Observable Atrial and Ventricular Fibrillation Episode Durations Are Conformant With a Power Law Based on System Size and Spatial Synchronization.

BACKGROUND: Atrial fibrillation (AF) and ventricular fibrillation (VF) episodes exhibit varying durations, with some spontaneously ending quickly while others persist. A quantitative framework to explain episode durations remains elusive. We hypothesized that observable self-terminating AF and VF episode lengths, whereby durations are known, would conform with a power law based on the ratio of system size and correlation length ([Formula: see text]. METHODS: Using data from computer simulations (2-dimensional sheet and 3-dimensional left-atrial), human ischemic VF recordings (256-electrode sock, n=12 patients), and human AF recordings (64-electrode basket-catheter, n=9 patients; 16-electrode HD-grid catheter, n=42 patients), conformance with a power law was assessed using the Akaike information criterion, Bayesian information criterion, coefficient of determination (R2, significance=P<0.05) and maximum likelihood estimation. We analyzed fibrillatory episode durations and [Formula: see text], computed by taking the ratio between system size ([Formula: see text], chamber/simulation size) and correlation length ([Formula: see text], measured from pairwise correlation coefficients over electrode/node distance). RESULTS: In all computer models, the relationship between episode durations and [Formula: see text] was conformant with a power law (Aliev-Panfilov R2: 0.90, P<0.001; Courtemanche R2: 0.91, P<0.001; Luo-Rudy R2: 0.61, P<0.001). Observable clinical AF/VF durations were also conformant with a power law relationship (VF R2: 0.86, P<0.001; AF basket R2: 0.91, P<0.001; AF grid R2: 0.92, P<0.001). [Formula: see text] also differentiated between self-terminating and sustained episodes of AF and VF (P<0.001; all systems), as well as paroxysmal versus persistent AF (P<0.001). In comparison, other electrogram metrics showed no statistically significant differences (dominant frequency, Shannon Entropy, mean voltage, peak-peak voltage; P>0.05). CONCLUSIONS: Observable fibrillation episode durations are conformant with a power law based on system size and correlation length.

A series of potent BODIPY photosensitisers featuring tellurophene motifs at boron.

This article describes the synthesis and photophysical properties of a series of BODIPY photosensitisers that feature tellurophene motifs appended at the boron centre. These compounds were obtained via nucleophilic substitution of various F-BODIPYs with lithiated tellurophene. The synthetic scope, photophysical characteristics and photosensitisation properties are discussed. Structural modifications around the BODIPY core resulted in an eight-fold improvement in light IC50 values compared to previous designs.

Catheter Ablation for Atrial Fibrillation-Influence of Modifiable Risk Factors and Ablation Modality on Procedural Efficacy and Safety.

BACKGROUND: Modifiable lifestyle risk factors, in particular obesity and related conditions, are important drivers of atrial fibrillation (AF), impacting the severity of symptoms and influence the efficacy and safety of treatment. OBJECTIVE: The study aimed to assess the impact of modifiable lifestyle factors on the effectiveness and safety of AF ablation, and examine the procedural characteristics, efficacy, safety and cost outcomes of cryoballoon vs radiofrequency ablation, in a real-world clinical setting. METHOD: Patients undergoing catheter ablation for AF (June 2017 to December 2020) were included in this retrospective analysis. Efficacy and safety outcomes were obtained from electronic medical records and state-wide databases. The primary outcome was successful isolation of the pulmonary veins and freedom from AF without repeat ablation or ongoing antiarrhythmic therapy at 12 months. RESULTS: The study included 141 patients (mean age 60±11 years, 57% male). The average body mass index (BMI) was 29.2±5.6 kg/m2. Ablation by cryoballoon was undertaken in 59% (radiofrequency 41%). Acutely successful pulmonary vein isolation was achieved in 92%, however, only 52% (n=74) met the primary outcome (successful isolation of the pulmonary veins and freedom from AF without repeat ablation or ongoing antiarrhythmic therapy) at 12 months. Successful management of AF was more likely in patients with lower BMI (p=0.006; particularly with BMI <27 kg/m2; p=0.004) and weight (p=0.003), and in those without obstructive sleep apnoea (p=0.032). The only independent predictor of the primary outcome was BMI (ß=0.25, p=0.004). Over 75% of complications occurred in those with BMI ≥27 kg/m2. CONCLUSIONS: Catheter ablation for AF is more likely to be unsuccessful in patients with uncontrolled risk factors, particularly obesity. Risk factor optimisation may improve procedural success and reduce the risk of procedural complications.

