Multicenter FIRM Registry for AF
Introduction
The success of pulmonary vein isolation (PVI) for atrial fibrillation (AF) may be improved if stable AF sources identified by Focal Impulse and Rotor ...Mapping (FIRM) are also eliminated. The long‐term results of this approach are unclear outside the centers where FIRM was developed; thus, we assessed outcomes of FIRM‐guided AF ablation in the first cases at 10 experienced centers.
Methods
We prospectively enrolled n = 78 consecutive patients (61 ± 10 years) undergoing FIRM guided ablation for persistent (n = 48), longstanding persistent (n = 7), or paroxysmal (n = 23) AF. AF recordings from both atria with a 64‐pole basket catheter were analyzed using a novel mapping system (Rhythm ViewTM; Topera Inc., CA, USA). Identified rotors/focal sources were ablated, followed by PVI.
Results
Each institution recruited a median of 6 patients, each of whom showed 2.3 ± 0.9 AF rotors/focal sources in diverse locations. 25.3% of all sources were right atrial (RA), and 50.0% of patients had ≥1 RA source. Ablation of all sources required a total of 16.6 ± 11.7 minutes, followed by PVI. On >1 year follow‐up with a 3‐month blanking period, 1 patient lost to follow‐up (median time to 1st recurrence: 245 days, IQR 145–354), single‐procedure freedom from AF was 87.5% (patients without prior ablation; 35/40) and 80.5% (all patients; 62/77) and similar for persistent and paroxysmal AF (P = 0.89).
Conclusions
Elimination of patient‐specific AF rotors/focal sources produced freedom‐from‐AF of ≈80% at 1 year at centers new to FIRM. FIRM‐guided ablation has a rapid learning curve, yielding similar results to original FIRM reports in each center's first cases.
Objectives This study sought to determine if the risk of mortality associated with inappropriate implantable cardioverter-defibrillator (ICD) shocks is due to the underlying arrhythmia or the shock ...itself. Background Shocks delivered from ICDs are associated with an increased risk of mortality. It is unknown if all patients who experience inappropriate ICD shocks have an increased risk of death. Methods We evaluated survival outcomes in patients with an ICD and a cardiac resynchronization therapy defibrillator enrolled in the LATITUDE remote monitoring system (Boston Scientific Corp., Natick, Massachusetts) through January 1, 2010. First shock episode rhythms from 3,809 patients who acutely survived the initial shock were adjudicated by 7 electrophysiologists. Patients with a shock were matched to patients without a shock (n = 3,630) by age at implant, implant year, sex, and device type. Results The mean age of the study group was 64 ± 13 years, and 78% were male. Compared with no shock, there was an increased rate of mortality in those who received their first shock for monomorphic ventricular tachycardia (hazard ratio HR: 1.65, p < 0.0001), ventricular fibrillation/polymorphic ventricular tachycardia (HR: 2.10, p < 0.0001), and atrial fibrillation/flutter (HR: 1.61, p = 0.003). In contrast, mortality after first shocks due to sinus tachycardia and supraventricular tachycardia (HR: 0.97, p = 0.86) and noise/artifact/oversensing (HR: 0.91, p = 0.76) was comparable to that in patients without a shock. Conclusions Compared with no shock, those who received their first shock for ventricular rhythms and atrial fibrillation had an increased risk of death. There was no significant difference in survival after inappropriate shocks for sinus tachycardia or noise/artifact/oversensing. In this study, the adverse prognosis after first shock appears to be more related to the underlying arrhythmia than to an adverse effect from the shock itself.
With the advent of cardiac resynchronization therapy, it was unclear what percentage of biventricular pacing would be required to obtain maximal symptomatic and mortality benefit from the therapy. ...The optimal percentage of biventricular pacing and the association between the amount of continuous pacing and survival is unknown.
The purpose of this study was to assess the optimal percentage of biventricular pacing and any association with survival in a large cohort of networked patients.
A large cohort of 36,935 patients followed up in a remote-monitoring network, the LATITUDE Patient Management system (Boston Scientific Corp., Natick, Massachusetts), was assessed to determine the association between the percentage of biventricular pacing and mortality.
The greatest magnitude of reduction in mortality was observed with a biventricular pacing achieved in excess of 98% of all ventricular beats. Atrial fibrillation and native atrial ventricular condition can limit a high degree of biventricular pacing. Incremental increases in mortality benefit are observed with an increasing percentage of biventricular pacing.
