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The BTK inhibitor ibrutinib is used to treat chronic lymphocytic leukaemia, however some patients develop resistance to the drug. Here, the authors use genomic analyses to examine the clonal evolution of 5 patients that develop resistance to ibrutinib.

Alpha-frequency band oscillations have been shown to be one of the most prominent aspects of neuronal ongoing oscillatory activity, as reflected by electroencephalography (EEG) recordings. First thought to reflect an idling state, a recent framework indicates that alpha power reflects cortical inhibition. In the present study, the role of oscillations in the upper alpha band (12 Hz) was investigated during a change detection test of short-term visual memory.If alpha oscillations arise from a purely inhibitory process, higher alpha power before sample stimulus presentation would be expected to correlate with poorer performance. Instead, participants with faster reaction times showed stronger alpha power before the sample stimulus in frontal and posterior regions.Additionally, faster participants showed stronger alpha desynchronization after the stimulus in a group of right frontal and left posterior electrodes. The same pattern of electrodes showed stronger alpha with higher working memory load, so that when more items were processed, alpha power desynchronized faster after the stimulus. During memory maintenance, alpha power was greater when more items were held in memory, likely due to a faster resynchronization. These data are consistent with the hypothesis that the level of suppression of alpha power by stimulus presentation is an important factor for successfully encoding visual stimuli. The data are also consistent with a role for alpha as actively participating in attentional processes.

The prevalence of congenital heart disease (CHD) has surged in recent decades, owing to a substantial reduction in mortality. As individuals with CHD age, they become increasingly susceptible to late complications including arrhythmias. These arrhythmias often arise decades after surgical intervention and significantly impact quality of life, hospitalizations, and mortality. Catheter ablation has gained widespread acceptance as a critical intervention for managing arrhythmias in patients with CHD. However, anatomical and physiological features unique to this population pose challenges to standard manual ablation procedures, potentially impacting safety and efficacy. Robotic magnetic-guided navigation (RMN) has emerged as a technological solution to address these challenges. By utilizing soft and flexible catheters equipped with magnets at their tips, RMN enables robotic steering and orientation of catheters in three-dimensional space. This technology overcomes obstacles such as distorted vascular pathways and complex post-surgical reconstructions to facilitate access to target chambers and improve maneuverability within the heart. In this review, we present an overview of the safety and efficacy evidence for RMN-guided catheter ablation in CHD patients and highlight potential advantages. Additionally, we provide a detailed case presentation illustrating the practical application of RMN technology in this population. Although the literature on RMN-guided ablation in patients with CHD remains limited, it has shown promise in achieving successful outcomes, particularly in cases where manual ablation failed or was deemed non-feasible. Further validation through large-scale prospective studies is necessary to fully ascertain the benefits of RMN technology in this patient population.

Patients with new-onset left bundle branch block (LBBB) after transcatheter aortic valve implantation (TAVI) are at risk of developing delayed high-degree atrioventricular block. Management of new-onset LBBB post-TAVI remains controversial. In the Co mparison of a Clinical M onitoring Strategy Versus E lectrophysiology-Guided Algorithmic Approach in Patients With a New LBBB After TAVI (COME-TAVI) trial, consenting patients with new-onset LBBB that persists on day 2 after TAVI, meeting exclusion/inclusion criteria, are randomized to an electrophysiological study (EPS)-guided approach or 30-day electrocardiographic monitoring. In the EPS-guided approach, patients with a His to ventricle (HV) interval ≥ 65 ms undergo permanent pacemaker implantation. Patients randomized to noninvasive monitoring receive a wearable continuous electrocardiographic recording and transmitting device for 30 days. Follow-up will be performed at 3, 6, and 12 months. The primary endpoint is a composite outcome designed to capture net clinical benefit. The endpoint incorporates major consequences of both strategies in patients with new-onset LBBB after TAVI, as follows: (i) sudden cardiac death; (ii) syncope; (iii) atrioventricular conduction disorder requiring a pacemaker (for a class I or IIa indication); and (iv) complications related to the pacemaker or EPS. The trial incorporates a Bayesian design with a noninformative prior, outcome-adaptive randomization (initially 1:1), and 2 prespecified interim analyses once 25% and 50% of the anticipated number of primary endpoints are reached. The trial is event-driven, with an anticipated upper limit of 452 patients required to reach 77 primary outcome events over 12 months of follow-up. In summary, the aim of this Bayesian multicentre randomized trial is to compare 2 management strategies in patients with new-onset LBBB post-TAVI-an EPS-guided approach vs noninvasive 30-day monitoring. Trial registration number: NCT03303612., (© 2023 The Authors.)

