KDM2A integrates DNA and histone modification signals through a CXXC/PHD module and direct interaction with HP1.

Functional genomic elements are marked by characteristic DNA and histone modification signatures. How combinatorial chromatin modification states are recognized by epigenetic reader proteins and how this is linked to their biological function is largely unknown. Here we provide a detailed molecular analysis of chromatin recognition by the lysine demethylase KDM2A. Using biochemical approaches we identify a nucleosome interaction module within KDM2A consisting of a CXXC type zinc finger, a PHD domain and a newly identified Heterochromatin Protein 1 (HP1) interaction motif that mediates direct binding between KDM2A and HP1. This nucleosome interaction module enables KDM2A to decode nucleosomal H3K9me3 modification in addition to CpG methylation signals. The multivalent engagement with DNA and HP1 results in a nucleosome binding circuit in which KDM2A can be recruited to H3K9me3-modified chromatin through HP1, and HP1 can be recruited to unmodified chromatin by KDM2A. A KDM2A mutant deficient in HP1-binding is inactive in an in vivo overexpression assay in zebrafish embryos demonstrating that the HP1 interaction is essential for KDM2A function. Our results reveal a complex regulation of chromatin binding for both KDM2A and HP1 that is modulated by DNA- and H3K9-methylation, and suggest a direct role for KDM2A in chromatin silencing

Loss of slc39a14 causes simultaneous manganese hypersensitivity and deficiency in zebrafish

Manganese neurotoxicity is a hallmark of Hypermanganesemia with Dystonia 2, an inherited manganese transporter defect caused by mutations in SLC39A14. To identify novel potential targets of manganese neurotoxicity we performed transcriptome analysis of slc39a14-/- mutant zebrafish unexposed and exposed to MnCl2. Differentially expressed genes mapped to the central nervous system and eye, and pathway analysis suggested that calcium dyshomeostasis and activation of the unfolded protein response are key features of manganese neurotoxicity. Consistent with this interpretation, MnCl2 exposure led to decreased whole animal calcium levels, locomotor defects and changes in neuronal activity within the telencephalon and optic tectum. In accordance with reduced tectal activity, slc39a14-/- zebrafish showed changes in visual phototransduction gene expression, absence of visual background adaptation and a diminished optokinetic reflex. Finally, numerous differentially expressed genes in mutant larvae normalised upon MnCl2 treatment indicating that, in addition to neurotoxicity, manganese deficiency is present either subcellularly or in specific cells or tissues. Overall, we assembled a comprehensive set of genes that mediate manganese-systemic responses and found a highly correlated and modulated network associated with calcium dyshomeostasis and cellular stress

Multi-national survey on the methods, efficacy, and safety on the post-approval clinical use of pulsed field ablation (MANIFEST-PF).

AIMS Pulsed field ablation (PFA) is a novel atrial fibrillation (AF) ablation modality that has demonstrated preferential tissue ablation, including no oesophageal damage, in first-in-human clinical trials. In the MANIFEST-PF survey, we investigated the 'real world' performance of the only approved PFA catheter, including acute effectiveness and safety-in particular, rare oesophageal effects and other unforeseen PFA-related complications. METHODS AND RESULTS This retrospective survey included all 24 clinical centres using the pentaspline PFA catheter after regulatory approval. Institution-level data were obtained on patient characteristics, procedure parameters, acute efficacy, and adverse events. With an average of 73 patients treated per centre (range 7-291), full cohort included 1758 patients: mean age 61.6 years (range 19-92), female 34%, first-time ablation 94%, paroxysmal/persistent AF 58/35%. Most procedures employed deep sedation without intubation (82.1%), and 15.1% were discharged same day. Pulmonary vein isolation (PVI) was successful in 99.9% (range 98.9-100%). Procedure time was 65 min (38-215). There were no oesophageal complications or phrenic nerve injuries persisting past hospital discharge. Major complications (1.6%) were pericardial tamponade (0.97%) and stroke (0.4%); one stroke resulted in death (0.06%). Minor complications (3.9%) were primarily vascular (3.3%), but also included transient phrenic nerve paresis (0.46%), and TIA (0.11%). Rare complications included coronary artery spasm, haemoptysis, and dry cough persistent for 6 weeks (0.06% each). CONCLUSION In a large cohort of unselected patients, PFA was efficacious for PVI, and expressed a safety profile consistent with preferential tissue ablation. However, the frequency of 'generic' catheter complications (tamponade, stroke) underscores the need for improvement

Male privilege revisited: how men in female‐dominated occupations notice and actively reframe privilege

Our article aims at refocusing the debate in privilege studies from tackling the invisibility to challenging justifications of gender privilege. Focusing on instances in which men acknowledge that they receive preferential treatment, this study sheds light on how privilege is perceived and talked about in interviews with men in female-dominated occupations. In contrast to existing literature on the invisibility of privilege to the privileged, our analysis shows that the privileging of men is indeed known to them. However, our interviewees then employ specific discursive strategies to actively reframe and thereby silence privilege. They either justify privilege as an individual achievement or as a natural advantage of male bodies. In our discussion, we show how these discursive reframings build on existing discourses on gendered bodies and neoliberal subjectivity. Based on our key argument that gendered privilege is not invisible, but it is acknowledged and then actively reframed and thereby silenced, we argue for expanding the focus of privilege studies: Instead of primarily investing in making privilege visible to those who have it, we need to challenge the discourses that allow for reframing and silencing it

Concomitant epicardial left atrial appendage ligation and left atrial ablation of atrial fibrillation: Safety, feasibility and outcome.

