Adherent skin barrier drape use is associated with a reduced risk of cardiac implantable device infection: Results from a prospective study of 14,225 procedures.

Background: Cardiac implantable electronic device (CIED) infection is a costly and highly morbid complication. Perioperative interventions, including the use of antibiotic pouches and intensified perioperative antibiotic regimens, have demonstrated marginal efficacy at reducing CIED infection. Additional research is needed to identify additional interventions to reduce infection risk. Objective: We sought to evaluate whether adherent skin barrier drape use is associated with a reduction in CIED infection. Methods: A prospective registry of all CIED implantation procedures was established at our institution in January 2007. The registry was established in collaboration with our hospital infection prevention team with a specific focus on prospectively identifying all potential CIED infections. All potential CIED infections were independently adjudicated by 2 physicians blinded to the use of an adherent skin barrier drape. Results: Over a 13-year period, 14,225 procedures were completed (mean age 72 ± 14 years; female 4,918 (35%); new implants 10,005 (70%); pulse generator changes 2585 (18%); upgrades 1635 (11%). Of those, 2469 procedures (17.4%) were performed using an adherent skin barrier drape. There were 103 adjudicated device infections (0.73%). The infection rate in patients in the barrier use groups was 8 of 2469 (0.32%) as compared with 95 of 11,756 (0.8%) in the nonuse group (P = .0084). In multivariable analysis, the use of an adherent skin barrier drape was independently associated with a reduction in infection (odds ratio 0.32; 95% confidence interval 0.154-0.665; P = .002). Conclusion: The use of an adherent skin barrier drape at the time of cardiac device surgery is associated with a lower risk of subsequent infection.

The lysosomal ß-glucocerebrosidase strikes mitochondria: implications for Parkinson's therapeutics.

Parkinson's disease (PD) is a neurodegenerative disorder primarily known for typical motor features that arise due to the loss of dopaminergic neurons in the substantia nigra. However, the precise molecular etiology of the disease is still unclear. Several cellular pathways have been linked to PD, including the autophagy-lysosome pathway (ALP), α-synuclein (α-syn) aggregation, and mitochondrial function. Interestingly, the mechanistic link between GBA1, the gene that encodes for lysosomal ß-glucocerebrosidase (GCase), and PD lies in the interplay between GCase functions in the lysosome and mitochondria. GCase mutations alter mitochondria-lysosome contact sites. In the lysosome, reduced GCase activity leads to glycosphingolipid buildup, disrupting lysosomal function and autophagy, thereby triggering α-syn accumulation. Additionally, α-syn aggregates reduce GCase activity, creating a self-perpetuating cycle of lysosomal dysfunction and α-syn accumulation. GCase can also be imported into the mitochondria, where it promotes the integrity and function of mitochondrial complex I. Thus, GCase mutations that impair its normal function increase oxidative stress in mitochondria, the compartment where dopamine is oxidized. In turn, the accumulation of oxidized dopamine-adducts further impairs GCase activity, creating a second cycle of GCase dysfunction. The oxidative state triggered by GCase dysfunction can also induce mitochondrial DNA damage which, in turn, can cause dopaminergic cell death. In this review, we highlight the pivotal role of GCase in PD pathogenesis and discuss promising examples of GCase-based therapeutics such as gene and enzyme replacement therapies, small molecule chaperones, and substrate reduction therapies, among others, as potential therapeutic interventions.

Do barrier dressings reduce cardiac implantable device infection: Protocol for a randomized controlled trial (BARRIER-PROTECT).