Background: Although depression is a major issue among farming population, to date, there have been few studies on specific agricultural activities. We aimed to investigate whether, among the entire French farm manager (FM) workforce, certain agricultural activities are more strongly associated with depression than others., Methods: This nationwide retrospective cohort study used data from an administrative health database available to the TRACTOR project. This database pertains to the entire French agricultural workforce (overseas workers not included). Data were analyzed from January 2021 to December 2022. All FMs that worked at least once over the period 2002-2016 were included. The outcome measure was the association between 26 agricultural activities and the risk of depression measured as hazard ratios (HRs) after adjusting for age, sex, and pre-existing medical comorbidities. The time to first depression insurance declaration, or first antidepressant prescription claim was used as the underlying timescale. For each activity, the reference/control group included all FMs that never performed the considered activity between 2002 and 2016, while the exposed group included FMs that performed the considered activity at least once from 2002 to 2016. Four sensitivity analyses were conducted to test hypotheses, and to address potential sources of bias., Findings: There were 84,507 (7.76%; 28.2 cases per 1000 person-years) depression cases among 1,088,561 FMs (mean age 46.6 [SD 14.1]). Compared to other activities, dairy farming (HR = 1.37, 95% confidence interval: 1.32-1.42), cow farming (HR = 1.53 [1.47-1.59]), poultry and rabbit farming (HR = 1.37 [1.27-1.50]), and mixed farming (HR = 1.30 [1.24-1.36]) were more strongly associated with depression. Sex differences were observed, with most of the time, risks higher for females than for males., Interpretation: Agricultural activities at risk of depression among the entire French agricultural workforce were identified. These findings do represent a crucial first step on the road to implement effective preventive measures against depression to determine where additional resources should be allocated to screen for depression, along with intervention., Funding: MIAI@Grenoble Alpes, and Mutualité Sociale Agricole., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The paper contents, including any opinions and/or conclusions expressed, are solely those of the authors., (© 2023 The Author(s).)

Introduction: Atrial fibrillation (AF) is a common chronic and progressive heart rhythm disorder. For those in whom sinus rhythm is desired, contemporary clinical practice guidelines recommend antiarrhythmic drugs (AADs) as the initial therapy. However, these medications have modest efficacy and are associated with significant adverse effects., Areas Covered: The current article reviews the evidence surrounding first-line catheter ablation, particularly the emerging evidence surrounding the use of cryoballoon ablation as a first-line therapy. The focus of the review is on the outcomes of arrhythmia freedom, quality of life, health-care utilization, and safety. In addition, the article will review novel cryoablation systems., Expert Opinion: Recent evidence suggests that cryoballoon ablation significantly improves arrhythmia outcomes (e.g. freedom from any atrial tachyarrhythmia or symptomatic atrial tachyarrhythmia, reduction in arrhythmia burden), patient-reported outcomes (e.g. symptoms and quality of life), and health-care resource utilization (e.g. hospitalization), without increasing the risk of adverse events. These findings are relevant to patients, providers, and health-care systems, as they help inform the decision-making regarding the initial choice of rhythm-control therapy in patients with treatment-naive AF.

Background: The identification of low-voltage proarrhythmic areas for catheter ablation of scar-mediated ventricular tachycardia (VT) remains challenging. Integration of myocardial perfusion imaging (single-photon emission computed tomography/computed tomography; SPECT/CT) and electroanatomical mapping (EAM) may improve delineation of the arrhythmogenic substrate., Objective: To assess the feasibility of SPECT/CT image integration with voltage maps using the EnSite Precision system (Abbott) in patients undergoing scar-mediated VT ablation., Methods: Patients underwent SPECT/CT imaging prior to left ventricular (LV) EAM with the EnSite Precision mapping system. The SPECT/CT, EAM data, and ablation lesions were retrospectively co-registered in the EnSite Precision system and exported for analysis. Segmental tissue viability scores were calculated based on SPECT/CT perfusion and electrogram bipolar voltage amplitude. Concordance, specificity, and sensitivity between the 2 modalities as well as the impact of SPECT/CT spatial resolution were evaluated., Results: Twenty subjects (95% male, 67 ± 7 years old, left ventricular ejection fraction 36% ± 11%) underwent EAM and SPECT/CT integration. A concordance of 70% was found between EAM and SPECT/CT for identification of cardiac segments as scar vs viable, with EAM showing a 68.5% sensitivity and 76.4% specificity when using SPECT/CT as a gold standard. Projection on low-resolution 3D geometries led to an average decrease of 38% ± 22% of the voltage points used., Conclusion: The study demonstrated the feasibility of integrating SPECT/CT with EAM performed retrospectively for characterization of anatomical substrates during VT ablation procedures., (© 2022 Heart Rhythm Society. Published by Elsevier Inc.)

