Catheter Ablation of Atrial Tachycardia after Pulmonary Vein Isolation in a Patient with Common Ostium of Inferior Pulmonary Veins: Case Report.

Background and Objectives: Atrial fibrillation (AF), a prevalent cardiac arrhythmia, significantly impacts the quality of life of those affected. The preferred treatment for symptomatic AF, particularly when pharmacological methods fall short, is catheter ablation with pulmonary vein isolation (PVI). While common pulmonary vein (PV) anatomical variants, such as the right accessory pulmonary vein and the common ostium of left pulmonary veins (LCPV), have been studied extensively, their impact on the long-term outcome of PVI is known to be minimal. However, data on less common anomalies, like the common ostium of the left and right inferior pulmonary vein (CIPV), remain scarce in the medical literature. This report aims to shed light on the challenges and outcomes of catheter ablation in a patient with a rare CIPV anomaly. By presenting this case, we contribute to the limited knowledge about the management of such unique anatomical variations in AF treatment and discuss the importance of individualized treatment approaches. Case Presentation: We present a case involving a 56-year-old male diagnosed with AF in 2018. Initial PVI treatment was successful, but the patient experienced symptom recurrence after three years. A preprocedural CT scan before the second ablation revealed a CIPV anomaly. During the repeat procedure, a right superior pulmonary vein (RSPV) reisolation was performed due to identified gaps in the previous ablation line. Post-procedure, the patient maintained a sinus rhythm and reported no further symptoms. Conclusions: This case highlights the importance of recognizing rare PV anatomies like CIPV in the effective management of AF. Tailored ablation strategies, accounting for unique anatomical conditions, can lead to successful long-term outcomes, reinforcing the need for personalized approaches in AF treatment, especially in cases involving complex anatomical variations.

Inappropriate shock delivery as a result of electromagnetic interference originating from the faulty electrical installation.

We present a case report of a 74-year-old male patient with an implantable cardioverter defibrillator who suffered an inappropriate defibrillation shock while bathing in the tub. Insight in the ICD stored electrogram episodes revealed electromagnetic interferences, with a typical 50 Hz electrical artifact mimicking fast ventricular tachycardia as a device misinterpreted. After this event, the maintenance workers investigated the electrical installation in the bathroom and revealed that there was voltage leaking between electrical installation and metal pipes. After the repair was completed without any additional programming, the patient has had no subsequent shocks.

Comparison of Gene Expression Responses in the Small Intestine of Mice Following Exposure to 3 Carcinogens Using the S1500+ Gene Set Informs a Potential Common Adverse Outcome Pathway.

Carcinogenesis of the small intestine is rare in humans and rodents. Oral exposure to hexavalent chromium (Cr(VI)) and the fungicides captan and folpet induce intestinal carcinogenesis in mice. Previously (Toxicol Pathol. 330:48-52), we showed that B6C3F1 mice exposed to carcinogenic concentrations of Cr(VI), captan, or folpet for 28 days exhibited similar histopathological responses including villus enterocyte cytotoxicity and regenerative crypt epithelial hyperplasia. Herein, we analyze transcriptomic responses from formalin-fixed, paraffin-embedded duodenal sections from the aforementioned study. TempO-Seq technology and the S1500+ gene set were used to analyze transcription responses. Transcriptional responses were similar between all 3 agents; gene-level comparison identified 126/546 (23%) differentially expressed genes altered in the same direction, with a total of 25 upregulated pathways. These changes were related to cellular metabolism, stress, inflammatory/immune cell response, and cell proliferation, including upregulation in hypoxia inducible factor 1 (HIF-1) and activator protein 1 (AP1) signaling pathways, which have also been shown to be related to intestinal injury and angiogenesis/carcinogenesis. The similar molecular-, cellular-, and tissue-level changes induced by these 3 carcinogens can be informative for the development of an adverse outcome pathway for intestinal cancer.

Miro's N-terminal GTPase domain is required for transport of mitochondria into axons and dendrites.