Background: Cardiac implantable electronic device (CIED) procedures can be associated with serious complications, including infection with significant mortality and morbidity, necessitating removal of the device and prolonged hospitalization. One potential pathophysiological mechanism is pocket contamination at the time of device implantation. Therefore, steps taken to prevent contamination at this stage can potentially reduce CIED infections.The barrier dressing, an adhesive material applied to the skin, has the potential to reduce the colonization of the surgical site with host flora that can predispose to infection. There are a limited number of randomized prospective studies on barrier dressing use during various surgeries, but it has never been systematically studied in CIED implantation. Objectives: Do Barrier Dressings Reduce Cardiac Implantable Device Infection? (BARRIER-PROTECT trial; NCT04591366) is a single-centre, prospective, double-armed, single-blinded, randomized controlled trial designed to evaluate the use of an intra-operative adhesive barrier dressing to reduce the risk of end-of-procedure pocket swab positivity. We hypothesize that adhesive draping during implant procedures will reduce the risk of contamination from the skin flora. Also, we aim to investigate if the end-of-procedure pocket swab culture positivity can be used as a potential surrogate marker of CIED infection. Methods and Design: Patients undergoing a second or later procedure on the same device pocket (pulse generator change, lead/pocket revision or upgrade) will be enrolled. Eligible and consenting patients will be equally randomized to the use of barrier dressing or not using an automated web-based system. Patients, but not the operator, will be blinded to the arm. The person performing the pocket swabs will also be blinded. The primary endpoint is the end-of-procedure pocket swab culture positivity. The main secondary endpoint is the CIED infection rate. Discussion: This is the first randomized controlled trial to assess the effectiveness of using a barrier adhesive draping on reducing the end-of-procedure pocket swab culture positivity. In this study, we are exploring a low-cost intervention that may significantly reduce CIED infection. Also, having a valid surrogate marker for CIED infection at the time of implant will facilitate design of future clinical trials.

Understanding the phenotypic variability in Niemann-Pick disease type C (NPC): a need for precision medicine.

Niemann-Pick type C (NPC) disease is a lysosomal storage disease (LSD) characterized by the buildup of endo-lysosomal cholesterol and glycosphingolipids due to loss of function mutations in the NPC1 and NPC2 genes. NPC patients can present with a broad phenotypic spectrum, with differences at the age of onset, rate of progression, severity, organs involved, effects on the central nervous system, and even response to pharmacological treatments. This article reviews the phenotypic variation of NPC and discusses its possible causes, such as the remaining function of the defective protein, modifier genes, sex, environmental cues, and splicing factors, among others. We propose that these factors should be considered when designing or repurposing treatments for this disease. Despite its seeming complexity, this proposition is not far-fetched, considering the expanding interest in precision medicine and easier access to multi-omics technologies.

Incidence of Atrial Fibrillation as the Initial Manifestation of Cardiac Sarcoidosis: Insights From a Catheter Ablation Registry.

Background: Cardiac sarcoidosis (CS) is a rare form of arrhythmogenic cardiomyopathy; a delayed diagnosis can lead to significant consequences. Patients with clinically manifest CS often have minimal extracardiac involvement and thus frequently present initially to cardiology. Indeed, certain specific arrhythmic scenarios should trigger investigations for undiagnosed CS. Atrial fibrillation (AF) has been described as one of the presenting features of CS; however, the incidence of this presentation is not known. Methods: At our institution, cardiac computerized tomography is routinely performed prior to catheter ablation for AF. Noncardiac incidental findings are described by radiologists and are followed-up by interval investigations. We systematically reviewed noncardiac reports from 1574 consecutive patients in our prospective AF ablation registry. Specifically, we used text-scraping techniques to search on the following keywords: "adenopathy" and "sarcoidosis." Detailed chart review of identified cases was then performed to evaluate results of interval investigations and assess long-term outcomes. Results: Twenty of 1574 patients (1.3%) had noncardiac reports containing "adenopathy" and/or "sarcoidosis." After interval imaging and a follow-up period averaging 60 ± 35 months, only 2 patients of 1574 (0.13%) were diagnosed with CS. Four of 20 (20%) had a previous history of extracardiac sarcoidosis, and another 1 of 20 (5%) was subsequently diagnosed with extracardiac sarcoidosis. However, none of these 5 patients had evidence of cardiac involvement. Conclusions: CS is a rare finding among patients undergoing a first-time AF ablation. Our findings suggest that AF is an uncommon initial presentation of CS. Thus, investigations for CS in patients with AF are not warranted routinely, unless additional suggestive clinical features are present.