Background: Early recurrence of atrial tachyarrhythmia (ERAT) is common after pulmonary vein isolation (PVI) and has been associated with an increased risk of late atrial fibrillation (AF) recurrence., Objective: The purpose of this study was to determine the incidence and outcomes of patients experiencing ERAT after PVI using advanced-generation ablation technologies., Methods: This is a prespecified substudy of the CIRCA-DOSE (Cryoballoon vs Irrigated Radiofrequency Catheter Ablation: Double-Short vs Standard Exposure Duration) trial, a prospective, randomized, multicenter study comparing PVI with contact force-guided radiofrequency ablation to secondary-generation cryoballoon ablation for paroxysmal AF. All study patients received an implantable cardiac monitor to allow continuous rhythm monitoring. ERAT was defined as any recurrent atrial tachyarrhythmia within the first 90 days after AF ablation., Results: ERAT occurred in 61% of the 346 patients at a median of 12 days (range 1-90 days) after ablation. ERAF was a significant predictor of late recurrence (60.1% with ER vs 25.9% without ER; P <.001) and symptomatic atrial tachyarrhythmia (31.6% with ERAF vs 6.7% without ERAF; P <.001). Receiver operating curve analyses revealed a strong correlation between ERAT timing and burden and late recurrence. Multivariate analysis identified ER timing (hazard ratio [HR] 2.90; 95% confidence interval [CI] 1.41-5.95; P = .004) and burden (HR 1.05 per 1% ER burden; 95% CI 1.04-1.07; P <.001) as strong independent predictors of late recurrence. Incidence rate, timing, burden, and prognostic significance of ER did not differ between the study groups., Conclusion: ERAT remains common after PVI despite use of advanced-generation ablation technologies. Early AF recurrence beyond 3 weeks after ablation is associated with increased risk of late recurrence., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Pulmonary vein (PV) stenosis is a complication of atrial fibrillation (AF) ablation. The incidence of PV stenosis after routine post-ablation imaging remains unclear and is limited to single-centre studies. Our objective was to determine the incidence and predictors of PV stenosis following circumferential radiofrequency ablation in the multicentre Adenosine Following Pulmonary Vein Isolation to Target Dormant Conduction Elimination (ADVICE) trial., Methods: Patients with symptomatic AF underwent circumferential radiofrequency ablation in one of 13 trial centres. Computed tomographic (CTA) or magnetic resonance (MRA) angiography was performed before ablation and 90 days after ablation. Two blinded reviewers measured PV diameters and areas. PVs with stenosis were classified as severe (> 70%), moderate (50%-70%), or mild (< 50%). Predictors of PV stenosis were identified by means of multivariable logistic regression., Results: A total of 197 patients (median age 59.5 years, 29.4% women) were included in this substudy. PV stenosis was identified in 41 patients (20.8%) and 47 (8.2%) of 573 ablated PVs. PV stenosis was classified as mild in 42 PVs (7.3%) and moderate in 5 PVs (0.9%). No PVs had severe stenosis. Both cross-sectional area and diameter yielded similar classifications for severity of PV stenosis. Diabetes was associated with a statistically significant increased risk of PV stenosis (OR 4.91, 95% CI 1.45-16.66)., Conclusions: In the first systematic multicentre evaluation of post-ablation PV stenosis, no patient acquired severe PV stenosis. Although the results are encouraging for the safety of AF ablation, 20.8% of patients had mild or moderate PV stenosis, in which the long-term effects are unknown., (Copyright © 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Introduction: Corrected QT (QTc) interval is an essential proarrhythmic risk biomarker, but recent data have identified limitations to its use. The J to T-peak (JTp) interval is an alternative biomarker for evaluating drug-induced proarrhythmic risk. The aim of this study was to evaluate pharmacological effects using spatial magnitude leads and DII electrocardiogram (ECG) leads and common ECG confounders (ie, stress and body temperature changes) on covariate adjusted QT (QTca), covariate adjusted JTp (JTpca), and covariate adjusted T-peak to T-end (Tpeca) intervals., Methods: Beagle dogs were exposed to body hyper- (42 °C) or hypothermic (33 °C) conditions or were administered epinephrine to assess confounding effects on heart rate corrected QTca, JTpca, and Tpeca intervals. Dofetilide (0.1, 0.3, 1.0 mg/kg), ranolazine (100, 140, 200 mg/kg), and verapamil (7, 15, 30, 43, 62.5 mg/kg) were administered to evaluate pharmacological effects., Results: Covariate adjusted QT (slope -12.57 ms/°C) and JTpca (-14.79 ms/°C) were negatively correlated with body temperature but Tpeca was minimally affected. Epinephrine was associated with QTca and JTpca shortening, which could be related to undercorrection in the presence of tachycardia, while minimal effects were observed for Tpeca. There were no significant ECG change following ranolazine administration. Verapamil decreased QTca and JTpca intervals and increased Tpeca, whereas dofetilide increased QTca and JTpca intervals but had inconsistent effects on Tpeca., Conclusion: Results highlight potential confounders on QTc interval, but also on JTpca and Tpeca intervals in nonclinical studies. These potential confounding effects may be relevant to the interpretation of ECG data obtained from nonclinical drug safety studies with Beagle dogs.

Objectives: This study evaluated the impact of contact force-guided radiofrequency ablation versus cryoballoon ablation on quality of life and health care utilization., Background: Traditional outcome parameters, such as arrhythmia-free survival, are insufficient to evaluate the clinical impact of atrial fibrillation (AF), as it fails to the capture patient- and health system-level differences in treatment approaches., Methods: The CIRCA-DOSE (Cryoballoon Vs. Contact-Force Atrial Fibrillation Ablation) study randomly assigned 346 patients with drug-refractory paroxysmal AF to contact force-guided radiofrequency or cryoballoon ablation. Health-related quality-of-life (HRQOL) was assessed at baseline, and at 6 and 12 months post-ablation using a disease-specific and generic HRQOL instruments. Health care utilization (hospitalization, emergency department visits, and cardioversion) and antiarrhythmic drug use for the 12 months preceding ablation was compared with the 12 months following ablation., Results: Disease-specific and generic HRQOL was moderately to severely impaired at baseline and improved significantly at 6 and 12 months of follow-up (median improvement in AFEQT [Atrial Fibrillation Effect on QualiTy of Life] score 32.4 [interquartile range: 17.7 to 48.9]). When compared with the 12 months pre-ablation, the proportion and absolute number of cardioversions decreased significantly (41.1% vs. 10.1% of patients, 137 vs. 35 events; p < 0.0001). Similar significant reductions in emergency department visits (66.7% vs. 25.1% of patients, 224 vs. 87 events; p < 0.0001), and hospitalizations (25.5% vs. 14.5% of patients, 86 vs. 50 events; p < 0.001) were observed. There were no significant differences between randomized groups., Conclusions: In this multicenter randomized trial, catheter ablation with advanced-generation technologies resulted in a significant improvement in HRQOL and a significant reduction in health care utilization in the year following AF ablation. (Cryoballoon vs. Irrigated Radiofrequency Catheter Ablation [CIRCA-DOSE]; NCT01913522)., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Use of intraprocedural observation and pharmacologic challenges have been proposed as means to differentiate permanent pulmonary vein (PV)-left atrial conduction block from inadequate ablation lesions., Objective: The purpose of this study was to determine the prevalence and clinical impact of spontaneous and adenosine-provoked reconnection using contemporary atrial fibrillation (AF) ablation technologies., Methods: The CIRCA-DOSE (Cryoballoon vs. Irrigated Radiofrequency Catheter Ablation: Double Short vs. Standard Exposure Duration) study enrolled 346 patients with paroxysmal AF and randomized them to contact force-guided radiofrequency ablation (CF-RF) or cryoballoon ablation. Patients underwent provocative testing with adenosine after a 20-minute observation period. All patients received an implantable cardiac monitor for arrhythmia monitoring., Results: Spontaneous reconnection was observed in 5.4% of PVs (71/1318) during the 20-minute postprocedure observation period, and dormant conduction was elicited in 5.7% of PVs (75/1318). Both spontaneous reconnection and dormant conduction were more common after CF-RF compared to cryoballoon ablation (P = .03 and P <.0001, respectively). Acute PV reconnection (spontaneous or adenosine-provoked) was associated with a significantly higher incidence of recurrent atrial tachyarrhythmia in the cryoballoon group (hazard ratio [HR] 2.39; 95% confidence interval [CI] 1.44-3.96; P = .0007) but not in the CF-RF group (HR 1.47; 95% CI 0.84-2.58; P = .16). In the absence of acute reconnection, the freedom from recurrent arrhythmia did not differ between groups (HR 0.95; 95% CI 0.6057-1.495; P = .83)., Conclusion: Patients without spontaneous or adenosine-provoked reconnection had better outcomes compared to those with acute PV reconnection, suggesting that efforts should be directed toward ensuring an ideal ablation lesion at the first attempt in order to achieve durable PV isolation., (Copyright © 2020 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Access to pacemakers and defibrillators is problematic in places with limited resources. Resterilization and reuse of implantable cardiac devices obtained post mortem from patients in wealthier nations have been undertaken, but uncertainty around the risk of infection is a concern., Methods: A multinational program was initiated in 1983 to provide tested and resterilized pacemakers and defibrillators to underserved nations; a prospective registry was established in 2003. Patients who received reused devices in this program were matched in a 1:3 ratio with control patients who received new devices implanted in Canada. The primary outcome was infection or device-related death, with mortality from other causes modeled as a competing risk., Results: Resterilized devices were implanted in 1051 patients (mean [±SD] age, 63.2±18.5 years; 43.6% women) in Mexico (36.0%), the Dominican Republic (28.1%), Guatemala (26.6%), and Honduras (9.3%). Overall, 85% received pacemakers and 15% received defibrillators, with one (55.5%), two (38.8%), or three (5.7%) leads. Baseline characteristics did not differ between these patients and the 3153 matched control patients. At 2 years of follow-up, infections had occurred in 21 patients (2.0%) with reused devices and in 38 (1.2%) with new devices (hazard ratio, 1.66; 95% confidence interval, 0.97 to 2.83; P = 0.06); there were no device-related deaths. The most common implicated pathogens were Staphylococcus aureus and S. epidermidis ., Conclusions: Among patients in underserved countries who received a resterilized and reused pacemaker or defibrillator, the incidence of infection or device-related death at 2 years was 2.0%, an incidence that did not differ significantly from that seen among matched control patients with new devices in Canada., (Copyright © 2020 Massachusetts Medical Society.)

Background: Pulmonary vein isolation by catheter ablation is a class IA indication for the treatment of symptomatic, drug-refractory, paroxysmal atrial fibrillation (PAF). Quality of life (QoL) has been identified as a clinically meaningful endpoint but has not been comprehensively evaluated to date., Objective: The purpose of this study was to evaluate the effects of cryoballoon ablation on long-term QoL., Methods: As part of the STOP-AF Post-Approval Study, QoL was assessed using the Short Form-12 Health Survey (SF-12) along with evaluation of arrhythmia-related symptoms through 36 months. A multivariate linear mixed effects regression was used to determine the association between atrial fibrillation symptoms and QoL scores, and univariate linear regressions were used to assess predictors of 36-month change in QoL scores., Results: Three hundred thirty-five subjects fully completed SF-12 forms at baseline, with 319, 308, 291, and 278 subjects completing surveys at the subsequent follow-up visits. Both physical and mental composite scores increased significantly from baseline (P <.001), and all arrhythmia symptoms significantly decreased from baseline (P <.001), with 62.0% of subjects reporting no symptoms at 6 months compared to 5.7% at baseline (P <.001). Presence of dyspnea and fatigue at baseline were univariate predictors of physical QoL improvement (P = .045 and 0.0497, respectively), whereas each year of age and each year of PAF duration were predictors of a decrease in mental QoL (P = .014 and .04, respectively)., Conclusion: Cryoballoon ablation for treatment of PAF results in a significant, and sustained, QoL improvement. The observed improvement in physical and mental health likely may be mediated by a reduction in symptom and arrhythmia burden., (Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Advanced generation ablation technologies have been developed to achieve more effective pulmonary vein isolation (PVI) and minimize arrhythmia recurrence after atrial fibrillation (AF) ablation., Methods: We randomly assigned 346 patients with drug-refractory paroxysmal AF to contact force-guided radiofrequency ablation (CF-RF; n=115), 4-minute cryoballoon ablation (Cryo-4; n=115), or 2-minute cryoballoon ablation (Cryo-2; n=116). Follow-up was 12 months. The primary outcome was time to first documented recurrence of symptomatic or asymptomatic atrial tachyarrhythmia (AF, atrial flutter, or atrial tachycardia) between days 91 and 365 after ablation or a repeat ablation procedure at any time. Secondary end points included freedom from symptomatic arrhythmia and AF burden. All patients received an implantable loop recorder., Results: One-year freedom from atrial tachyarrhythmia defined by continuous rhythm monitoring was 53.9%, 52.2%, and 51.7% with CF-RF, Cryo-4, and Cryo-2, respectively ( P =0.87). One-year freedom from symptomatic atrial tachyarrhythmia defined by continuous rhythm monitoring was 79.1%, 78.2%, and 73.3% with CF-RF, Cryo-4, and Cryo-2, respectively ( P =0.26). Compared with the monitoring period before ablation, AF burden was reduced by a median of 99.3% (interquartile range, 67.8%-100.0%) with CF-RF, 99.9% (interquartile range, 65.3%-100.0%) with Cryo-4, and 98.4% (interquartile range, 56.2%-100.0%) with Cryo-2 ( P =0.36). Serious adverse events occurred in 3 patients (2.6%) in the CF-RF group, 6 patients (5.3%) in the Cryo-4 group, and 7 patients (6.0%) in the Cryo-2 group, with no significant difference between groups ( P =0.24). The CF-RF group had a significantly longer procedure duration but significantly shorter fluoroscopy exposure ( P <0.001 vs cryoballoon groups)., Conclusions: In this multicenter, randomized, single-blinded trial, CF-RF and 2 different regimens of cryoballoon ablation resulted in no difference in 1-year efficacy, which was 53% by time to first recurrence but >98% burden reduction as assessed by continuous cardiac rhythm monitoring., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01913522.

Minipigs are an emerging nonrodent alternative for ocular toxicology owing to anatomical similarities in the minipig eyes when compared to humans. Ocular structures and components from Göttingen minipigs were characterized and compared to species commonly used in toxicology. Ocular reference data from Göttingen minipig including intraocular pressure, vitreous electrolyte and thiol concentration, and electroretinography (ERG) data are essential to model characterization and data interpretation during drug safety assessments. Intravitreal positive control agents including gentamicin, indocyanine green, and glycine were used to demonstrate ERG alterations caused by retinal cell toxicity, light transmission obstruction, or neurotransmission interferences, respectively. Electrolyte concentrations of the aqueous and vitreous humors from Göttingen minipigs were similar to other species including humans. The reference data presented herein supports the use of the Göttingen minipig as an alternate nonrodent species in ocular toxicology.