Outcomes With Single-Site Dual-Lumen Versus Multisite Cannulation for Adults With COVID-19 Respiratory Failure Receiving Venovenous Extracorporeal Membrane Oxygenation.

OBJECTIVES: To determine whether multisite versus single-site dual-lumen (SSDL) cannulation is associated with outcomes for COVID-19 patients requiring venovenous extracorporeal membrane oxygenation (VV-ECMO). DESIGN: Retrospective analysis of the Extracorporeal Life Support Organization Registry. Propensity score matching (2:1 multisite vs SSDL) was used to control for confounders. PATIENTS: The matched cohort included 2,628 patients (1,752 multisite, 876 SSDL) from 170 centers. The mean ( sd ) age in the entire cohort was 48 (11) years, and 3,909 (71%) were male. Patients were supported with mechanical ventilation for a median (interquartile range) of 79 (113) hours before VV-ECMO support. INTERVENTIONS: None. MEASUREMENTS: The primary outcome was 90-day survival. Secondary outcomes included survival to hospital discharge, duration of ECMO support, days free of ECMO support at 90 days, and complication rates. MAIN RESULTS: There was no difference in 90-day survival (49.4 vs 48.9%, p = 0.66), survival to hospital discharge (49.8 vs 48.2%, p = 0.44), duration of ECMO support (17.9 vs 17.1 d, p = 0.82), or hospital length of stay after cannulation (28 vs 27.4 d, p = 0.37) between multisite and SSDL groups. More SSDL patients were extubated within 24 hours (4% vs 1.9%, p = 0.001). Multisite patients had higher ECMO flows at 24 hours (4.5 vs 4.1 L/min, p < 0.001) and more ECMO-free days at 90 days (3.1 vs 2.0 d, p = 0.02). SSDL patients had higher rates of pneumothorax (13.9% vs 11%, p = 0.03). Cannula site bleeding (6.4% vs 4.7%, p = 0.03), oxygenator failure (16.7 vs 13.4%, p = 0.03), and circuit clots (5.5% vs 3.4%, p = 0.02) were more frequent in multisite patients. CONCLUSIONS: In this retrospective study of COVID-19 patients requiring VV-ECMO, 90-day survival did not differ between patients treated with a multisite versus SSDL cannulation strategy and there were only modest differences in major complication rates. These findings do not support the superiority of either cannulation strategy in this setting.

BODIPYs with Chalcogenophenes at Boron: Synthesis and Properties.

Reported herein are the synthesis and characterization of BODIPYs bearing heterocycles at boron. To synthesize this series, various chalcogenophenes (furan, thiophene, selenophene, and tellurophene) were lithiated and then used as nucleophiles to attack the boron center of a parent F-BODIPY. Compounds in the series were compared with respect to their photophysical and structural properties, and trends were discussed. By virtue of the "heavy atom effect", as the mass of the heterocycle appended to the BODIPY core increases, compounds exhibit a higher singlet oxygen quantum yield. The BODIPY with tellurophene at boron exhibits the highest quantum yield (ΦΔ = 0.68) in the series and reduced emission (Φf = 0.01).

Pseudo loss of capture on 12 lead electrocardiogram in patient with an implantable cardiac defibrillator.

This case report presents a 70-year-old-male, brought in by ambulance for assessment of chest pain and presyncope, with a paced ECG showing possible non-capture following ventricular pacing spikes. This was demonstrated to be pseudo non-capture with a 12-lead electrocardiogram performed in emergency and a device interrogation demonstrating ventricular capture.

Evaluating the magnet response in deep subcutaneous implanted cardioverter defibrillator implants.

INTRODUCTION: The manufacturer of subcutaneous implantable cardioverter defibrillators (S-ICDs) acknowledges that 'deep implants' may fail to elicit a magnet response, however, does not define 'deep implant' or recommend a maximum implant depth. This study aims to systematically evaluate the effect of subcutaneous tissue depth and magnet types on evoked magnet response. METHODS: Sunshine Coast University Hospital's S-ICD cohort underwent magnet response evaluation; where bar and donut magnets were compared and the evoked magnet response was recorded in three separate zones, guided by a template. Ordinal regression (OR) models assessed the relationship between the evoked magnet response and tissue depth (TD), measured via post-implant X-Ray. The patient's ability to hear the magnet response audible tone was recorded. RESULTS: Patients (n = 39) with measurable TD (n = 30) were analyzed. The bar magnet evoked a magnet response in all zones in 53% of patients, compared with 73% of patients with the donut magnet (p = 0.18). The relationship between bar magnet response and TD showed the odds of an evoked magnet response decreased by 11% every 1 mm increase in TD (OR of 0.89, p < 0.01), whereas the donut magnet decreased by 16% per 1 mm (OR of 0.84, p < 0.01). Directly over the S-ICD was the most effective in evoking magnet response with the bar (85% of patients), and off-centre was most effective for the donut magnet (100%). BMI and Praetorian score were not significantly associated with magnet response. We found 23% of patients were unable to detect the audible tone. CONCLUSION: We observed a statistically significant association between TD and ability to evoke magnet response. The bar magnet was less reliable than the donut magnet for therapy inhibition in deep implants.