Contexte: La sarcoïdose cardiaque (SC) est une forme rare de cardiomyopathie arythmogène; un retard dans le diagnostic peut entraîner d'importantes conséquences. Les patients qui présentent une SC cliniquement manifeste ont souvent une atteinte extracardiaque minime, et consultent donc souvent d'abord en cardiologie. En effet, certains scénarios arythmiques précis devraient déclencher la recherche de signes d'une SC non diagnostiquée. La fibrillation auriculaire (FA) a été décrite comme un signe indicateur de SC; on ne connaît toutefois pas l'incidence de ce signe. Méthodologie: Dans notre établissement, la tomodensitométrie cardiaque est souvent réalisée avant une ablation par cathéter de la FA. Les découvertes non cardiaques fortuites sont décrites par les radiologues, puis font l'objet d'un suivi par des examens d'imagerie réalisés à intervalles déterminés. Nous avons systématiquement évalué les éléments non cardiaques signalés chez 1 574 patients consécutifs dans notre registre prospectif sur l'ablation de la FA. Nous avons utilisé des techniques de dépouillement du texte pour trouver les mots-clés suivants : « adenopathy ¼ (adénopathie) et « sarcoidosis ¼ (sarcoïdose). Un examen du dossier médical complet des cas retenus a été réalisé pour évaluer les résultats des examens de suivi et évaluer les résultats à long terme. Résultats: Parmi les 1 574 patients, 20 (1,3 %) présentaient des notes non cardiaques contenant les termes « adenopahy ¼ (adénopathie) ou « sarcoidosis ¼ (sarcoïdose). Après l'examen d'imagerie et une période de suivi d'une durée moyenne de 60 ±35 mois, seuls deux patients (0,13 %) ont reçu un diagnostic de SC. Quatre des 20 patients visés (20 %) présentaient des antécédents de sarcoïdose extracardiaque, et un patient sur 20 (5 %) a reçu un diagnostic de sarcoïdose extracardiaque à la suite de l'intervention. Toutefois, aucun de ces cinq patients ne montrait de signes d'atteinte cardiaque. Conclusions: La SC est une occurrence rare chez les patients qui subissent une première ablation de la FA. Nos constats indiquent que la FA est une présentation initiale peu commune de la SC. Aussi, la recherche de la SC chez les patients atteints de FA n'est pas justifiée dans une procédure de routine, à moins que d'autres caractéristiques cliniques pointant vers cette affection ne soient présentes.

A Mouse Systems Genetics Approach Reveals Common and Uncommon Genetic Modifiers of Hepatic Lysosomal Enzyme Activities and Glycosphingolipids.

Identification of genetic modulators of lysosomal enzyme activities and glycosphingolipids (GSLs) may facilitate the development of therapeutics for diseases in which they participate, including Lysosomal Storage Disorders (LSDs). To this end, we used a systems genetics approach: we measured 11 hepatic lysosomal enzymes and many of their natural substrates (GSLs), followed by modifier gene mapping by GWAS and transcriptomics associations in a panel of inbred strains. Unexpectedly, most GSLs showed no association between their levels and the enzyme activity that catabolizes them. Genomic mapping identified 30 shared predicted modifier genes between the enzymes and GSLs, which are clustered in three pathways and are associated with other diseases. Surprisingly, they are regulated by ten common transcription factors, and their majority by miRNA-340p. In conclusion, we have identified novel regulators of GSL metabolism, which may serve as therapeutic targets for LSDs and may suggest the involvement of GSL metabolism in other pathologies.

Standard vs Augmented Ablation of Paroxysmal Atrial Fibrillation for Reduction of Atrial Fibrillation Recurrence: The AWARE Randomized Clinical Trial.