Mitochondria are dynamically transported in and out of neuronal processes to maintain neuronal excitability and synaptic function. In higher eukaryotes, the mitochondrial GTPase Miro binds Milton/TRAK adaptor proteins linking microtubule motors to mitochondria. Here we show that Drosophila Miro (dMiro), which has previously been shown to be required for kinesin-driven axonal transport, is also critically required for the dynein-driven distribution of mitochondria into dendrites. In addition, we used the loss-of-function mutations dMiroT25N and dMiroT460N to determine the significance of dMiro's N-terminal and C-terminal GTPase domains, respectively. Expression of dMiroT25N in the absence of endogenous dMiro caused premature lethality and arrested development at a pupal stage. dMiroT25N accumulated mitochondria in the soma of larval motor and sensory neurons, and prevented their kinesin-dependent and dynein-dependent distribution into axons and dendrites, respectively. dMiroT25N mutant mitochondria also were severely fragmented and exhibited reduced kinesin and dynein motility in axons. In contrast, dMiroT460N did not impair viability, mitochondrial size, or the distribution of mitochondria. However, dMiroT460N reduced dynein motility during retrograde mitochondrial transport in axons. Finally, we show that substitutions analogous to the constitutively active Ras-G12V mutation in dMiro's N-terminal and C-terminal GTPase domains cause neomorphic phenotypic effects that are likely unrelated to the normal function of each GTPase domain. Overall, our analysis indicates that dMiro's N-terminal GTPase domain is critically required for viability, mitochondrial size, and the distribution of mitochondria out of the neuronal soma regardless of the employed motor, likely by promoting the transition from a stationary to a motile state.

A Morphology-Preserving Algorithm for Denoising of EMG-Contaminated ECG Signals.

Goal: Clinical interpretation of an electrocardiogram (ECG) can be detrimentally affected by noise. Removal of the electromyographic (EMG) noise is particularly challenging due to its spectral overlap with the QRS complex. The existing EMG-denoising algorithms often distort signal morphology, thus obscuring diagnostically relevant information. Methods: Here, a new iterative regeneration method (IRM) for efficient EMG-noise suppression is proposed. The main hypothesis is that the temporary removal of the dominant ECG components enables extraction of the noise with the minimum alteration to the signal. The method is validated on SimEMG database of simultaneously recorded reference and noisy signals, MIT-BIH arrhythmia database and synthesized ECG signals, both with the noise from MIT Noise Stress Test Database. Results: IRM denoising and morphology-preserving performance is superior to the wavelet- and FIR-based benchmark methods. Conclusions: IRM is reliable, computationally non-intensive, fast and applicable to any number of ECG channels recorded by mobile or standard ECG devices.

Telemedicine in the Era of a Pandemic: Usefulness of a Novel Three-Lead ECG.

The 12-lead electrocardiogram (ECG) is a first-line diagnostic tool for patients with cardiac symptoms. As observed during the COVID-19 pandemic, the ECG is essential to the initial patient evaluation. The novel KardioPal three-lead-based ECG reconstructive technology provides a potential alternative to a standard ECG, reducing the response time and cost of treatment and improving patient comfort. Our study aimed to evaluate the diagnostic accuracy of a reconstructed 12-lead ECG obtained by the KardioPal technology, comparing it with the standard 12-lead ECG, and to assess the feasibility and time required to obtain a reconstructed ECG in a real-life scenario. A prospective, nonrandomized, single-center, adjudicator-blinded trial was conducted on 102 patients during the COVID-19 pandemic at the Dedinje Cardiovascular Institute in Belgrade. The KardioPal system demonstrated a high feasibility rate (99%), with high specificity (96.3%), sensitivity (95.8%), and diagnostic accuracy (96.1%) for obtaining clinically relevant matching of reconstructed 12-lead compared to the standard 12-lead ECG recording. This novel technology provided a significant reduction in ECG acquisition time and the need for personnel and space for obtaining ECG recordings, thereby reducing the risk of viral transmission and the burden on an already overwhelmed healthcare system such as the one experienced during the COVID-19 pandemic.

A Database of Simultaneously Recorded ECG Signals With and Without EMG Noise.

Goal: Noise on recorded electrocardiographic (ECG) signals may affect their clinical interpretation. Electromyographic (EMG) noise spectrally coincides with the QRS complex, which makes its removal particularly challenging. The problem of evaluating the noise-removal techniques has commonly been approached by algorithm testing on the contaminated ECG signals constructed ad hoc as an additive mixture of a noise-free ECG signal and noise. Consequently, there is an absence of a unique/standard database for testing and comparing different denoising methods. We present a SimEMG database recorded by a novel acquisition method that allows for direct recording of the genuine EMG-noise-free and -contaminated ECG signals. The database is available as open source.

Racial and ethnic characteristics and cancer-specific survival in Primary Malignant Cardiac Tumors.

Background: There is limited insight into the epidemiological characteristics and effect of race and ethnicity on Primary Malignant Cardiac Tumors (PMCTs). Objectives: Comparison of clinical characteristics and cancer-specific survival outcomes of major races in the United States from the Surveillance, Epidemiology and End-Result (SEER) registry. Methods: ICD-O-3 codes were used to identify PMCTs for the years 1975 to 2015. Three major races were identified-"White", "Black", and "Asian/Pacific Islander". Cancer-specific survival outcomes were compared using Kaplan-Meier analysis across and amongst races, based on tumor histology. A subgroup analysis of cancer-specific survival was performed between "Hispanics" and "non-Hispanics." Results: Seven hundred and twenty patients were identified-47% females and 79% White, mean age at diagnosis (47 ± 20 years). Black patients were significantly younger (39 ± 18 years) and presented more commonly with angiosarcomas (53%). Non-angiogenic sarcomas and lymphomas were the most common tumors in the White (38%) and Asian/Pacific Islander (34%) cohorts. For a median follow-up period of 50 (IQR3-86) months, cancer-specific survival (mean ± SD, in months) was worse in Blacks (9 ± 3) as compared to Whites (15 ± 1) and Asian/Pacific Islander (14 ± 1) (p-value; Black vs. White <0.001; Black vs. Asian/Pacific Islanders = 0.017, White vs. Asian/Pacific Islanders = 0.3). Subgroup analysis with 116 (16%) Hispanics (40% females; mean age of 40 ± 20 years) showed a longer mean cancer-specific survival of 16.9 ± 2.4 months as compared to 13.6 ± 1.1 months in non-Hispanics (p = 0.011). Conclusion: Black and non-Hispanic patients have poorer cancer-specific survival in PMCTs.

Severe pacemaker pocket infection during the COVID-19 pandemic, transvenous lead removal.

INTRODUCTION: The estimated infection rate after permanent endocardial lead implantation is between 1% and 2%. Pacemaker lead endocarditis is treated with total removal of the infected device and proper antibiotics. In this case report, we present a patient with delayed diagnosis and treatment due to the COVID-19 outbreak. CASE REPORT: An 88-year-old, pacemaker dependent woman with diagnosed pacemaker pocket infection was admitted to the University Cardiovascular institute. The patient had a prolonged follow-up time due to the COVID-19 outbreak. She missed her routine checkup and came to her local hospital when the generator had already protruded completely, to the point where she held it in her own hand. Transthoracic echocardiogram showed possible vegetations on the lead. Transesophageal echocardiography was not performed due to the COVID-19 pandemic. On the day after the admission the patient underwent transvenous removal of the pacemaker lead using a 9 French gauge rotational extraction sheathe (Cook Medical). The extracted lead was covered in a thin layer of vegetations. Further follow-ups showed good recovery with no complications. CONCLUSIONS: A case showing delayed treatment of pacemaker pocket infection, due to delayed follow-up time during the COVID-19 pandemic. This patient underwent successful transvenous removal of the infected pacemaker lead, along with adequate antibiotic therapy, which has proven to be the most effective method of treating cardiac device-related endocarditis.

Direct-acting oral anticoagulants versus warfarin in relation to risk of gastrointestinal bleeding: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Direct-acting oral anticoagulants (DOACs) are increasingly used, with studies showing a lower risk of gastrointestinal bleeding (GIB), but overall data for GIB risk remains debatable. The objective was to assess non-fatal and fatal GIB risk in patients on DOACs compared with warfarin from randomized clinical trials (RCTs). METHODS: RCTs comparing warfarin and DOACs for various indications (atrial fibrillation, thromboembolism, insertion of mechanical heart valves) were included. The primary endpoint was any GIB event. Other clinical events, such as fatal GIB, and effects of age (≤60 years or older), time in therapeutic range for warfarin, and choice of individual DOACs on GIB risk, were also assessed. RESULTS: 14 RCTs were included, comprising 87,407 participants (DOACs n=46,223, warfarin control n=41,184). The risk of GIB with DOACs was similar to that of warfarin (relative risk [RR] 1.04, 95% confidence interval [CI] 0.85-1.27). Compared with warfarin, rivaroxaban (RR 1.23, 95%CI 1.03-1.48) and dabigatran (RR 1.38, 95%CI 1.12-1.71) had a higher risk of any GIB, whereas fatal GIB risk was lower in the DOACs group (RR 0.36, 95%CI 0.15-0.82). The risk of DOAC-related fatal GIB was lower in patients aged ≤60 years and in those with poor coagulation control (RR 0.39, 95%CI 0.15-0.98). CONCLUSIONS: DOACs compared with warfarin have a lower risk of fatal GIB, especially in those aged <60 years and those with poor coagulation control. However, the risk of GIB was comparable with warfarin and DOACs, except for rivaroxaban and dabigatran.

Extraction-free whole transcriptome gene expression analysis of FFPE sections and histology-directed subareas of tissue.

We describe the use of a ligation-based targeted whole transcriptome expression profiling assay, TempO-Seq, to profile formalin-fixed paraffin-embedded (FFPE) tissue, including H&E stained FFPE tissue, by directly lysing tissue scraped from slides without extracting RNA or converting the RNA to cDNA. The correlation of measured gene expression changes in unfixed and fixed samples using blocks prepared from a pellet of a single cell type was R2 = 0.97, demonstrating that no significant artifacts were introduced by fixation. Fixed and fresh samples prepared in an equivalent manner produced comparable sequencing depth results (+/- 20%), with similar %CV (11.5 and 12.7%, respectively), indicating no significant loss of measurable RNA due to fixation. The sensitivity of the TempO-Seq assay was the same whether the tissue section was fixed or not. The assay performance was equivalent for human, mouse, or rat whole transcriptome. The results from 10 mm2 and 2 mm2 areas of tissue obtained from 5 µm thick sections were equivalent, thus demonstrating high sensitivity and ability to profile focal areas of histology within a section. Replicate reproducibility of separate areas of tissue ranged from R2 = 0.83 (lung) to 0.96 (liver) depending on the tissue type, with an average correlation of R2 = 0.90 across nine tissue types. The average %CVs were 16.8% for genes expressed at greater than 200 counts, and 20.3% for genes greater than 50 counts. Tissue specific differences in gene expression were identified and agreed with the literature. There was negligible impact on assay performance using FFPE tissues that had been archived for up to 30 years. Similarly, there was negligible impact of H&E staining, facilitating accurate visualization for scraping and assay of small focal areas of specific histology within a section.

SIGNAL TRANSDUCTION. Membrane potential modulates plasma membrane phospholipid dynamics and K-Ras signaling.

Plasma membrane depolarization can trigger cell proliferation, but how membrane potential influences mitogenic signaling is uncertain. Here, we show that plasma membrane depolarization induces nanoscale reorganization of phosphatidylserine and phosphatidylinositol 4,5-bisphosphate but not other anionic phospholipids. K-Ras, which is targeted to the plasma membrane by electrostatic interactions with phosphatidylserine, in turn undergoes enhanced nanoclustering. Depolarization-induced changes in phosphatidylserine and K-Ras plasma membrane organization occur in fibroblasts, excitable neuroblastoma cells, and Drosophila neurons in vivo and robustly amplify K-Ras-dependent mitogen-activated protein kinase (MAPK) signaling. Conversely, plasma membrane repolarization disrupts K-Ras nanoclustering and inhibits MAPK signaling. By responding to voltage-induced changes in phosphatidylserine spatiotemporal dynamics, K-Ras nanoclusters set up the plasma membrane as a biological field-effect transistor, allowing membrane potential to control the gain in mitogenic signaling circuits.

Terminal remission is possible in some patients with juvenile myoclonic epilepsy without therapy.

INTRODUCTION: Juvenile myoclonic epilepsy is considered to be a chronic disease requiring lifelong antiepileptic treatment. The aim of this study was both to identify factors predicting the kind of seizure control and to investigate the outcome in patients after therapy withdrawal. MATERIAL AND METHODS: The study included 87 patients (49 female, 38 male), aged from 17.5 to 43.5 years, referred to our Department between 1987 and 2008, with the seizure onset at the age of 14.3±2.9, and followed up for 13.3±5.8 years on average (from 5 to 23 years). RESULTS: Sixty seven (77.0%) patients were fully controlled; whereas 13.8% had persistent seizures and 9.2% showed pseudoresistance. The combination of three seizure types and focal electroencephalogram features were independent factors of poor seizure control. Therapy was discontinued in 34 patients either by the treating physician (in 21 patients) or by the patients themselves (in 13 cases). In 18 subjects, all seizure types relapsed after 1.1 year on average (from 7 days to 4 years) and therapy was resumed in them. All patients but three (10/13), who stopped the treatment themselves, experienced recurrences. Seizure freedom off drugs was recorded in 10.3% patients. Nonintrusive myoclonic seizures recurred in 0.5-3 years as their only seizure type in four patients, but without reintroducing medication in three patients. CONCLUSION: Combination of seizure types and focal electroencephalogram features are significant factors of pharmacoresistancy. Continuous pharmacotherapy is required in majority of patients, although about 10% of them appear to have permanent remission without therapy in adolescence.

PINK1-mediated phosphorylation of Miro inhibits synaptic growth and protects dopaminergic neurons in Drosophila.

Mutations in the mitochondrial Ser/Thr kinase PINK1 cause Parkinson's disease. One of the substrates of PINK1 is the outer mitochondrial membrane protein Miro, which regulates mitochondrial transport. In this study, we uncovered novel physiological functions of PINK1-mediated phosphorylation of Miro, using Drosophila as a model. We replaced endogenous Drosophila Miro (DMiro) with transgenically expressed wildtype, or mutant DMiro predicted to resist PINK1-mediated phosphorylation. We found that the expression of phospho-resistant DMiro in a DMiro null mutant background phenocopied a subset of phenotypes of PINK1 null. Specifically, phospho-resistant DMiro increased mitochondrial movement and synaptic growth at larval neuromuscular junctions, and decreased the number of dopaminergic neurons in adult brains. Therefore, PINK1 may inhibit synaptic growth and protect dopaminergic neurons by phosphorylating DMiro. Furthermore, muscle degeneration, swollen mitochondria and locomotor defects found in PINK1 null flies were not observed in phospho-resistant DMiro flies. Thus, our study established an in vivo platform to define functional consequences of PINK1-mediated phosphorylation of its substrates.

Memory, synapse stability, and ß-adducin.

In this issue of Neuron, two studies by Pielage et al. and Bednarek and Caroni suggest that the cytoskeleton regulator ß-Adducin provides an activity-dependent switch controlling synapse disassembly and assembly at the Drosophila neuromuscular junction (NMJ) and the mouse hippocampus. In mice, the ß-Adducin switch is required for the improvement of learning and memory induced by enriched environments.

Mitochondrial transport dynamics in axons and dendrites.

Mitochondrial dynamics and transport have emerged as key factors in the regulation of neuronal differentiation and survival. Mitochondria are dynamically transported in and out of axons and dendrites to maintain neuronal and synaptic function. Transport proceeds through a controlled series of plus- and minus-end directed movements along microtubule tracks (MTs) that are often interrupted by short stops. This bidirectional motility of mitochondria is facilitated by plus end-directed kinesin and minus end-directed dynein motors, and may be coordinated and controlled by a number of mechanisms that integrate intracellular signals to ensure efficient transport and targeting of mitochondria. In this chapter, we discuss our understanding of mechanisms that facilitate mitochondrial transport and delivery to specific target sites in dendrites and axons.