frequency of NK cells from infected women and their neonates was correlated with the production of inflammatory cytokines in the serum. The expression of NKG2A and NKp30, as well as degranulation of NK cells in pregnant women with ongoing infection, were both negatively correlated to estradiol level. Furthermore, NK cells from the neonates born to infected women were significantly decreased and also correlated to estradiol level. This study highlights the relationship between NK cells, inflammation, and estradiol in patients with ongoing infection, providing new insights into the impact of maternal SARS-CoV-2 infection on the neonate., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Carbonnel, Daclin, Tarantino, Groiseau, Morin, Rousseau, Vasse, Hertig, Kennel, Ayoubi and Vieillard.)

Young people living with HIV (YPLH) are at risk for poor treatment adherence. Short message service (SMS) interventions can improve adherence, yet few exist for YPLH. Our study investigated preferences for a game-based SMS intervention among YPLH in Ghana. Thirty-two YPLH, ages 18 to 24, were recruited from an HIV clinic to complete in-depth interviews. Content analysis of interview data revealed areas of technology use relevant to intervention implementation, including mobile communication preferences, internet access, and mobile game use. Participants reported high perceived utility towards intervention features: treatment reminders, gamification components, and involvement of supportive individuals (e.g., providers). Issues with privacy, literacy, and cultural/developmental appropriateness were among concerns raised. Suggestions were made for strengthening basic SMS features (e.g., using code words to protect privacy) and incorporating advanced features (e.g., simplifying game interactions). This novel approach may help engage YPLH in HIV care if carefully developed with attention towards its mechanisms and user preferences., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Although antiretroviral therapy (ART) has changed the expected health outcomes for HIV, there are still issues related to stigma, how people living with HIV are perceived, and the availability of social support. The purpose of this study was to explore the associations between family structure and psychosocial wellbeing reflected by perceived HIV stigma and social support among adolescents living with HIV in Kumasi, Ghana. This article used baseline data from two mixed methods studies that evaluated the safety and preliminary efficacy of group-based support programs for ART adherence improvement among adolescents living in Kumasi, Ghana ( N = 70, aged 12-18 years). A multivariate linear regression analysis was employed to examine the associations between family structure and the outcomes of stigma and social support. The main variables for family structure were single mothers and female caregivers. We found that single motherhood was a significant determinant of stigma. When compared to other categories of caregiver types, adolescents being raised by their single mothers was associated with a 0.259 decrease in the mean internal HIV stigma score ( p = 0.029). Also, for female adolescents, being raised by a female guardian (e.g., mother, aunt, grandmother, and sister) was associated with a 20.92 point increase in the overall support index ( p = 0.005). This study shows that the type of parent or guardian, and their gender, influences the perceived stigma and available social support among adolescents living with HIV in Ghana. Vulnerable subgroups of adolescents living with HIV, particularly those raised up by male caregivers, should be provided with additional support., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wowolo, Cao, Bosomtwe, Enimil, Tarantino, Barker and Galárraga.)

We review the current data on epidemiology, the clinical significance, the pathophysiologic mechanisms, and the treatment of VAs in the setting of COVID-19. VAs prevail in 0.15% to 8% of hospitalized patients, but only sustained and rapid tachyarrhythmias are purportedly associated with a significant increase in mortality. Multiple factors can elicit VAs, which are ultimately deemed to be a marker of severe systemic disease rather than a distinct cardiac condition. Even though the electrophysiologist plays a determinant role in the secondary prevention of VAs, a multidisciplinary approach is indispensable for primary prophylaxis and acute management., Competing Interests: Disclosure Dr A. Natale has received speaker honoraria from Boston Scientific, Biosense Webster, St. Jude Medical, Biotronik, and Medtronic; and is a consultant for Biosense Webster, St. Jude Medical, and Janssen. Dr L. Di Biase is a consultant for Biosense Webster, RMG, Stereotaxis, Boston Scientific, and Abbott. Dr L. Di Biase received speaker honoraria/travel from Medtronic, Atricure, and Biotronik. All other authors have reported that they have no relationships relevant to the contents of this article to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Amyotrophic Lateral Sclerosis is a neurodegenerative disease caused by progressive loss of motor neurons, which severely compromises skeletal muscle function. Evidence shows that muscle may act as a molecular powerhouse, whose final signals generate in patients a progressive loss of voluntary muscle function and weakness leading to paralysis. This pathology is the result of a complex cascade of events that involves a crosstalk among motor neurons, glia, and muscles, and evolves through the action of converging toxic mechanisms. In fact, mitochondrial dysfunction, which leads to oxidative stress, is one of the mechanisms causing cell death. It is a common denominator for the two existing forms of the disease: sporadic and familial. Other factors include excitotoxicity, inflammation, and protein aggregation. Currently, there are limited cures. The only approved drug for therapy is riluzole, that modestly prolongs survival, with edaravone now waiting for new clinical trial aimed to clarify its efficacy. Thus, there is a need of effective treatments to reverse the damage in this devastating pathology. Many drugs have been already tested in clinical trials and are currently under investigation. This review summarizes the already tested drugs aimed at restoring muscle-nerve cross-talk and on new treatment options targeting this tissue.