Role of interatrial conduction in atrial fibrillation: Mechanistic insights from renewal theory-based fibrillatory dynamic analysis.

Background: Interatrial conduction has been postulated to play an important role in atrial fibrillation (AF). The pathways involved in interatrial conduction during AF remain incompletely defined. Objective: We recently showed physiological assessment of fibrillatory dynamics could be performed using renewal theory, which determines rates of phase singularity formation (λf) and destruction (λd). Using the renewal approach, we aimed to understand the role of the interatrial septum and other electrically coupled regions during AF. Method: RENEWAL-AF is a prospective multicenter observational study recruiting AF ablation patients (ACTRN 12619001172190). We studied unipolar electrograms obtained from 16 biatrial locations prior to ablation using a 16-electrode Advisor HD Grid catheter. Renewal rate constants λf and λd were calculated, and the relationships between these rate constants in regions of interatrial connectivity were examined. Results: Forty-one AF patients (28.5% female) were recruited. A positive linear correlation was observed between λf and λd (1) across the interatrial septum (λf r2 = 0.5, P < .001, λd r2 = 0.45, P < .001), (2) in regions connected by the Bachmann bundle (right atrial appendage-left atrial appendage λf r2 = 0.29, P = .001; λd r2 = 0.2, P = .008), and (3) across the inferior interatrial routes (cavotricuspid isthmus-left atrial septum λf r2 = 0.67, P < .001; λd r2 = 0.55, P < .001). Persistent AF status and left atrial volume were found to be important effect modifiers of the degree of interatrial renewal rate statistical correlation. Conclusion: Our findings support the role of interseptal statistically determined electrical disrelation in sustaining AF. Additionally, renewal theory identified preferential conduction through specific interatrial pathways during fibrillation. These findings may be of importance in identifying clinically significant targets for ablation in AF patients.

Dark Dynamic Therapy: Photosensitization without Light Excitation Using Chemiluminescence Resonance Energy Transfer in a Dioxetane-Erythrosin B Conjugate.

Reactive oxygen species (e.g., singlet oxygen) are the primary cytotoxic agents used in the clinically approved technique photodynamic therapy (PDT). Although singlet oxygen has high potential to effectively kill tumor cells, its production via light excitation of a photosensitizer has been limited by the penetration depth and delivery of light in tissue. To produce singlet oxygen without light excitation, we describe the use of Schaap's chemiluminescent scaffold comprising an adamantylidene-dioxetane motif. Functionalizing this scaffold with a photosensitizer, Erythrosin B, resulted in spontaneous chemiluminescence resonance energy transfer (CRET) leading to the production of singlet oxygen. We show that this compound is cell permeable and that the singlet oxygen produced via CRET is remarkably efficient in killing cancer cells at low micromolar concentrations. Moreover, we demonstrate that protection of the phenol on the chemiluminescent scaffold with a nitroreductase-responsive trigger group allows for cancer-selective dark dynamic cell death. Here, we present the concept of dark dynamic therapy using a small cell-permeable molecule capable of producing the effects of PDT in cells, without light.

Molecular Signature Predictive of Long-Term Liver Fibrosis Progression to Inform Antifibrotic Drug Development.