Importance: Recurrent atrial fibrillation (AF) commonly occurs after catheter ablation and is associated with patient morbidity and health care costs. Objective: To evaluate the superiority of an augmented double wide-area circumferential ablation (WACA) compared with a standard single WACA in preventing recurrent atrial arrhythmias (AA) (atrial tachycardia, atrial flutter, or atrial fibrillation [AF]) in patients with paroxysmal AF. Design, Setting, and Participants: This was a pragmatic, multicenter, prospective, randomized, open, blinded end point superiority clinical trial conducted at 10 university-affiliated centers in Canada. The trial enrolled patients 18 years and older with symptomatic paroxysmal AF from March 2015 to May 2017. Analysis took place between January and April 2022. Analyses were intention to treat. Interventions: Patients were randomized (1:1) to receive radiofrequency catheter ablation for pulmonary vein isolation with either a standard single WACA or an augmented double WACA. Main Outcomes and Measures: The primary outcome was AA recurrence between 91 and 365 days postablation. Patients underwent 42 days of ambulatory electrocardiography monitoring after ablation. Secondary outcomes included need for repeated catheter ablation and procedural and safety variables. Results: Of 398 patients, 195 were randomized to the single WACA (control) arm (mean [SD] age, 60.6 [9.3] years; 65 [33.3%] female) and 203 to the double WACA (experimental) arm (mean [SD] age, 61.5 [9.3] years; 66 [32.5%] female). Overall, 52 patients (26.7%) in the single WACA arm and 50 patients (24.6%) in the double WACA arm had recurrent AA at 1 year (relative risk, 0.92; 95% CI, 0.66-1.29; P = .64). Twenty patients (10.3%) in the single WACA arm and 15 patients (7.4%) in the double WACA arm underwent repeated catheter ablation (relative risk, 0.72; 95% CI, 0.38-1.36). Adjudicated serious adverse events occurred in 13 patients (6.7%) in the single WACA arm and 14 patients (6.9%) in the double WACA arm. Conclusions and Relevance: In this randomized clinical trial of patients with paroxysmal AF, additional ablation by performing a double ablation lesion set did not result in improved freedom from recurrent AA compared with a standard single ablation set. Trial Registration: ClinicalTrials.gov Identifier: NCT02150902.

A Randomized Trial of Lenient Versus Strict Arm Instruction Post Cardiac Device Surgery (LENIENT).

BACKGROUND: Arm restriction after cardiac implantable electronic device (CIED) placement is common practice despite minimal supporting evidence. Patients receive a range of restriction recommendations of variable durations with the goal of reducing complications such as wound dehiscence, infection, lead dislodgement, or hematoma formation. These movement limitations can lead to emotional stress and anxiety, complications such as frozen shoulder, and upper extremity venous thrombosis due to immobilization. There are no published clinical trials assessing the benefits and risks of arm restrictions post-CIED implant. OBJECTIVES: The randomized trial of lenient vs strict arm and activity instruction post-CIED surgery (LENIENT trial; NCT04915261) is a single center nonblinded randomized prospective study designed to evaluate lenient compared to restrictive post-CIED care instructions. We hypothesize that there will be no significant difference in complications between the arms. METHODS/DESIGN: All patients receiving a de novo CIED or those with upgrades and revisions requiring a new lead implant will be enrolled. Subjects are enrolled in a nonblinded randomized prospective trial with 6 randomly assigned 8-month periods, during which either a lenient or restrictive postoperative activity instructions will be given to all patients. Postoperative instructions are given at the time of discharge and further reinforced by recurrent interactive voice recognition (IVR) phone calls, text messages and emails. The requirement for individual consent has been waived. The primary end point is a composite of (1) lead dislodgement, (2) frozen shoulder, (3) upper extremity venous thrombosis, (4) clinically significant hematoma, and (5) infection occurring within 52 weeks of index surgery. The study is a noninferiority trial with a sample size of 1,250 per group. DISCUSSION: This is the first large randomized clinical trial designed to establish an evidence-based postoperative standard of care for patients undergoing CIED implantation. This will improve the quality of care provided to patients and help guide implanting physicians providing postoperative care instructions. TRIAL REGISTRATION: ClinicalTrials.gov NCT04915261.

Genetic Background Matters: Population-Based Studies in Model Organisms for Translational Research.

We are all similar but a bit different. These differences are partially due to variations in our genomes and are related to the heterogeneity of symptoms and responses to treatments that patients exhibit. Most animal studies are performed in one single strain with one manipulation. However, due to the lack of variability, therapies are not always reproducible when treatments are translated to humans. Panels of already sequenced organisms are valuable tools for mimicking human phenotypic heterogeneities and gene mapping. This review summarizes the current knowledge of mouse, fly, and yeast panels with insightful applications for translational research.

Rhythm-Monitoring Strategy and Arrhythmia Recurrence in Atrial Fibrillation Ablation Trials: A Systematic Review.

Background: : The rhythm-monitoring strategy after catheter ablation (CA) for atrial fibrillation (AF) impacts the detection of atrial arrhythmia recurrence and is not well characterized. We performed a systematic review and meta-regression analysis to determine whether the duration and mode of rhythm monitoring after CA affects detection of atrial arrhythmia recurrence. Methods: Databases were systematically searched for randomized controlled trials of adult patients undergoing first CA for AF from 2007 to 2021. Duration and strategy of rhythm monitoring were extracted. Meta-regression was used to identify any association between duration of monitoring and detection of atrial arrhythmia recurrence. The primary measure of outcome was single-procedure recurrence of atrial arrhythmia. Results: The search strategy yielded 57 trial arms from 56 randomized controlled trials comprising 5322 patients: 36 arms of patients with paroxysmal AF (PAF), and 21 arms of patients with persistent AF (PeAF) or both PAF/PeAF. Intermittent monitoring was associated with detection of significantly less atrial arrhythmia recurrence than continuous monitoring in PAF arms (31.2% vs 46.9%, P = 0.001), but not in PeAF/PAF-PeAF combined arms (43.3% vs 63.6%, P = 0.12). No significant relationship was seen between the duration of intermittent rhythm monitoring and atrial arrhythmia recurrence detection in either the PAF (P = 0.93) or PeAF/PAF-PeAF combined arms (P = 0.20). Conclusions: Continuous rhythm monitoring detected higher atrial arrhythmia recurrence rates, compared to intermittent rhythm monitoring, in patients with PAF. The duration of intermittent monitoring did not show a statistically significant relationship to the yield of arrhythmia detection, in near identical cohorts of trial subjects undergoing similar interventions, with clinical and research implications.

Contexte: La stratégie qui consiste à surveiller le rythme cardiaque après une ablation par cathéter dans le traitement de la fibrillation auriculaire (FA) a un effet sur la détection de récidive de l'arythmie auriculaire, mais elle n'est pas bien définie. Nous avons mené une revue systématique et une méta-régression pour déterminer si le mode employé pour surveiller le rythme après une ablation par cathéter et la durée de cette surveillance ont un effet sur la détection de récidive de l'arythmie auriculaire. Méthodologie: Des bases de données ont été systématiquement épluchées à la recherche d'essais contrôlés randomisés menés auprès d'adultes subissant leur première ablation par cathéter pour une FA entre 2007 et 2021. La durée et la stratégie utilisées dans la surveillance du rythme ont été recensées. La méta-régression a été utilisée pour déceler tout lien entre la durée de la surveillance et la détection d'une récidive de l'arythmie auriculaire. Le paramètre d'évaluation principal était la récidive de l'arythmie auriculaire avec une seule intervention. Résultats: La stratégie de recherche a fait ressortir 57 groupes de 56 essais contrôlés randomisés comprenant 5 322 patients : 36 groupes de patients présentant une FA paroxystique et 21 groupes de patients présentant une FA persistante ou ces deux types de FA (paroxystique et persistante). La surveillance intermittente a été associée à une moins grande détection de cas d'arythmie auriculaire récidivante, comparativement à la surveillance constante (31,2 % vs 46,9 %, p = 0,001), ce qui n'a pas été le cas dans les groupes où les types de FA (persistante ou paroxystique et persistante) étaient combinés (43,3 % vs 63,6 %, p = 0,12). Aucun lien notable n'a été observé entre la durée de la surveillance intermittente du rythme et la détection de l'arythmie auriculaire récidivante dans le groupe FA paroxystique (p = 0,93) ou dans le groupe des types de FA combinés (p = 0,20). Conclusions: Le taux de détection de l'arythmie auriculaire récidivante était plus élevé avec la surveillance constante qu'avec la surveillance intermittente chez les patients atteints de FA paroxystique. La durée de la surveillance intermittente n'a pas eu de lien statistiquement significatif avec le rendement de détection de l'arythmie, dans des cohortes presque identiques de participants aux essais subissant des interventions similaires, comportant des implications cliniques ou expérimentales.

Should they stay, or should they go: Do we need to remove the old cardiac implantable electronic device if a new system is required on the contralateral side?

Background: Ipsilateral approach in patients requiring cardiac implantable electronic device (CIED) revision or upgrade may not be feasible, primarily due to vascular occlusion. If a new CIED is implanted on the contralateral side, a common practice is to explant the old CIED to avoid device interaction. Objective: The purpose of this study was to assess a conservative approach of abandoning the old CIED after implanting a new contralateral device. Methods: We used an artificial intelligence algorithm to analyze postimplant chest radiographs to identify those with multiple CIEDs. Outcomes of interest included device interaction, abandoned CIED elective replacement indicator (ERI) behavior, subsequent programming changes, and explant of abandoned CIED. Theoretical risk of infection with removal of abandoned CIED was estimated using a validated scoring system. Results: Among 12,045 patients, we identified 40 patients with multiple CIEDs. Occluded veins were the most common indication for contralateral implantation (n = 27 [67.5%]). Fifteen abandoned CIEDs reached ERI, with 4 reverting to VVI 65. One patient underwent explant due to device interaction, and 2 required device reprogramming. Of 32 patients with an implantable cardioverter-defibrillator, 8 (25%) had treated ventricular arrhythmia. There were no failed or inappropriate therapies due to interaction. Eighteen patients (45%) had hypothetical >1% annual risk of hospitalization for device infection if the abandoned CIED had been explanted. Conclusion: In patients requiring new CIED implant on the contralateral side, abandoning the old device is feasible. This approach may reduce the risk of infection and concerns regarding abandoned leads and magnetic resonance imaging scans. Knowledge of ERI behavior is essential to avoid device interactions.

Outcomes of a comprehensive strategy during repeat atrial fibrillation ablation.

BACKGROUND/PURPOSE: Atrial fibrillation (AF) recurs post-ablation in 30-40% of patients. The approach to a repeat ablation, beyond isolation of reconnected pulmonary veins (PVs), is not well established. We sought to prospectively assess outcomes and predictors of recurrence among consecutive patients who underwent repeat AF ablation with a standardized approach. METHODS: This was a single-center prospective study of consecutive patients who underwent repeat AF ablation. Our protocol consisted of six steps: PV re-isolation, ablation of left atrial low-voltage areas (LVAs), ablation of isoproterenol-induced non-PV triggers, electrophysiology study (EPS) and ablation of induced AVNRT/AVRT, ablation of induced clinical atrial flutters, and lastly empiric ablation as per operator discretion if no other ablation was performed. RESULTS: Among 725 AF ablations performed during the study period, 74 were repeat ablations. Of those undergoing repeat ablation, 53 (72%) had PV reconnection, 30 (41%) had LVAs, seven (10%) had non-PV triggers, five (7%) had AVNRT, and 15 (20%) had typical atrial flutter. Following repeat ablation, arrhythmia-free survival was 65% at 1 year. The absence of PV reconnection was the only factor independently associated with recurrence after repeat ablation (recurrence rate 71%, adjusted OR 7.91, 95% CI 2.31-27.16, p = 0.001). CONCLUSIONS: A comprehensive approach to repeat AF ablation including PV re-isolation, LVA ablation, non-PV trigger ablation, EPS, and flutter ablation was associated with a 65% 1-year arrhythmia-free survival. The absence of PV reconnection was the only independent predictor of arrhythmia recurrence. Further research is needed to identify therapies beyond PV isolation for patients undergoing repeat ablation.

Identification of genetic modifiers of murine hepatic ß-glucocerebrosidase activity.

The acid ß-glucocerebrosidase (GCase) enzyme cleaves glucosylceramide into glucose and ceramide. Loss of function variants in the gene encoding for GCase can lead to Gaucher disease and Parkinson's disease. Therapeutic strategies aimed at increasing GCase activity by targeting a modulating factor are attractive and poorly explored. To identify genetic modifiers, we measured hepatic GCase activity in 27 inbred mouse strains. A genome-wide association study (GWAS) using GCase activity as a trait identified several candidate modifier genes, including Dmrtc2 and Arhgef1 (p=2.1x10-7), and Grik5 (p=2.1x10-7). Bayesian integration of the gene mapping with transcriptomics was used to build integrative networks. The analysis uncovered additional candidate GCase regulators, highlighting modules of the acute phase response (p=1.01x10-8), acute inflammatory response (p=1.01x10-8), fatty acid beta-oxidation (p=7.43x10-5), among others. Our study revealed previously unknown candidate modulators of GCase activity, which may facilitate the design of therapies for diseases with GCase dysfunction.

Proteomic Analysis of Niemann-Pick Type C Hepatocytes Reveals Potential Therapeutic Targets for Liver Damage.

Niemann-Pick type C disease (NPCD) is a lysosomal storage disorder caused by mutations in the NPC1 gene. The most affected tissues are the central nervous system and liver, and while significant efforts have been made to understand its neurological component, the pathophysiology of the liver damage remains unclear. In this study, hepatocytes derived from wild type and Npc1-/- mice were analyzed by mass spectrometry (MS)-based proteomics in conjunction with bioinformatic analysis. We identified 3832 proteins: 416 proteins had a p-value smaller than 0.05, of which 37% (n = 155) were considered differentially expressed proteins (DEPs), 149 of them were considered upregulated, and 6 were considered downregulated. We focused the analysis on pathways related to NPC pathogenic mechanisms, finding that the most significant changes in expression levels occur in proteins that function in the pathways of liver damage, lipid metabolism, and inflammation. Moreover, in the group of DEPs, 30% (n = 47) were identified as lysosomal proteins and 7% (n = 10) were identified as mitochondrial proteins. Importantly, we found that lysosomal DEPs, including CTSB/D/Z, LIPA, DPP7 and GLMP, and mitocondrial DEPs, AKR1B10, and VAT1 had been connected with liver fibrosis, damage, and steatosis in previous studies, validiting our dataset. Our study found potential therapeutic targets for the treatment of liver damage in NPCD.

Prevalence of Left Atrial Appendage Thrombus in Patients Anticoagulated With Direct Oral Anticoagulants: Systematic Review and Meta-analysis.

BACKGROUND: Multiple studies have examined the prevalence of left atrial appendage thrombus (LAAT) in patients anticoagulated with direct oral anticoagulants (DOACs) and have reported conflicting results. METHODS: Studies reporting the prevalence of LAAT on transesophageal echocardiography (TEE) after 3 or more weeks of DOAC therapy were identified. The proportions of anticoagulated patients diagnosed with LAAT were pooled using random-effects models. Prespecified subgroup analyses by the indication of TEE (pre-atrial fibrillation [AF] ablation vs cardioversion) and TEE strategy (routine use vs selective) were conducted via stratification. RESULTS: Forty studies were identified: 22 full manuscripts and 18 abstracts. Only 11 studies performed TEE routinely. Most studies included patients with paroxysmal AF and low thromboembolic risk. The pooled prevalence of LAAT was 2.5% (95% confidence interval [1.6%-3.4%]). The prevalence of LAAT is lower in the pre-AF ablation group compared with pre-cardioversion (1.1% vs 4.0%, P = 0.033). Routine TEE strategy yielded a lower LAAT prevalence in both groups (0.1% vs 2.3%, P = 0.002 and 3.2% vs 5.8%, P = 0.432, respectively). CONCLUSION: The reported prevalence of LAAT on TEE in patients treated with DOACs is highly variable. Factors associated with a high LAAT prevalence were pre-cardioversion indication and selective TEE strategy. Routine use of TEE before AF ablation may not be warranted.

INTRODUCTION: De nombreuses études ont porté sur la prévalence des thrombi se formant dans l'appendice auriculaire gauche (TAAG) chez les patients qui reçoivent des anticoagulants oraux directs (AOD) et ont révélé des résultats contradictoires. MÉTHODES: Nous avons recensé les études qui ont fait état de la prévalence des TAAG à l'échocardiographie transœsophagienne (ETO) trois semaines ou plus après le traitement par AOD. Les modèles à effets aléatoires ont permis de regrouper les patients qui prenaient des anticoagulants et avaient reçu un diagnostic de TAAG. Nous avons réalisé les analyses de sous-groupes prédéterminés par l'indication d'ETO (fibrillation auriculaire [FA] avant l'ablation vs FA avant la cardioversion) et la stratégie d'utilisation de l'ETO (systématique vs sélective) grâce à la stratification. RÉSULTATS: Nous avons recensé 40 études : 22 manuscrits complets et 18 résumés. Seules 11 études portaient sur l'utilisation systématique de l'ETO. La plupart des études portaient sur des patients qui étaient atteints de FA paroxystique et exposés à un faible risque thromboembolique. La prévalence groupée de TAAG était de 2,5 % (intervalle de confiance à 95 % [1,6 %-3,4 %]). La prévalence de TAAG était plus faible dans le groupe de FA avant l'ablation que dans le groupe de FA avant la cardioversion (1,1 % vs 4,0 %, P = 0,033). La stratégie d'utilisation systématique de l'ETO a permis d'obtenir une prévalence plus faible de TAAG dans les deux groupes (0,1 % vs 2,3 %, P = 0,002 et 3,2 % vs 5,8 %, P = 0,432, respectivement). CONCLUSION: La prévalence de TAAG à l'ETO chez les patients traités par AOD varie beaucoup. Les facteurs associés à une prévalence élevée de TAAG étaient l'indication avant la cardioversion et la stratégie d'utilisation sélective de l'ETO. L'utilisation systématique de l'ETO avant l'ablation peut ne pas être justifiée.

High-power, short-duration atrial fibrillation ablation compared with a conventional approach: Outcomes and reconnection patterns.

BACKGROUND: The effectiveness, safety, and pulmonary vein (PV) reconnection patterns of point-by-point high-power, short-duration (HPSD) ablation relative to conventional force-time integral (FTI)-guided strategies for atrial fibrillation (AF) ablation are unknown. OBJECTIVES: To compare 1-year freedom from atrial arrhythmia (AA), complication rates, procedural times, and PV reconnection patterns with HPSD AF AF ablation versus an FTI-guided low-power, long-duration (LPLD) strategy. METHODS: We compared consecutive patients undergoing a first ablation procedure for paroxysmal or persistent AF. The HPSD protocol utilized a power of 50 W and durations of 6-8 s posteriorly and 8-10 s anteriorly. The LPLD protocol was FTI-guided with a power of ≤25 W posteriorly (FTI ≥ 300g·s) and ≤35 W anteriorly (FTI ≥ 400g·s). RESULTS: In total, 214 patients were prospectively included (107 HPSD, 107 LPLD). Freedom from AA at 1 year was achieved in 79% in the HPSD group versus 73% in the LPLD group (p = .339; adjusted hazard ratio with HPSD, 0.67; 95% confidence interval, 0.36-1.23; p < .004 for non-inferiority). Procedure duration was shorter in the HPSD group (229 ± 60 vs. 309 ± 77 min; p < .005). Patients undergoing repeat ablation had a higher propensity for reconnection at the right PV carina in the HPSD group compared with the LPLD group (14/30 = 46.7% vs. 7/34 = 20.6%; p = .035). There were no differences in complication rates. CONCLUSION: HPSD AF ablation resulted in similar freedom from AAs at 1 year, shorter procedure times, and a similar safety profile when compared with an LPLD ablation strategy. Patients undergoing HPSD ablation required more applications at the right carina to achieve isolation, and had a significantly higher rate of right carinal reconnections at redo procedures.