Aims: We evaluated the efficacy of an ablation strategy empirically targeting pulmonary veins (PVs) and posterior wall (PW) and the prevalence and clinical impact of extrapulmonary trigger inducibility and ablation in a large cohort of patients with persistent atrial fibrillation (PerAF)., Methods and Results: A total of 1803 PerAF patients were prospectively enrolled. All patients underwent pulmonary vein antrum isolation (PVAI) extended to the entire PW. A standardized protocol was performed to confirm persistent PVAI and elicit any triggers originating from non-PV sites. All non-PV triggers initiating sustained atrial tachyarrhythmias were ablated. Ablation of non-PV sites triggering non-sustained runs (<30 s) of atrial tachyarrhythmias or promoting frequent premature atrial complexes (≥10/min) was left to operator's discretion. Overall, 1319 (73.2%) patients had documented triggers from non-PV areas. After 17.4 ± 8.5 months of follow-up, the cumulative freedom from atrial tachyarrhythmias among patients without inducible non-PV triggers (n = 484) was 70.2%. Patients with ablation of induced non-PV triggers had a significantly higher arrhythmia control than those whose triggers were not ablated (67.9% vs. 39.4%, respectively; P < 0.001). After adjusting for clinically relevant variables, patients in whom non-PV triggers were documented but not ablated had an increased risk of arrhythmia relapse (hazard ratio: 2.39; 95% confidence interval: 2.01-2.83; P < 0.001)., Conclusion: Pulmonary vein antrum isolation extended to the entire PW might provide acceptable long-term arrhythmia-free survival in PerAF patients without inducible non-PV triggers. In our population of PerAF patients, non-PV triggers could be elicited in ∼70% of PerAF patients and their elimination significantly improved outcomes., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Objectives: This study sought to report the incidence of device-related thrombosis (DRT) and thromboembolic (TE) events when an alternative to clopidogrel is prescribed in loss-of-function (LOF) allele carriers of the cytochrome P450 2C19 (CYP2C19) gene., Background: LOF polymorphisms of the CYP2C19 gene are associated with reduced hepatic bioactivation of clopidogrel., Methods: A total of 1,002 Watchman patients were included. Six hundred forty-five patients underwent CYP2C19 genetic testing; among patients with clopidogrel resistance, clopidogrel was replaced by either prasugrel (pilot cohort) or half dose direct oral anticoagulant ([DOAC]/Group 1), both in combination with aspirin. We compared the incidence of DRT/TE events among genotyped patients and a control group which received standard dual antiplatelet therapy (DAPT) (Group 2; n = 357). All reported events occurred during a timeframe between 45- and 180-day follow-up transesophageal echocardiograms, when the 2 different antithrombotic strategies (genotype-guided vs standard DAPT) were adopted., Results: In the pilot cohort (n = 244), bleeding events occurred in 10.2% of patients who received aspirin plus prasugrel, leading to early discontinuation of the prasugrel-based protocol. DOAC Group 1 patients (n = 401), 25.7% were reduced metabolizers, and clopidogrel was replaced by half dose direct oral anticoagulant. DRT was documented in 1 (0.2%) patient of Group 1 and 7 (1.96%) patients of Group 2 (log-rank P = 0.021). The composite endpoint of DRT/TE events was significantly lower among patients receiving a genotype-guided antithrombotic strategy (0.75% vs 3.10%; log-rank P = 0.017)., Conclusions: In Watchman patients, a genotype-based antithrombotic strategy with aspirin plus half dose DOAC in reduced clopidogrel metabolizers was superior to standard DAPT with respect to DRT/TE events., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021. Published by Elsevier Inc.)