BACKGROUND & AIMS: There is a major unmet need to assess the prognostic impact of antifibrotics in clinical trials because of the slow rate of liver fibrosis progression. We aimed to develop a surrogate biomarker to predict future fibrosis progression. METHODS: A fibrosis progression signature (FPS) was defined to predict fibrosis progression within 5 years in patients with hepatitis C virus and nonalcoholic fatty liver disease (NAFLD) with no to minimal fibrosis at baseline (n = 421) and was validated in an independent NAFLD cohort (n = 78). The FPS was used to assess response to 13 candidate antifibrotics in organotypic ex vivo cultures of clinical fibrotic liver tissues (n = 78) and cenicriviroc in patients with nonalcoholic steatohepatitis enrolled in a clinical trial (n = 19, NCT02217475). A serum protein-based surrogate FPS was developed and tested in a cohort of compensated cirrhosis patients (n = 122). RESULTS: A 20-gene FPS was defined and validated in an independent NAFLD cohort (adjusted odds ratio, 10.93; area under the receiver operating characteristic curve, 0.86). Among computationally inferred fibrosis-driving FPS genes, BCL2 was confirmed as a potential pharmacologic target using clinical liver tissues. Systematic ex vivo evaluation of 13 candidate antifibrotics identified rational combination therapies based on epigallocatechin gallate, which were validated for enhanced antifibrotic effect in ex vivo culture of clinical liver tissues. In patients with nonalcoholic steatohepatitis treated with cenicriviroc, FPS modulation was associated with 1-year fibrosis improvement accompanied by suppression of the E2F pathway. Induction of the PPARα pathway was absent in patients without fibrosis improvement, suggesting a benefit of combining PPARα agonism to improve the antifibrotic efficacy of cenicriviroc. A 7-protein serum protein-based surrogate FPS was associated with the development of decompensation in cirrhosis patients. CONCLUSION: The FPS predicts long-term fibrosis progression in an etiology-agnostic manner, which can inform antifibrotic drug development.

Electrogram analysis to detect cathodal and anodal capture in left ventricular cardiac resynchronization pacing leads.

AIMS: Our study analyzed cardiac electrograms (EGMs) to identify characteristics for detecting cathodal, anodal, or cathodal-anodal (simultaneous) capture in left ventricular (LV) quadripolar pacing leads of cardiac resynchronization therapy (CRT) patients. The relationship between these EGM characteristics and the electrocardiogram (ECG) was also examined. METHODS: We performed a retrospective analysis of 54 bipolar pacing configurations across nine patients with implanted CRT devices and quadripolar leads who had undergone a 12 lead ECG optimization. Three pacing tests (cathode unipolar, anode unipolar, and bipolar) per bipolar pair were performed, examining ECG and EGM morphology changes accompanying each test and any transitions of morphology or amplitude during voltage stepdown. RESULTS: During the cathode and anode unipolar pacing tests, the EGM was biphasic (negative/positive) or monophasic (positive) in 52/53 (98%), and biphasic (positive/negative) or monophasic (negative) in 50/51 (98%), respectively. During bipolar LV capture threshold testing, 30 bipolar pairs displayed a sudden increase in EGM amplitude (median 9.4 mV, interquartile range [7-14 mV]) when transitioning from cathodal-anodal capture to cathodal or anodal capture. Ninety percent of these EGM transitions had a corresponding simultaneous change in ECG, while 10% had no ECG changes. Two patients demonstrated "quad-site" capture on their quadripolar lead with multipoint pacing enabled and cathodal-anodal capture from each stimulus. CONCLUSION: EGM characteristics during LV pacing tests can reliably detect cathodal, anodal, or cathodal-anodal capture, with greater sensitivity than 12 lead ECG changes. Integration of EGM analysis into routine CRT device follow up can be performed easily and may have implications for CRT efficacy.

Introducing the Tellurophene-Appended BODIPY: PDT Agent with Mass Cytometry Tracking Capabilities.

The synthesis and characterization of the first BODIPY appended to the five-membered heterocylic tellurophene [Te] moiety is reported. By incorporating tellurophene at the meso position, the tellurophene-appended boron-dipyrromethene dye (BODIPY) acts as a multimodal agent, becoming a potent photosensitizer with a mass cytometry tag. To synthesize the compound, we developed a method to enable late-stage Suzuki-Miyaura coupling by preparing and isolating tellurophene-2-BPin in a one-step procedure from the parent tellurophene. Coupling to a meso-substituted BODIPY functionalized with a pendant aryl bromide provides the desired tellurophene-appended BODIPY. This compound demonstrated a singlet oxygen quantum yield of 0.26 ± 0.01 and produced a light dose-dependent cytotoxicity with nanomolar IC50 values against 2D cultured HeLa cells and high efficacy against 3D cultured HeLa tumor spheroids, proving to be a strong photosensitizer. The presence of the tellurophene moiety could be detected using mass cytometry, thus showcasing the ability of a tellurophene-appended BODIPY as a novel photodynamic-therapy-mass-cytometry theranostic agent.

Prospective cross-sectional study using Poisson renewal theory to study phase singularity formation and destruction rates in atrial fibrillation (RENEWAL-AF): Study design.

