The limited utility of electrocardiography variables used to predict arrhythmia in psychotropic drug overdose

OBJECTIVE: The aim of the present study was to examine the relationship between serious arrhythmias in patients with psychotropic drug overdose and electrocardiography (ECG) findings that have been suggested previously to predict this complication. METHODS: Thirty-nine patients with serious arrhythmias (ventricular tachycardia, supraventricular tachycardia or cardiac arrest) after tricyclic antidepressant overdose or thioridazine overdose were compared with 117 controls with clinically significant overdose matched to each case for the drug ingested. These patients with psychotropic drug overdose had presented for treatment to the Department of Clinical Toxicology, Newcastle and to the Princess Alexandra Hospital, Brisbane. The heart rate, the QRS width, the QTc and QT intervals, the QT dispersion, and the R wave and R/S ratios in aVR on the initial ECGs were compared in cases and controls. RESULTS: The cases had taken dothiepin (16 patients), doxepin (six patients), thioridazine (five patients), amitriptyline (five patients), nortriptyline (three patients), imipramine (one patient) and a combination of dothiepin and thioridazine (three patients). In 20 of the 39 patients with arrhythmias, the arrhythmia had been a presumed ventricular tachycardia. Of the other 19 patients, 15 patients had a supraventricular tachycardia, two patients had cardiac arrests (one asystole, one without ECG monitoring) and two patients had insufficient data recorded to make classification of the arrhythmias possible. The QRS was ≥ 100 ms in 82% of cases but also in 76% of controls. QRS ≥ 160 ms had a sensitivity of only 13% and occurred in 2% of controls. QRS > 120 ms, QTc > 500 and the R/S ratio in aVR appeared to have a stronger association with the occurrence of arrhythmia: QRS > 120 ms (odds ratio [OR], 3.56; 95% confidence interval [CI], 1.46–8.68), QTc > 500 (OR, 3.07; 95% CI, 1.33–7.07), and R/S ratio in aVR > 0.7 (OR, 16; 95% CI, 3.47–74). Excluding thioridazine overdoses and performing the analysis for tricyclic antidepressant overdoses alone gave increased odds ratios for QRS > 120 ms (OR, 4.83; 95% CI, 1.73–13.5) and QTc > 500 (OR, 4.5; 95% CI, 1.56–13) but had little effect on that for the R/S ratio in aVR > 0.7 (OR, 14.5; 95% CI, 3.10–68). CONCLUSION: ECG measurements were generally weakly related to the occurrence of arrhythmia and should not be used as the sole criteria for risk assessment in tricyclic antidepressant overdose. The frequently recommended practice of using either QRS ≥ 100 ms or QRS ≥ 160 ms to predict arrhythmias is not supported by our study. R/S ratio in aVR > 0.7 was most strongly related to arrhythmia but had estimated positive and negative predictive values of only 41% and 95%, respectively. The use of these specific predictors in other drug overdoses is not recommended without specific studies

Activation of TRPV2 and BKCa channels by the LL-37 enantiomers stimulates calcium entry and migration of cancer cells.

International audienceExpression of the antimicrobial peptide hCAP18/LL-37 is associated to malignancy in various cancer forms, stimulating cell migration and metastasis. We report that LL-37 induces migration of three cancer cell lines by activating the TRPV2 calcium-permeable channel and recruiting it to pseudopodia through activation of the PI3K/AKT pathway. Ca2+ entry through TRPV2 cooperated with a K+ efflux through the BKCa channel. In a panel of human breast tumors, the expression of TRPV2 and LL-37 was found to be positively correlated. The D-enantiomer of LL-37 showed identical effects as the L-peptide, suggesting that no binding to a specific receptor was involved. LL-37 attached to caveolae and pseudopodia membranes and decreased membrane fluidity, suggesting that a modification of the physical properties of the lipid membrane bilayer was the underlying mechanism of its effects

Regulation of hepatic cardiolipin metabolism by TNFα: Implication in cancer cachexia

International audienceCardiolipin (CL) content accumulation leads to an increase in energy wasting in liver mitochondria in a rat model of cancer cachexia in which tumor necrosis factor alpha (TNFα) is highly expressed. In this study we investigated the mechanisms involved in liver mitochondria CL accumulation in cancer cachexia and examined if TNFα was involved in this process leading to mitochondrial bioenergetics alterations. We studied gene, protein expression and activity of the main enzymes involved in CL metabolism in liver mitochondria from a rat model of cancer cachexia and in HepaRG hepatocyte-like cells exposed to 20 ng/ml of TNFα for 12 h. Phosphatidylglycerolphosphate synthase (PGPS) gene expression was increased 2.3-fold (p < 0.02) and cardiolipin synthase (CLS) activity decreased 44% (p < 0.03) in cachectic rat livers compared to controls. CL remodeling enzymes monolysocardiolipin acyltransferase (MLCL AT-1) activity and tafazzin (TAZ) gene expression were increased 30% (p < 0.01) and 50% (p < 0.02), respectively, in cachectic rat livers compared to controls. Incubation of hepatocytes with TNFα increased CL content 15% (p < 0.05), mitochondrial oxygen consumption 33% (p < 0.05), PGPS gene expression 44% (p < 0.05) and MLCL AT-1 activity 20% (p < 0.05) compared to controls. These above findings strongly suggest that in cancer cachexia, TNFα induces a higher energy wasting in liver mitochondria by increasing CL content via upregulation of PGPS expression

Abbreviated Antiplatelet Therapy After Coronary Stenting in Patients With Myocardial Infarction at High Bleeding Risk.