Objectives: The aim of this study was to evaluate the efficacy of radiofrequency (RF) energy applications targeting the atrial side of a significant residual leak in patients with acute and chronic evidence of incomplete percutaneous left atrial appendage (LAA) occlusion., Background: RF applications have been proved to prevent recanalization of intracranial aneurysms after coil embolization, thereby favoring complete sealing. From a mechanistic standpoint, in vitro and in vivo experiments have demonstrated that RF promotes collagen deposition and tissue retraction., Methods: Forty-three patients (mean age 75 ± 7 years mean CHA 2 DS 2 -VASc score 4.6 ± 1.4, mean HAS-BLED score 4.0 ± 1.1) with residual leaks ≥4 mm after Watchman implantation were enrolled. Procedural success was defined as complete LAA occlusion or presence of a mild or minimal (1- to 2-mm) peridevice leak on follow-up transesophageal echocardiography (TEE), which was performed approximately 45 days after the procedure., Results: RF-based leak closure was performed acutely after Watchman implantation in 19 patients (44.2%) or scheduled after evidence of significant leaks on follow-up TEE in 24 others (55.8%). The median leak size was 5 mm (range: 4-7 mm). On average, 18 ± 7 RF applications per patient (mean maximum contact force 16 ± 3 g, mean power 44 ± 2 W, mean RF time 5.1 ± 2.5 minutes) were performed targeting the atrial edge of the leak. Post-RF median leak size was 0 mm (range: 0-1 mm). A very low rate (2.3% [n = 1]) of major periprocedural complications was observed. Follow-up TEE revealed complete LAA sealing in 23 patients (53.5%) and negligible residual leaks in 15 (34.9%)., Conclusions: RF applications targeting the atrial edge of a significant peri-Watchman leak may promote LAA sealing via tissue remodeling, without increasing complications. (RF Applications for Residual LAA Leaks [REACT]; NCT04726943)., Competing Interests: Funding Support and Author Disclosures Dr Burkhardt is a consultant for Biosense Webster and Stereotaxis. Dr Di Biase is a consultant for Biosense Webster, Boston Scientific, Stereotaxis, and St. Jude Medical; and has received speaker honoraria from Medtronic, Atricure, EPiEP, and Biotronik. Dr Natale has received speaker honoraria from Abbott, Biosense Webster, Boston Scientific, Biotronik, Baylis, Medtronic; and is a consultant for Biosense Webster, St. Jude Medical, and Janssen. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021. Published by Elsevier Inc.)

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

Purpose: First-line catheter ablation of ventricular tachycardia/ventricular fibrillation (VT/VF) in patients with ischemic cardiomyopathy (ICM) has been associated with improved outcomes; however, most benefit seems to be in patients with moderately depressed left ventricular ejection fraction (LVEF). Herein, outcomes were stratified based on LVEF., Methods: A meta-analysis of randomized controlled trials (RCTs) evaluating first-line ablation versus medical therapy in patients with VT and ICM was performed. Risk estimates and 95% confidence intervals (CI) were measured., Results: Four RCTs with a total of 505 patients (mean age 66 ± 9 years, 89% male, 80% with previous revascularization) were included. Mean LVEF was 35 ± 8%. At a mean follow-up of 24 ± 9 months, a significant benefit in survival-free from appropriate implantable cardioverter-defibrillator (ICD) therapies was observed in all patients undergoing first-line catheter ablation compared with medical management (RR 0.70, 95% CI 0.56-0.86). In patients with moderately depressed LVEF (> 30-50%), first-line VT ablation was associated with a statistically significant reduction in the composite endpoint of survival free from VT/VF and appropriate ICD therapies (HR 0.52, 95% CI 0.36-0.76), whereas there was no difference in patients with severely depressed LVEF (≤30%) (HR 0.56, 95% CI 0.24-1.32). Funnel plots did not show asymmetry suggesting lack of bias., Conclusions: Patients with ICM and VT undergoing first-line ablation have a significantly lower rate of appropriate ICD therapies without a mortality difference compared with patients receiving an initial approach based on medical therapy. The beneficial effect of a first-line ablation approach was only observed in patients with moderately depressed LVEF (> 30-50%)., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Associations between sexual risk behavior (SRB) and sexual violence perpetration (SVP) contribute to the intersecting HIV and sexual violence epidemics in South Africa. We examined SVP and SRB, and their potential correlates among South African boys (N = 80; ages 15-17). Fifty-one percent endorsed SVP in the past year; 61% engaged in past-3-month SRB. Whereas most unique correlates were socio-structural, family, or community factors, correlates shared across behaviors were behavior-specific social norm perceptions and cognitive factors. In final multivariate models, food insecurity and positive attitudes toward delaying sex were associated with SVP (odds ratios [ORs] = 3.05 and 0.37, respectively), and community violence exposure, gender equitable social norm perceptions, positive attitudes toward delaying sex, and intentions to obtain sexual consent were associated with SRBs (ORs = 1.56-1.57, 0.90-0.38, 0.58-0.60, respectively). Interventions to address HIV/sexual violence risk among adolescents in South Africa should be integrated and multilevel.