BACKGROUND: Unstable functional reentrant circuits known as rotors have been consistently observed in atrial fibrillation and are mechanistically believed critical to the maintenance of the arrhythmia. Recently, using a Poisson renewal theory-based quantitative framework, we have demonstrated that rotor formation (λf) and destruction rates (λd) can be measured using in vivo electrophysiologic data. However, the association of λf and λd with clinical, electrical, and structural markers of atrial fibrillation phenotype is unknown. METHODS: RENEWAL-AF is a multicenter prospective cross-sectional study recruiting adult patients with paroxysmal or persistent atrial fibrillation undergoing clinically indicated catheter ablation. Patients will undergo intraprocedural electrophysiologic atrial fibrillation mapping, with λf and λd to be determined from 2-minute unipolar electrogram recordings acquired before ablation. The primary objective will be to determine the association of λf and λd as markers of fibrillatory dynamics with clinical, electrical, and structural markers of atrial fibrillation clinical phenotype, measured by preablation transthoracic echocardiogram and cardiac magnetic resonance imaging. An exploratory objective is the noninvasive assessment of λf and λd using surface ECG characteristics via a machine learning approach. RESULTS: Not applicable. CONCLUSION: This pilot study will provide insight into the correlation between λf/λd with clinical, electrophysiological, and structural markers of atrial fibrillation phenotype and provide a foundation for the development of noninvasive assessment of λf/λd using surface ECG characteristics will help expand the use of λf/λd in clinical practice.

Cardiac arrest in a mother and daughter and the identification of a novel RYR2 variant, predisposing to low penetrant catecholaminergic polymorphic ventricular tachycardia in a four-generation Canadian family.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited arrhythmia syndrome characterized by adrenergically driven ventricular arrhythmia predominantly caused by pathogenic variants in the cardiac ryanodine receptor (RyR2). We describe a novel variant associated with cardiac arrest in a mother and daughter. METHODS: Initial sequencing of the RYR2 gene identified a novel variant (c.527G > T, p.R176L) in the index case (the mother), and her daughter. Structural analysis demonstrated the variant was located within the N-terminal domain of RyR2, likely leading to a gain-of-function effect facilitating enhanced calcium ion release. Four generation cascade genetic and clinical screening was carried out. RESULTS: Thirty-eight p.R176L variant carriers were identified of 94 family members with genetic testing, and 108 family members had clinical evaluations. Twelve carriers were symptomatic with previous syncope and 2 additional survivors of cardiac arrest were identified. Thirty-two had clinical features suggestive of CPVT. Of 52 noncarriers, 11 had experienced previous syncope with none exhibiting any clinical features of CPVT. A documented arrhythmic event rate of 2.89/1000 person-years across all carriers was calculated. CONCLUSION: The substantial variability in phenotype and the lower than previously reported penetrance is illustrative of the importance of exploring family variants beyond first-degree relatives.

Noroviruses subvert the core stress granule component G3BP1 to promote viral VPg-dependent translation.

Knowledge of the host factors required for norovirus replication has been hindered by the challenges associated with culturing human noroviruses. We have combined proteomic analysis of the viral translation and replication complexes with a CRISPR screen, to identify host factors required for norovirus infection. The core stress granule component G3BP1 was identified as a host factor essential for efficient human and murine norovirus infection, demonstrating a conserved function across the Norovirus genus. Furthermore, we show that G3BP1 functions in the novel paradigm of viral VPg-dependent translation initiation, contributing to the assembly of translation complexes on the VPg-linked viral positive sense RNA genome by facilitating ribosome recruitment. Our data uncovers a novel function for G3BP1 in the life cycle of positive sense RNA viruses and identifies the first host factor with pan-norovirus pro-viral activity.

Estimating Sample-Specific Regulatory Networks.

Biological systems are driven by intricate interactions among molecules. Many methods have been developed that draw on large numbers of expression samples to infer connections between genes (or their products). The result is an aggregate network representing a single estimate for the likelihood of each interaction, or "edge," in the network. Although informative, aggregate models fail to capture population heterogeneity. Here we propose a method to reverse engineer sample-specific networks from aggregate networks. We demonstrate our approach in several contexts, including simulated, yeast microarray, and human lymphoblastoid cell line RNA sequencing data. We use these sample-specific networks to study changes in network topology across time and to characterize shifts in gene regulation that were not apparent in the expression data. We believe that generating sample-specific networks will greatly facilitate the application of network methods to large, complex, and heterogeneous multi-omic datasets, supporting the emerging field of precision network medicine.