Pharmacological Management of Atrial Fibrillation: One, None, One Hundred Thousand

Abstract atrial fibrillation (AF) is associated with a significant burden of morbidity and increased risk of mortality. Antiarrhythmic drug therapy remains a cornerstone to restore and maintain sinus rhythm for patients with paroxysmal and persistent AF based on current guidelines. However, conventional drugs have limited efficacy, present problematic risks of proarrhythmia and cause significant noncardiac organ toxicity. Thus, inadequacies in current therapies for atrial fibrillation have made new drug development crucial. New antiarrhythmic drugs and new anticoagulant agents have changed the current management of AF. This paper summarizes the available evidence regarding the efficacy of medications used for acute management of AF, rhythm and ventricular rate control, and stroke prevention in patients with atrial fibrillation and focuses on the current pharmacological agents

Surgical Risk Factors for Ischemic Stroke Following Coronary Artery Bypass Grafting. A Multi-Factor Multimodel Analysis

Background: Ischemic stroke after coronary artery bypass (CABG) has been often linked to aortic manipulation during surgery. Objectives: The objective of the study was to estimate the rate of postoperative ischemic stroke within 30 days from CABG by surgical risk factors alone or in combination. Methods: The multinomial propensity score for multiple treatments was used to create six models with a total of 16,255 consecutive patients undergoing isolated CABG. For each model, a different classification variable was used to stratify patients. Results: Balance achieved in all models was substantial, enabling unbiased estimation of the treatment estimand. Both off-pump techniques with (0.009; 95% CI 0.006–0.011) or without proximal anastomoses (0.005; 0.005–0.003), and surgery performed on the beating heart using cardiopulmonary bypass with (0.009; 0.006–0.011) or without proximal anastomoses (0.024; 0.021–0.029) showed a mean stroke estimate significantly lower than the other techniques. Off-pump surgery and on-pump surgery without an aortic cross-clamp yielded nearly equal incidences of stroke (0.012; 0.008–0.015 and 0.018; 0.012–0.023, respectively). Using an aortic cross-clamp significantly increased the stroke estimate (0.075; 0.061–0.088), whereas using a side-biting clamp did not (0.039; 0.033–0.044). The number of aortic touches (0.029; 0.026–0.031) and the number of proximal anastomoses (0.044; 0.035–0.047) did not significantly increase the incidence of stroke. Conclusions: Aortic cross-clamping was found to be the primary cause of post-CABG ischemic stroke. Instead, additional aortic manipulation from a side-biting clamp, on-pump surgery, multiple aortic touches, number of proximal anastomoses, and aortic cannulation were found not to increase the estimate of stroke significantly. Further research on this topic is warranted

Abnormally high risk of stroke in Brugada syndrome

BACKGROUND The present study sought to evaluate the incidence of cerebrovascular events in a large cohort of patients with Brugada syndrome (BrS) analysing possible predictors, clinical characteristics and prognosis of cardioembolic events secondary to atrial fibrillation. METHODS A total of 671 consecutive patients (age 42.1 ± 17.0 years; men 63%) with a diagnosis of BrS were retrospectively analysed over a mean follow-up period of 10.8 ± 5.5 years. The diagnosis of ischemic stroke was made according to the AHA/ASA guidelines using computed tomography (CT) and angio-CT in the emergency department. RESULTS Among 671 patients with BrS, 79 (11.8%) had atrial fibrillation. The incidence of cardioembolic stroke in patients with BrS and atrial fibrillation was 13.9% (11 events). These patients had a low CHA2DS2Vasc score (82%, 0 and 1). Patients with transient ischemic attack/stroke were more frequently asymptomatic (91 vs. 25%; P < 0.0001) and older (59.4 ± 11.2 vs. 43.9 ± 16.7; P = 0.004) as compared with those without cerebrovascular events. CONCLUSION The incidence of cardioembolic stroke in patients with BrS and atrial fibrillation was unexpectedly high. The cerebrovascular accidents were often the presenting clinical manifestation and were significantly associated with asymptomatic atrial fibrillation and older age. CHADS2 and CHA2DS2Vasc scores did not predict the unexpectedly high risk of thromboembolic events in this group of patients. The use of more invasive diagnostic tools might be useful in order to increase the rate of atrial fibrillation detection

Drug-Induced Brugada Syndrome in Children Clinical Features, Device-Based Management, and Long-Term Follow-Up