Introduction: Delays for consultation of more than six months exist for uterine cancer. Delays in diagnosis of more than five years exist for vulvar cancer. The peak incidence of these neoplasms appear after the age of 65 years. Patient's symptoms are characteristically swelling, vaginal bleeding or itching. This study aims to understand what is happening during this period for women over 65 years old. It also tries to identify triggers during the help-seeking period., Methods: Qualitative studies using semi-structured interviews with dual analyses (semio-pragmatic and psychodynamic) have been conducted on a population of older (65+) gynaecologic cancer patients, recruited from a French oncology centre., Results: Twelve patients were interviewed. Patients' courses of action were determined by the characteristics of their symptoms, their feelings and their emotions. Representations, subjective beliefs and past experiences were employed to make sense of their symptoms. The patient's friend and family circle had an important role in incentivizing the patient to seek consultation. Multiple factors affected the path towards consulting the doctor. The initial medical contact included several challenges. The patient would consult a doctor earlier if he had more information about his illness and if his relationship with the doctor was better., Conclusion: Our findings are similar to those of other cancers. The peculiarity for this population appears to be the different representations of age-related changes in the reproductive system, and the taboo associated with this issue when facing friends and family., (Copyright © 2019 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Seizures are amongst the most frequent neurological issues encountered in pre-clinical safety testing. The objective was to characterize EEG morphologies and premonitory signs in drug-induced seizures in preclinical species. A comparative (inter-species) retrospective analysis for drug-induced seizures recorded by video-telemetry was conducted in rats (n = 53), dogs (n = 195), and non-human primates (n = 234). The most frequent premonitory signs were, in rats, myoclonus (100%), tremors (93%), salivation (75%), partial ptosis (58%) and chewing/bruxism (58%); in dogs, tremors (77%), ataxia/uncoordination (60%), myoclonus (45%), salivation (43%), excessive licking (38%), high vocalization (38%) and decreased activity (34%); in non-human primates, tremors (79%), decreased activity (70%), myoclonus (57%), retching/emesis (37%), hunched posture (30%) and ataxia/uncoordination (27%). Seizure duration ranged from 3 s to 14 min with an average of 46 ± 21 s, comparable across species. At seizure onset, spike frequency averaged 9.4 Hz for the three species compared to 4.3 Hz at seizure end. Peak average amplitudes were attained at mid-seizure and amplitudes at seizure end decreased from peak but remained higher than onset amplitudes. Spike duration was inversely correlated with frequency and presented a crescendo pattern. Morphological characteristics can serve to refine automated EEG analysis. From a regulatory perspective, the most common paradigm is to use the most sensitive species in seizure liability studies but translational potential and clinical relevance may be under represented in the decision making process in some cases. EEG morphologies during drug-induced seizures presented remarkable similarities between species and tremors were identified as a predominant premonitory clinical sign in all species., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Compelling evidence showing a link between atrial fibrillation (AF) and cognitive decline and dementia is accumulating., Methods: Blinded Randomized Trial of Anticoagulation to Prevent Ischemic Stroke and Neurocognitive Impairment in Atrial Fibrillation (BRAIN-AF) is a prospective, multicentric, double-blind, randomized-controlled trial, recruiting patients with nonvalvular AF and a low risk of stroke. Patients with a high risk of bleeding will be excluded from the study. Participants will be randomized to receive either rivaroxaban (15 mg daily) or standard of care (placebo in patients without vascular disease or acetylsalicylic acid 100 mg daily in patients with vascular disease)., Results: The primary outcome is the composite of stroke, transient ischemic attack, and cognitive decline (defined by a decrease in the Montreal Cognitive Assessment score ≥ 3 at any follow-up visit after baseline). Approximately 3250 patients will be enrolled in approximately 130 clinical sites until 609 adjudicated primary outcome events have occurred., Conclusions: BRAIN-AF determines whether oral anticoagulation therapy with rivaroxaban compared with standard of care reduces the risk of stroke, transient ischemic attack, or cognitive decline in patients with nonvalvular AF and a low risk of stroke., (Copyright © 2019 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to assess the feasibility, safety, and outcomes of a stepwise combined percutaneous approach that includes transvenous lead extraction (TLE) followed by baffle stenting and device reimplantation in patients with D-transposition of the great arteries (D-TGA) and atrial baffle dysfunction., Background: Management of baffle leak or stenosis in patients with D-TGA and atrial switch surgery is challenging in the presence of transvenous cardiac implantable electronic devices. Baffle complications hinder device-related interventions and addressing baffle dysfunction often requires TLE., Methods: All consecutive patients with D-TGA and TLE followed by a percutaneous baffle intervention at the Montreal Heart Institute between 2009 and 2018 were enrolled., Results: Ten patients, median 38.6 years of age (range 15.2 to 50.6 years), 5 males (50.0%) were included. Procedures were performed for a device-related indication in 5 patients (50.0%) and for baffle dysfunction in 5 patients (50.0%). A total of 19 leads (17 pacing, 2 defibrillation) were targeted, with a median time from implantation of 8.7 (range 4.3 to 22.1) years. A laser sheath was most frequently required for successful TLE, which was achieved in all patients. Immediate baffle stenting was performed in 9 patients (90.0%) and immediate device reimplantation in 6 (60.0%). During a median follow-up of 3.0 (range 0.1 to 8.2) years, the only complication was subpulmonary atrioventricular valve damage requiring surgery in 1 patient, 8 months after the procedure., Conclusions: A combined approach with TLE followed by baffle stenting and reimplantation appears to be safe and feasible in D-TGA patients with atrial switch, baffle dysfunction, and transvenous leads., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The prevalence of atrial fibrillation (AF) is on the rise in the aging population with congenital heart disease (CHD). A few case series have described the feasibility and early outcomes associated with radiofrequency catheter ablation of AF centered on electrically isolating pulmonary veins (PV) in patients with CHD. In contrast, cryoballoon ablation has not previously been studied in this patient population despite its theoretical advantages, which include a favorable safety profile and shorter procedural time., Aim: To assess the safety and feasibility of cryoballoon ablation for AF in an initial cohort of patients with CHD., Methods: The study population consisted of consecutive patients with CHD and cryoballoon ablation for AF at the Montreal Heart Institute between December 2012 and June 2017. Procedural complications, acute success, and 1-year freedom from recurrent AF after a single procedure with or without antiarrhythmic drugs were assessed. Procedures were performed under conscious sedation. Left atrial access was obtained via a single transseptal puncture or through an existing atrial septal defect (ASD). Cryoballoon occlusion was assessed by distal injection of 50% diluted contrast into the pulmonary vein. At least one 240-second cryothermal application was performed upon obtaining complete pulmonary vein occlusion. Following ablation, patients were routinely followed at outpatient visits at 1, 3, 6, and 12 mo, and then annually., Results: Ten patients, median age 57.9 (interquartile range 48.2-61.7) years, 60% female, met inclusion criteria and were followed for 2.8 (interquartile range 1.4-4.5) years. Two had moderately complex CHD (sinus venosus ASD with partial anomalous pulmonary venous return; aortic coarctation with a persistent left superior vena cava), with the remainder having simple defects. AF was paroxysmal in 8 (80.0%) and persistent in 2 (20.0%) patients. The pulmonary vein anatomy was normal in 6 (60.0%) patients. Four had left common PV ( n = 3) and/or 3 right PV ( n = 2). Electrical pulmonary vein isolation (PVI) was acutely successful in all. One patient had transient phrenic nerve palsy that recovered during the intervention. No major complication occurred. One year after a single ablation procedure, 6 (60%) patients remained free from AF. One patient with recurrent AF had recovered pulmonary vein conduction and underwent a second PVI procedure. A second patient had ablation of an extra-pulmonary vein trigger for AF., Conclusion: Cryoballoon ablation for AF is feasible and safe in patients with simple and moderate forms of CHD, with an excellent acute success rate and modest 1-year freedom from recurrent AF., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interest to declare.

Seizures are amongst the most frequent neurological issues encountered in pre-clinical safety testing. The objective was to characterize EEG morphologies and premonitory signs in drug-induced seizures in preclinical species. A comparative (inter-species) retrospective analysis for drug-induced seizures recorded by video-telemetry was conducted in rats (n = 53), dogs (n = 195), and non-human primates (n = 234). The most frequent premonitory signs were, in rats, myoclonus (100%), tremors (93%), salivation (75%), partial ptosis (58%) and chewing/bruxism (58%); in dogs, tremors (77%), ataxia/uncoordination (60%), myoclonus (45%), salivation (43%), excessive licking (38%), high vocalization (38%) and decreased activity (34%); in non-human primates, tremors (79%), decreased activity (70%), myoclonus (57%), retching/emesis (37%), hunched posture (30%) and ataxia/uncoordination (27%). Seizure duration ranged from 3 s to 14 min with an average of 46 ± 21 s, comparable across species. At seizure onset, spike frequency averaged 9.4 Hz for the three species compared to 4.3 Hz at seizure end. Peak average amplitudes were attained at mid-seizure and amplitudes at seizure end decreased from peak but remained higher than onset amplitudes. Spike duration was inversely correlated with frequency and presented a crescendo pattern. Morphological characteristics can serve to refine automated EEG analysis. From a regulatory perspective, the most common paradigm is to use the most sensitive species in seizure liability studies but translational potential and clinical relevance may be under represented in the decision making process in some cases. EEG morphologies during drug-induced seizures presented remarkable similarities between species and tremors were identified as a predominant premonitory clinical sign in all species., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)