Every effort should be made to reduce native atrioventricular conduction with cardiac resynchronization therapy systems in an attempt to achieve biventricular pacing as close to 100% as possible.
Schistosomiasis is a tropical parasitic disease afflicting ~200 million people worldwide and current therapy depends on a single drug (praziquantel) which exhibits several non-optimal features. These ...shortcomings underpin the need for next generation anthelmintics, but the process of validating physiologically relevant targets ('target selection') and pharmacologically profiling them is challenging. Remarkably, even though over a quarter of current human therapeutics target rhodopsin-like G protein coupled receptors (GPCRs), no library screen of a flatworm GPCR has yet been reported. Here, we have pharmacologically profiled a schistosome serotonergic GPCR (Sm.5HTR) implicated as a downstream modulator of PZQ efficacy, in a miniaturized screening assay compatible with high content screening. This approach employs a split luciferase based biosensor sensitive to cellular cAMP levels that resolves the proximal kinetics of GPCR modulation in intact cells. Data evidence a divergent pharmacological signature between the parasitic serotonergic receptor and the closest human GPCR homolog (Hs.5HTR7), supporting the feasibility of optimizing parasitic selective pharmacophores. New ligands, and chemical series, with potency and selectivity for Sm.5HTR over Hs.5HTR7 are identified in vitro and validated for in vivo efficacy against schistosomules and adult worms. Sm.5HTR also displayed a property resembling irreversible inactivation, a phenomenon discovered at Hs.5HTR7, which enhances the appeal of this abundantly expressed parasite GPCR as a target for anthelmintic ligand design. Overall, these data underscore the feasibility of profiling flatworm GPCRs in a high throughput screening format competent to resolve different classes of GPCR modulators. Further, these data underscore the promise of Sm.5HTR as a chemotherapeutically vulnerable node for development of next generation anthelmintics.
•Peptide-based ligands (1) possess a wide chemical and structural diversity;•(2) feature excellent biorecognition activity•(3) can target proteins, viruses, and cell therapeutics;•(4) are ...biochemically stable and safe;•(5) can be mass manufactured affordably and with no variability.
Following the consolidation of therapeutic proteins in the fight against cancer, autoimmune, and neurodegenerative diseases, recent advancements in biochemistry and biotechnology have introduced a host of next-generation biotherapeutics, such as CRISPR-Cas nucleases, stem and car-T cells, and viral vectors for gene therapy. With these drugs entering the clinical pipeline, a new challenge lies ahead: how to manufacture large quantities of high-purity biotherapeutics that meet the growing demand by clinics and biotech companies worldwide. The protein ligands employed by the industry are inadequate to confront this challenge: while featuring high binding affinity and selectivity, these ligands require laborious engineering and expensive manufacturing, are prone to biochemical degradation, and pose safety concerns related to their bacterial origin. Peptides and pseudopeptides make excellent candidates to form a new cohort of ligands for the purification of next-generation biotherapeutics. Peptide-based ligands feature excellent target biorecognition, low or no toxicity and immunogenicity, and can be manufactured affordably at large scale. This work presents a comprehensive and systematic review of the literature on peptide-based ligands and their use in the affinity purification of established and upcoming biological drugs. A comparative analysis is first presented on peptide engineering principles, the development of ligands targeting different biomolecular targets, and the promises and challenges connected to the industrial implementation of peptide ligands. The reviewed literature is organized in (i) conventional (α-)peptides targeting antibodies and other therapeutic proteins, gene therapy products, and therapeutic cells; (ii) cyclic peptides and pseudo-peptides for protein purification and capture of viral and bacterial pathogens; and (iii) the forefront of peptide mimetics, such as β-/γ-peptides, peptoids, foldamers, and stimuli-responsive peptides for advanced processing of biologics.
Atrial fibrillation (AF) is a leading cause of total and fatal ischemic stroke. Stroke risk after AF ablation appears to be favorably affected; however, it is largely unknown whether the benefit ...extends to all stroke CHADS2 risk profiles of AF patients.
To determine if ablation of atrial fibrillation reduces stroke rates in all risk groups.
A total of 4212 consecutive patients who underwent AF ablation were compared (1:4) with 16,848 age-/sex-matched controls with AF (no ablation) and to 16,848 age-/sex-matched controls without AF. Patients were enrolled from the large ongoing prospective Intermountain Atrial Fibrillation Study and were followed for at least 3 years.
Of the 37,908 patients, the mean age was 65.0 ± 13 years and 4.4% (no AF), 6.3% (AF, no ablation), and 4.5% (AF ablation) patients had a prior stroke (P < .0001). The profile of CHADS2 scores between comparative groups was similar: 0-1 (69.3%, no AF; 62.3%, AF, no ablation; 63.6%, AF ablation), 2-3 (26.5%, no AF; 29.7%, AF, no ablation; 28.7%, AF ablation), and ≥4 (4.3%, no AF; 8.0%, AF, no ablation; 7.7%, AF ablation). A total of 1296 (3.4%) patients had a stroke over the follow-up period. Across all CHADS2 profiles and ages, AF patients with ablation had a lower long-term risk of stroke compared to patients without ablation. Furthermore, AF ablation patients had similar long-term risks of stroke across all CHADS2 profiles and ages compared to patients with no history of AF.
In our study populations, AF ablation patients have a significantly lower risk of stroke compared to AF patients who do not undergo ablation independent of baseline stroke risk score.
Many centers use radiofrequency (RF) energy at 25–35 W for 30–60 seconds. There is a safety concern about using higher power, especially on the posterior wall.
The purpose of this study was to ...examine complication rates for atrial fibrillation (AF) ablations performed with high-power, short-duration RF energy.
We examined the complication rates of 4 experienced centers performing AF ablations at RF powers from 45–50 W for 2–15 seconds per lesion. In total, 13,974 ablations were performed in 10,284 patients. On the posterior wall, 11,436 ablations used 45–50 W for 2–10 seconds, and 2538 ablations used power reduced to 35 W for 20 seconds. Esophageal temperature monitoring was used in 13,858 (99.2%).
Demographics were age 64 ± 11 years, male 68%, left atrial size 4.4 ± 0.7 cm, paroxysmal AF 37%, persistent AF 42%, longstanding AF 20%, antiarrhythmic drugs failed 1.4 ± 0.7, hypertension 54%, diabetes 15%, previous cerebrovascular accident/transient ischemic attack 7%, and CHA2DS2-VASc score 2.1 ± 1.4. Procedural time was 116 ± 41 minutes. Complications were death in 2 (0.014%; 1 due to stroke and 1 due to atrioesophageal fistula), pericardial tamponade in 33 (0.24%; 26 tapped, 7 surgical), strokes <48 hours in 6 (0.043%), strokes 48 hours–30 days in 6 (0.043%), pulmonary vein stenosis requiring intervention in 2 (0.014%), phrenic nerve paralysis in 2 (0.014%; both resolved), steam pops 2 (0.014%) without complications, and catheter char 0 (0.00%). There was 1 atrioesophageal fistula in 11,436 ablations using power 45–50 W on the posterior wall and 3 in 2538 ablated with 35 W on the posterior wall (P = .021), although 2 of the 3 had no esophageal monitoring during a fluoroless procedure.
AF ablations can be performed at 45–50 W for short durations with very low complication rates. High-power, short-duration ablations have the potential to shorten procedural and total RF times and create more localized and durable lesions.
Background Vismodegib, a first-in-class Hedgehog pathway inhibitor, was US Food and Drug Administration (FDA) approved for advanced basal cell carcinomas (BCCs) based on a single, nonrandomized, ...phase-II trial. Consequently, additional clinical data are critical to confirm the efficacy and safety of vismodegib. Objective We sought to assess efficacy and safety of vismodegib, while providing early drug access to patients with advanced BCC and limited treatment options. Methods This was an open-label, multicenter study in patients with advanced BCC inappropriate for radiotherapy or surgery. Patients received 150 mg vismodegib daily until disease progression or intolerable toxicity. Tumor response was assessed via Response Evaluation Criteria in Solid Tumors version 1.0. Results A total of 119 patients with advanced BCC took vismodegib for a median of 5.5 months. Objective responses occurred in 46.4% of locally advanced BCC and 30.8% of patients with metastatic BCC. Response was negatively associated with prior systemic therapy in patients with locally advanced BCC ( P = .002). Mean follow-up for safety was 6.5 months, with muscle spasms (70.6%), dysgeusia (70.6%), alopecia (58.0%), and diarrhea (25.2%) as the most common adverse events. Limitations Abbreviated follow-up time because of study termination upon FDA approval was a limitation. Conclusion This study provides important clinical data supporting the efficacy and safety of vismodegib. Larger studies are underway to assess predictors of response and long-term outcomes.
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