ObjectivesThe goal of this study was to investigate the clinical features, management, and long-term follow-up of children with drug-induced Brugada syndrome (BS).BackgroundPatients with BS <12 years of age with a spontaneous type I electrocardiogram have a higher risk of arrhythmic events. Data on drug-induced BS in patients <12 years of age are lacking.MethodsAmong 505 patients with ajmaline-induced BS, subjects ≤12 years of age at the time of diagnosis were considered as children and eligible for this study.ResultsForty children (60% male; age 8 ± 2.8 years) were included. Twenty-four children (60%) had a family history of sudden death. Two (5%) had a previous episode of aborted sudden death, and 8 (20%) had syncope. Children experienced more frequent episodes of sinus node dysfunction (SND) compared with older subjects (7.5% vs. 1.5%; p = 0.04) and had a comparable incidence of atrial tachyarrhythmias. Children more frequently experienced episodes of ajmaline-induced sustained ventricular arrhythmias (VAs) compared with older patients (10.0% vs. 1.3%; p = 0.005). Twelve children (30%) received an implantable cardioverter-defibrillator (ICD). After a mean follow-up time of 83 ± 51 months, none of the children died suddenly. Spontaneous sustained VAs were documented in 1 child (2%). Among children with ICD, 1 (8%) experienced an appropriate shock, 4 (33%) had inappropriate ICD shocks, and 4 (33%) experienced device-related complications.ConclusionsDrug-induced BS is associated with atrial arrhythmias and SND. Children are at higher risk of ajmaline-induced VAs. The rate of device-related complications, leading to lead replacement or inappropriate shocks, is considerable and even higher than with appropriate interventions. Based on these findings, the optimal management of BS in childhood should remain individualized, taking into consideration the patient's clinical history and family's wishes

Minimally Invasive Mitral Valve Surgery: A Systematic Review

In the recent years minimally invasive mitral valve surgery (MIMVS) has become a well-established and increasingly used option for managing patients with a mitral valve pathology. Nonetheless, whether the purported benefits of MIMVS translate into clinically important outcomes remains controversial. Therefore, in this paper we provide an overview of MIMVS and discuss results, morbidity, mortality, and quality of life following mitral minimally invasive procedures. MIMVS has been proven to be a feasible alternative to the conventional full sternotomy approach with low perioperative morbidity and short-term mortality. Reported benefits of MIMVS include also decreased postoperative pain, improved postoperative respiratory function, reduced surgical trauma, and greater patient satisfaction. Finally, compared to standard surgery, MIMVS demonstrated comparable efficacy across a range of long-term efficacy measures such as freedom from reoperation and long-term survival

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Implications of improved representations of plant respiration in a changing climate

Land-atmosphere exchanges influence atmospheric CO2. Emphasis has been on describing photosynthetic CO2 uptake, but less on respiration losses. New global datasets describe upper canopy dark respiration (R d) and temperature dependencies. This allows characterisation of baseline R d, instantaneous temperature responses and longer-term thermal acclimation effects. Here we show the global implications of these parameterisations with a global gridded land model. This model aggregates R d to whole-plant respiration R p, driven with meteorological forcings spanning uncertainty across climate change models. For pre-industrial estimates, new baseline R d increases R p and especially in the tropics. Compared to new baseline, revised instantaneous response decreases R p for mid-latitudes, while acclimation lowers this for the tropics with increases elsewhere. Under global warming, new R d estimates amplify modelled respiration increases, although partially lowered by acclimation. Future measurements will refine how R d aggregates to whole-plant respiration. Our analysis suggests R p could be around 30% higher than existing estimates.C.H. acknowledges the NERC CEH National Capability fund. We acknowledge the many climate research centres that contributed GCM outputs in to the Coupled Model Intercomparison Project (CMIP5) database. The support of the Australian Research Council to O.K.A. and P.M. (DP130101252, CE140100008, FT0991448, FT110100457) is acknowledged, as are awards DE-FG02-07ER64456 from the US Department of Energy, Office of Science, Office of Biological and Environmental Research and DEB-1234162 from the U.S. National Science Foundation (NSF) Long-Term Ecological Research Program (to P.B.R.); and National Science Foundation International Polar Year Grant (to K.L.G.). L.M.M. acknowledges the support of the Natural Environment Research Council (NERC) South American Biomass Burning Analysis (SAMBBA) project grant code NE/ J010057/1

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin