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AIMS: Mitral valve prolapse (MVP) is a common valvular heart disease with a prevalence of >2% in the general adult population. Despite this high incidence, there is a limited understanding of the molecular mechanism of this disease, and no medical therapy is available for this disease. We aimed to elucidate the genetic basis of MVP in order to better understand this complex disorder.METHODS AND RESULTS: We performed a meta-analysis of six genome-wide association studies that included 4884 cases and 434 649 controls. We identified 14 loci associated with MVP in our primary analysis and 2 additional loci associated with a subset of the samples that additionally underwent mitral valve surgery. Integration of epigenetic, transcriptional, and proteomic data identified candidate MVP genes including LMCD1, SPTBN1, LTBP2, TGFB2, NMB, and ALPK3. We created a polygenic risk score (PRS) for MVP and showed an improved MVP risk prediction beyond age, sex, and clinical risk factors.CONCLUSION: We identified 14 genetic loci that are associated with MVP. Multiple analyses identified candidate genes including two transforming growth factor-β signalling molecules and spectrin β. We present the first PRS for MVP that could eventually aid risk stratification of patients for MVP screening in a clinical setting. These findings advance our understanding of this common valvular heart disease and may reveal novel therapeutic targets for intervention.KEY QUESTION: Expand our understanding of the genetic basis for mitral valve prolapse (MVP). Uncover relevant pathways and target genes for MVP pathophysiology. Leverage genetic data for MVP risk prediction.KEY FINDING: Sixteen genetic loci were significantly associated with MVP, including 13 novel loci. Interesting target genes at these loci included LTBP2, TGFB2, ALKP3, BAG3, RBM20, and SPTBN1. A risk score including clinical factors and a polygenic risk score, performed best at predicting MVP, with an area under the receiver operating characteristics curve of 0.677.TAKE-HOME MESSAGE: Mitral valve prolapse has a polygenic basis: many genetic variants cumulatively influence pre-disposition for disease. Disease risk may be modulated via changes to transforming growth factor-β signalling, the cytoskeleton, as well as cardiomyopathy pathways. Polygenic risk scores could enhance the MVP risk prediction.

Self-supervised learning (SSL) techniques have been widely used to learn compact and informative representations from high-dimensional complex data. In many computer vision tasks, such as image classification, such methods achieve state-of-the-art results that surpass supervised learning approaches. In this paper, we investigate whether SSL methods can be leveraged for the task of learning accurate state representations of games, and if so, to what extent. For this purpose, we collect game footage frames and corresponding sequences of games' internal state from three different 3D games: VizDoom, the CARLA racing simulator and the Google Research Football Environment. We train an image encoder with three widely used SSL algorithms using solely the raw frames, and then attempt to recover the internal state variables from the learned representations. Our results across all three games showcase significantly higher correlation between SSL representations and the game's internal state compared to pre-trained baseline models such as ImageNet. Such findings suggest that SSL-based visual encoders can yield general -- not tailored to a specific task -- yet informative game representations solely from game pixel information. Such representations can, in turn, form the basis for boosting the performance of downstream learning tasks in games, including gameplaying, content generation and player modeling., Comment: Conference on Games (CoG) 2022

Taranjeet Jolly,1 Zeeshan Mansuri,2 Chintan Trivedi,3 Mahwish Adnan,4 Steven P Cohen,5 To-Nhu Vu6 1Department of Psychiatry & Behavioral Health, Penn State University College of Medicine, Inpatient Child and Adolescent Psychiatry, Pennsylvania Psychiatric Institute, Harrisburg, PA, USA; 2Department of Psychiatry, Boston Children’s Hospital/Harvard Medical School, Boston, MA, USA; 3Psychiatry Department, St. David’s Medical Center, Austin, TX, USA; 4Department of Psychiatry, Mercy Hospital and Medical Center, Lincolnwood, IL, USA; 5Department of Anesthesiology & Critical Care medicine, Neurology and Physical Medicine & Rehabilitation, Johns Hopkins School of Medicine, Baltimore, MD, USA; 6Department of Anesthesia & Pain Medicine, Penn State University College of Medicine, Hershey, PA, USACorrespondence: Taranjeet JollyDepartment of Psychiatry & Behavioral Health, Penn State College of Medicine, Inpatient Child and Adolescent Psychiatry, Pennsylvania Psychiatric Institute, 2501 N 3rd Street, Harrisburg, PA, USATel +1 734-837-6549Email tjolly@pennstatehealth.psu.eduObjective: Data defining and subsequently guiding the use of psychotropic medications in children and adolescents is sparse. We conducted a meta-analysis of randomized control trials to examine the effectiveness of psychotropic medications in children and adolescents with chronic pain.Methods: We conducted a comprehensive literature search from published studies, and annual scientific sessions of psychiatry conferences. We identified double-blind, randomized control trials (RCTs) in which psychotropic medications were compared to placebo. Data was collected for the total number of patients, baseline characteristics, and changes in pain score. Meta-analysis was performed using a random effect model evaluating average change in pain score and the number of patients with a reduction in pain score for both groups. Pooled data are expressed as standardized mean differences (SMD) and odds ratios (OR) with 95% confidence intervals (CI).Results: We found 5 studies that included amitriptyline (n=2), citalopram (n=1), buspirone (n=1) and duloxetine (n=1). In the pooled analysis for the difference in the average change in pain score, 4 RCTs with 395 patients were included. After 12– 13 weeks of therapy, reductions in pain score were significantly greater in the psychotropic drug group as compared to placebo (SMD: − 0.77, 95% CI − 1.54, 0.0001, p= 0.05). For the analysis on the number of patients with a reduction in pain, data were available for 445 patients (224-medication group, 221-placebo group). More patients in the psychotropic drug group experienced a meaningful reduction in pain score at 12– 13 weeks of therapy compared to placebo (OR 1.66, 95% CI 1.08– 2.54, p= 0.02).Conclusion: The results of this meta-analysis demonstrate significant analgesic efficacy of psychotropic medications in the management of children with chronic pain. This review is limited by the small number of studies included for analysis. There is a pressing need for more robust clinical trials to further investigate these promising findings.Keywords: chronic pediatric pain, psychotropic, anti-depressants, anti-anxiety medications, meta-analysis

Background We evaluated long‐term outcome of isolation of pulmonary veins, left atrial posterior wall, and superior vena cava, including time to recurrence and prevalent triggering foci at repeat ablation in patients with paroxysmal atrial fibrillation with or without cardiovascular comorbidities. Methods and Results A total of 1633 consecutive patients with paroxysmal atrial fibrillation that were arrhythmia‐free for 2 years following the index ablation were classified into: group 1 (without comorbidities); n=692 and group 2 (with comorbidities); n=941. We excluded patients with documented ablation of areas other than pulmonary veins, the left atrial posterior wall, and the superior vena cava at the index procedure. At 10 years after an average of 1.2 procedures, 215 (31%) and 480 (51%) patients had recurrence with median time to recurrence being 7.4 (interquartile interval [IQI] 4.3–8.5) and 5.6 (IQI 3.8–8.3) years in group 1 and 2, respectively. A total of 201 (93.5%) and 456 (95%) patients from group 1 and 2 underwent redo ablation; 147/201 and 414/456 received left atrial appendage and coronary sinus isolation and 54/201 and 42/456 had left atrial lines and flutter ablation. At 2 years after the redo, 134 (91.1%) and 391 (94.4%) patients from group 1 and 2 receiving left atrial appendage/coronary sinus isolation remained arrhythmia‐free whereas sinus rhythm was maintained in 4 (7.4%) and 3 (7.1%) patients in respective groups undergoing empirical lines and flutter ablation ( P Conclusions Very late recurrence of atrial fibrillation after successful isolation of pulmonary veins, regardless of the comorbidity profile, was majorly driven by non‐pulmonary vein triggers and ablation of these foci resulted in high success rate. However, presence of comorbidities was associated with significantly earlier recurrence.

Background We compared the cognitive status and quality of life in patients with atrial fibrillation undergoing left atrial appendage occlusion (LAAO) or remaining on oral anticoagulation (OAC) after atrial fibrillation ablation. Methods and Results Cognition was assessed by the Montreal Cognitive Assessment (MoCA) survey at baseline and follow‐up. Consecutive patients receiving LAAO or OAC after atrial fibrillation ablation were screened, and patients with a score of ≤17 were excluded from the study. Quality of life was measured at baseline and 1 year using the Atrial Fibrillation Effect on Quality of Life survey. A total of 50 patients (CHA 2 DS 2 ‐VASc [congestive heart failure, hypertension, age≥75 years, diabetes mellitus, stroke or transient ischemic attack, vascular disease, age 65–74 years, sex category] score: 3.30±1.43) in the LAAO group and 48 (CHA 2 DS 2 ‐VASc score 2.73±1.25) in the OAC group were included in this prospective study. Mean baseline MoCA score was 26.18 and 26.08 in the LAAO and OAC groups, respectively ( P =0.846). At 1 year, scores were 26.94 and 23.38 in the respective groups. MoCA score decreased by an estimated −2.74 (95% CI, −3.61 to −1.87; P P =0.07). After adjusting for baseline clinical characteristics, remaining on OAC was an independent predictor of MoCA change at 1 year (regression coefficient, −3.38; 95% CI, −4.75 to −2.02; P Conclusions In this series, a significant difference in the postprocedure MoCA score was observed in postablation patients with atrial fibrillation receiving LAAO versus remaining on OAC with a substantial decline in the score in the OAC group. However, quality of life improved similarly across groups. Registration https://www.ClinicalTrials.gov . Unique identifier: NCT01816308

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 One thousand two 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 value = 0.021). The composite endpoint of DRT/TE events was significantly lower among patients receiving a genotype-guided antithrombotic strategy (0.75% vs 3.1%; log-rank P value = 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.

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 ( 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.

Although pharmacological rhythm control of AF in patients with heart failure with reduced ejection fraction (HFrEF) does not seem to provide any benefit over rate control, catheter ablation of AF has been shown to improve clinical outcomes. These results can be explained with higher success rates of catheter ablation in restoring and maintaining sinus rhythm compared with antiarrhythmic drugs. In addition, pharmacotherapy is not void of side-effects, which are thought to offset its potential antiarrhythmic benefits. Therefore, efforts should be made towards optimisation of ablation techniques for AF in patients with HFrEF.

Gianni, Carola/0000-0002-8174-7207; Rocca, Domenico Della/0000-0003-3837-3462; /0000-0002-5487-0728 WOS: 000459889100007 PubMed: 30312757 BACKGROUND Spontaneous echocardiographic contrast ("smoke") within the left atrial cavity on transesophageal echocardiography (TEE) suggests low blood flow velocities in the heart that may lead to thromboembolic (TE) events. OBJECTIVE The purpose of this study was to evaluate the risk of TE events in the periprocedural period and at long-term follow-up in atrial fibrillation (AF) patients having dense smoke on preprocedural TEE. METHODS A total of 2511 patients undergoing AF ablation were included in this analysis. They were classified as group 1 (dense smoke detected on TEE at baseline; n = 234) and group 2 (no smoke on baseline TEE; n = 2277). Patients were followed up for TE events, which included both stroke and transient ischemic attacks (TIAs). In order to attenuate the observed imbalance in baseline covariates between the study groups, a propensity score matching technique was used (covariates were age, sex, AF type, diabetes, and CHADS(2)-VASc score). RESULTS In the periprocedural period, no TE events were reported in group 1 and 3 events (0.13%) were reported in group 2. At follow-up of 6.62 +/- 62.01 years, 6 (2.6%) TE complications (2 TIA, 4 stroke) occurred in group 1 and 16 (0.70%) TE complications (6 TIA, 10 stroke) in group 2 (P = .004). In the propensity-matched population, 6 (2.56%) TE complications occurred in group 1 and 1 (0.2%) in group 2 (P = .007). CONCLUSION In our study population, the presence of dense left atrial smoke did not show any correlation with periprocedural TE events in patients undergoing catheter ablation with uninterrupted anticoagulation. However, significant association was observed with late stroke/TIA, irrespective of CHA(2)DS(2)-VASc score.

Aims The long-term outcomes of left atrial appendage electrical isolation (LAAEI) in patients with non-paroxysmal atrial fibrillation (AF) have corroborated the significant role of the LAA in this arrhythmia. We sought to investigate the incremental benefit of LAAEI in patients undergoing catheter ablation for persistent AF or long-standing persistent AF (LSPAF). Methods and results A systematic review of Medline, Cochrane, and Embase for all the clinical studies in which assessment LAAEI in non-paroxysmal AF patients was performed. The benefit of LAAEI in patients with AF was analysed from seven studies that enrolled a total of 930 patients [mean age 63 ± 5 years; male: 69%]. All studies included patients with either persistent AF or LSPAF or the combination of them. The overall freedom from all-arrhythmia recurrence at 12 months of follow-up off antiarrhythmic medications in patients who underwent LAAEI was 75.5% vs. 43.9% in those in whom only standard ablation was performed [56% relative reduction and 31.6% absolute reduction; risk ratio (RR) 0.44, 95% confidence interval (95% CI) 0.31-0.64; P

Objectives: Inflammation is one of the predictors of atrial fibrillation (AF) following surgical or interventional cardiac procedures. Recent evidence suggests that colchicine may represent a new strategy to prevent AF following cardiac procedures. This study aims to assess the antiinflammatory efficacy of colchicine in prevention of early AF event (EAFE). Materials and Methods: We reviewed all available studies that assessed the effectiveness of colchicine therapy on the occurrence of AF in patients undergoing cardiac procedures. Meta-analysis was performed by random effect inverse variance-weighted method by entering AF events and the total population from each study. Results: After thorough review of the databases, we found three studies comparing colchicine and placebo which had EAFE as the outcome. Of 584 patients, 286 patients were on colchicine and 298 on placebo. All the three studies were randomized. After pooled analysis, colchicine was associated with significant reduction in AF events compared to placebo (odds ratio = 0.44 [0.29, 0.66], P < 0.001). There was no statistical heterogeneity between included studies (χ2 = 0.45, P = 0.80, I2 = 0%). Conclusion: Colchicine may prove beneficial in the prevention of AF following cardiac surgery. Further research is warranted.

Ablation of longstanding persistent atrial fibrillation (LSPAF) is the most challenging procedure in the treatment of AF, either by surgical or by percutaneous approach.We investigated the difference in success and complication rates between combined surgical epicardial and endocardial catheter ablation procedure and our standard endocardial ablation procedure.Twenty-four consecutive patients (group 1) with LSPAF and enlarged left atrium (4.5 cm) underwent a combined procedure, consisting of surgical, closed-chest, epicardial, radiofrequency ablation (nContact, NC, USA) via pericardial access, and concomitant endocardial ablation (hybrid procedure). Procedural complications and long-term outcomes were compared to those of 35 consecutive patients who refused the hybrid procedure and underwent standard endocardial only ablation (group 2). Baseline characteristics were comparable. In group 1, 1 patient (4.2%) developed post-procedural cardio-embolic stroke and 3 (12.5%) died (1 atrio-esophageal fistula, 1 fatal stroke, 1 of unknown cause in early follow-up), while no strokes or deaths occurred in group 2. Overall complication rates were higher for group 1 (P = 0.036). At 24-month follow-up, 4 (19%) patients in group 1 and 19 (54.3%) in group 2 were arrhythmia-free after a single procedure, on or off antiarrhythmic drugs (P0.001). Total procedural time (276.9 ± 63.5 vs. 203.15 ± 67.3 minutes) and length of hospital stay (5 [IQR 3-8] vs. 1 [IQR 1-3] days were significantly shorter for group 2 (P0.001).In patients with LSPAF and enlarged left atrium, a concomitant combined surgical/endocardial ablation approach increases complication rate and does not improve outcomes when compared to extensive endocardial ablation only.

Whether ablation of non-pulmonary vein (PV) triggers after pulmonary vein antrum isolation (PVAI) improves the long-term procedure outcome in patients with paroxysmal atrial fibrillation (PAF) and left ventricular systolic dysfunction is unknown.We sought to evaluate whether a more extensive ablation procedure improves outcomes at follow-up.Consecutive patients with PAF refractory to antiarrhythmic drugs presenting for PVAI were prospectively studied. Patients were categorized into 2 groups: patients with left ventricular ejection fraction (LVEF) ≤35% (group I; n = 175) and patients with LVEF ≥50% (group II; n = 545). Patients in group I were further divided according to whether additional ablation of non-PV triggers was performed (group IA; n = 88) or not (group IB; n = 87). Long-term ablation success off antiarrhythmic drugs after a single procedure was analyzed.Patients in group I had more non-PV triggers than did patients in group II (69.1% vs 26.6%; P.001). During a follow-up of 15.8 ± 4.7 months, fewer patients in group I remained free from recurrences than those in group II (53.7% vs 81.7%; P.001). Long-term ablation success was higher in group IA than in group IB (75.0% vs 32.2%; P.001) and similar to that in group II (75.0% vs 81.7%; P = .44). In multivariate analysis, LVEF ≤35% (hazard ratio 1.68; P = .003) and non-PV triggers (hazard ratio 3.12; P.001) were independent predictors of recurrences.In patients with PAF and left ventricular systolic dysfunction, ablation of non-PV triggers in addition to PVAI significantly improves their long-term procedure outcome.

Background Transesophageal echocardiography (TEE) is recommended in patients undergoing atrial fibrillation (AF) ablation, but use of this strategy is variable. Objective To evaluate whether TEE is necessary before AF ablation in patients treated with novel oral anticoagulants (NOACs). Methods We performed a prospective multicenter registry of AF patients undergoing radiofrequency catheter ablation on uninterrupted NOACs (apixaban and rivaroxaban). All patients were on NOACs for at least 4 weeks before ablation. Heparin bolus was administered to all patients before transseptal catheterization to maintain a target activated clotting time above 300 seconds. A subset of 86 patients underwent brain diffuse magnetic resonance imaging (dMRI) to detect silent cerebral ischemia (SCI). Results A total of 970 patients (514 [53%] apixaban patients and 456 [47%] rivaroxaban patients) were enrolled for this study. The mean age was 69.5 ± 9.0 years, with 824 patients (85%) having nonparoxysmal AF, and 636 patients (65.6%) were male. The average CHA 2 DS 2 -VASc score was 3.01 ± 1.3 and CHADS 2 score was ≥2 in 609 patients (62.8%). Intracardiac echocardiogram ruled out left atrial appendage thrombus in all patients whose left atrial appendage was visualized (692, 71%), and detected "smoke" in 407 patients (42%). SCI at postprocedure dMRI was detected in 2.3% (2/86). One thromboembolic event (transient ischemic attack) (0.10%) with positive dMRI occurred in a patient on uninterrupted rivaroxaban with longstanding persistent AF. Conclusion Our study illustrates that performing AF ablation while on uninterrupted apixaban and rivaroxaban without TEE is feasible and safe. This finding has important clinical and economic relevance.

The impact of amiodarone on ablation outcome in longstanding persistent atrial fibrillation (LSPAF) patients is not known yet.The purpose of this study was to assess the effect of amiodarone on procedural-outcomes in LSPAF patients undergoing catheter ablation.We enrolled 112 LSPAF patients on amiodarone and scheduled to undergo atrial fibrillation (AF) ablation. Patients were randomized to amiodarone discontinuation 4 months before ablation (group 1, n = 56) and a control group (group 2, n = 56) in which ablation was performed without amiodarone discontinuation. All patients underwent pulmonary vein (PV) antrum and posterior wall isolation, defragmentation and extra PV triggers ablation. Patients were followed up for recurrence for 32 ± 8 months post-ablation. Repeat procedures in all recurrent patients were performed off amiodarone.During ablation, AF termination was more frequent in group 2 compared to group 1 [44 (79%) vs 32 (57%), P = .015]. After high-dosage isoproterenol, more non-PV triggers were disclosed in group 1 compared to group 2 (42 [75%] vs 24 [43%] respectively, P.001). Group 2 had lower procedure, radiofrequency and fluoroscopy times compared to group 1 (2.7 ± 1 vs 3.1 ± 1 h, 69 ± 13 min vs 87 ± 11 min and 64 ± 14 min vs 85 ± 18 min respectively, p.05). At 32 ± 8 month follow-up, on or off antiarrhythmic drug success rate was 37 (66%) in group 1 and 27 (48%) in group 2 (P = .04). During redo, new non-PV trigger sites were identified in group 2 patients.Periprocedural continuous amiodarone was associated with higher organization rate and lower radiofrequency ablation rate. However, masking non-PV triggers increased the late recurrence rate.

Atrioesophageal fistula (AEF) is a rare but devastating complication of radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF). Surgical repair and esophageal stents are available treatment options for AEF. We report outcomes of these 2 management strategies.Nine patients with AEF post-RFCA for AF were included in this study. AEF was diagnosed based on symptoms and chest CT imaging. Of the 9 patients, 5 received stents and 4 underwent surgical repair of fistula.AF ablation was performed under general anesthesia (n = 4) or conscious sedation (n = 5). During ablation, RF power was maintained between 25 and 35 Watts in areas close to the esophagus and energy delivery discontinued when esophageal temperature reached 38 °C. Seven patients underwent ablation with 3.5-mm open-irrigated catheter, 1 with 8-mm nonirrigated catheter, and 1 had surgical epicardial ablation. Seven patients received proton pump inhibitor and sucralfate before and after procedure. AEF symptoms developed within 2–6 weeks from ablation. Esophageal stenting was performed in 5 patients (median age 58 years, median time from RFCA 4 weeks) and 4 underwent surgical repair (median age 54 years, median time from RFCA 4 weeks) within 2–4 hours from diagnosis. All 5 patients receiving stents died within 1 week of the procedure due to cerebral embolism, septic shock, or respiratory failure. On the other hand, the 4 patients that received surgical repair were alive at median follow-up of 2.1 years (P = 0.005).Esophageal stenting should be discouraged and prompt surgical repair is crucial for survival in patients with atrioesophageal fistula.

Thromboembolic events represent one of the most serious complications of atrial fibrillation (AF). Left atrial appendage (LAA) clots are the dominant cause of such events in AF patients. Therefore, LAA closure devices have been developed. We sought to evaluate the follow-up and management of early