IntroductionWe present initial results of patients undergoing a combined procedure of epicardial LAA ligation in addition to left atrial ablation for AF.Methods9 patients were included for additional use of LARIAT as an individual treatment approach for AF. First an epicardial LAA ligation was performed, in the same procedure left atrial ablations consisting of PVI and additional substrate based modifying ablations were performed. Follow-up at 3 months and 12 months was performed.ResultsThere was only 1 minor procedural complication (11%) involving epicardial bleeding and 2 late adverse events of pericardial tamponade and stroke. At the final follow-up (median 20 months) 7 patients were in stable sinus rhythm (78%) and 2 pts had reduced AF burden.ConclusionConcomitant epicardial LAA ligation and ablation is feasible in selected patients with a reasonable risk profile. More prospective data are required to validate the safety and efficacy

Long-Term Outcomes after Catheter Ablation of Ventricular Tachycardia in Dilated vs. Ischemic Cardiomyopathy

Ischemic (ICM) and dilated cardiomyopathy (DCM) represent the two main underlying heart diseases in patients referred for catheter ablation of ventricular tachycardia (VT). While VT ablation in ischemic cardiomyopathy is relatively well-studied, data in patients with DCM are still scarce. The study aimed to compare the acute and long-term outcomes in patients with ICM and DCM who underwent VT ablation at a high-volume center. Consecutive patients who underwent VT ablation from April 2018 to April 2021 were included retrospectively. Patients with ischemic cardiomyopathy were compared to those with dilated cardiomyopathy. The primary endpoint was rate of VT recurrences, the secondary endpoints included overall mortality, rehospitalization because of cardiac condition (VT, acute heart failure, acute myocardial infarction, heart transplantation or implantation of left ventricular assisting device), and major adverse cardiac events (MACE) at long-term follow-up. A total of 225 patients admitted for first VT ablation were included. A total of 156 patients (69%) revealed ICM and 69 (31%) DCM. After a mean follow-up of 22 months, the primary endpoint of VT recurrence occurred significantly more often in the patients with dilated cardiomyopathy (ICM n = 47; 37% vs. DCM n = 34; 64%; p = 0.001). In regard to the secondary endpoint of overall mortality, there was no difference between the two patient cohorts (DCM n = 9; 15% vs. ICM n = 22; 16%; p = 0.677); the patients with DCM showed significantly higher rehospitalization rates due to cardiac conditions (75% vs. 59%; p = 0.038) and more frequent MACE (68% vs. 52%; p= 0.036). In a Cox regression model, electrical storm at admission was shown to be a predictor for VT recurrence after successful catheter ablation (HR = 1.942: 95% CI 1.237–3.050; p = 0.004), while the ablation of every induced VT morphology during the procedure (HR = 0.522; 95% CI = 0.307–0.885; p = 0.016) contributed to a positive long-term outcome. DCM is associated with a higher risk of VT recurrence after catheter ablation compared to ICM. Furthermore, patients with DCM are more frequent re-hospitalized in the majority of cases due the VT recurrence. There is no difference in the long-term mortality between the two cohorts

Recurrent Atrial Fibrillation Ablation after Initial Successful Pulmonary Vein Isolation

Background: Pulmonary vein isolation (PVI) is an effective treatment option for patients with symptomatic atrial fibrillation (AF). However, the electrical recovery of pulmonary veins (PVs) is the main trigger for AF recurrences. This study investigates the characteristics of patients admitted for redo AF ablation, the PV reconnection rates depending on previous ablation modalities and the impact of different ablation strategies for redo procedures. Methods: Consecutive patients undergoing first redo AF ablation were included. Patients were grouped according to the electrical recovery of at least one PV. The impacts of the technique for first AF ablation on PV reconnection rates and patients with and without PV reconnection were compared. Different ablation strategies for redo procedures were compared and its recurrence rates after a mean follow-up of 25 ± 20 months were investigated. Results: A total of 389 patients (68 ± 10 years; 57% male; 39% paroxysmal AF) underwent a first redo. The median time between the first and redo procedure was 40 ± 39 months. Radiofrequency was used in 278 patients, cryoballoon was used in 85 patients and surgical AF ablation was performed on 26 patients. In total, 325 patients (84%) had at least one PV reconnected, and the mean number of reconnected PVs was 2.0 ± 1.3, with significant differences between ablation approaches (p for all = 0.002); this was mainly due to differences in the left inferior PV and right superior PV reconnections. The presence of PV reconnection during redo was not associated with better long-term success compared to completely isolated PVs (67% vs. 67%; log-rank p = 0.997). Overall, the different ablation strategies for redos were comparable regarding AF recurrences during follow-up (p = 0.079), with the ablation approach having no impact in the case of left atrial low voltage or without. Conclusions: PV reconnections after initial successful PVI are common among all techniques of AF ablation. Long-term rhythm control off antiarrhythmic drugs was possible in 2/3 of all patients after the redo procedure; however, different ablation strategies with extra-PV trigger ablation did not improve long-term success. Patients with recurrent AF after PVI constitute a challenging group of patients