BACKGROUND The optimal duration of antiplatelet therapy (APT) after coronary stenting in patients at high bleeding risk (HBR) presenting with an acute coronary syndrome remains unclear. OBJECTIVES The objective of this study was to investigate the safety and efficacy of an abbreviated APT regimen after coronary stenting in an HBR population presenting with acute or recent myocardial infarction. METHODS In the MASTER DAPT trial, 4,579 patients at HBR were randomized after 1 month of dual APT (DAPT) to abbreviated (DAPT stopped and 11 months single APT or 5 months in patients with oral anticoagulants) or nonabbreviated APT (DAPT for minimum 3 months) strategies. Randomization was stratified by acute or recent myocardial infarction at index procedure. Coprimary outcomes at 335 days after randomization were net adverse clinical outcomes events (NACE); major adverse cardiac and cerebral events (MACCE); and type 2, 3, or 5 Bleeding Academic Research Consortium bleeding. RESULTS NACE and MACCE did not differ with abbreviated vs nonabbreviated APT regimens in patients with an acute or recent myocardial infarction (n = 1,780; HR: 0.83; 95% CI: 0.61-1.12 and HR: 0.86; 95% CI: 0.62-1.19, respectively) or without an acute or recent myocardial infarction (n = 2,799; HR: 1.03; 95% CI: 0.77-1.38 and HR: 1.13; 95% CI: 0.80-1.59; Pinteraction = 0.31 and 0.25, respectively). Bleeding Academic Research Consortium 2, 3, or 5 bleeding was significantly reduced in patients with or without an acute or recent myocardial infarction (HR: 0.65; 95% CI: 0.46-0.91 and HR: 0.71; 95% CI: 0.54-0.92; Pinteraction = 0.72) with abbreviated APT. CONCLUSIONS A 1-month DAPT strategy in patients with HBR presenting with an acute or recent myocardial infarction results in similar NACE and MACCE rates and reduces bleedings compared with a nonabbreviated DAPT strategy. (Management of High Bleeding Risk Patients Post Bioresorbable Polymer Coated Stent Implantation With an Abbreviated Versus Prolonged DAPT Regimen [MASTER DAPT]; NCT03023020)

Catching Element Formation In The Act

Gamma-ray astronomy explores the most energetic photons in nature to address some of the most pressing puzzles in contemporary astrophysics. It encompasses a wide range of objects and phenomena: stars, supernovae, novae, neutron stars, stellar-mass black holes, nucleosynthesis, the interstellar medium, cosmic rays and relativistic-particle acceleration, and the evolution of galaxies. MeV gamma-rays provide a unique probe of nuclear processes in astronomy, directly measuring radioactive decay, nuclear de-excitation, and positron annihilation. The substantial information carried by gamma-ray photons allows us to see deeper into these objects, the bulk of the power is often emitted at gamma-ray energies, and radioactivity provides a natural physical clock that adds unique information. New science will be driven by time-domain population studies at gamma-ray energies. This science is enabled by next-generation gamma-ray instruments with one to two orders of magnitude better sensitivity, larger sky coverage, and faster cadence than all previous gamma-ray instruments. This transformative capability permits: (a) the accurate identification of the gamma-ray emitting objects and correlations with observations taken at other wavelengths and with other messengers; (b) construction of new gamma-ray maps of the Milky Way and other nearby galaxies where extended regions are distinguished from point sources; and (c) considerable serendipitous science of scarce events -- nearby neutron star mergers, for example. Advances in technology push the performance of new gamma-ray instruments to address a wide set of astrophysical questions.Comment: 14 pages including 3 figure

Absorb bioresorbable scaffold versus xience metallic stent for prevention of restenosis following percutaneous coronary intervention in patients at high risk of restenosis: rationale and design of the COMPARE ABSORB trial

Background: The advent of bioresorbable vascular scaffolds (BVS) was considered as a potential improvement in percutaneous coronary intervention (PCI) after the groundbreaking development of drug eluting stents (DES). However, the clinical performance, long-term safety and efficacy of BVS in complex coronary lesions remain uncertain. COMPARE ABSORB, a multicenter, single blind, prospective randomized trial, aims to compare the clinical outcomes between the Absorb BVS and Xience everolimus-eluting metallic stent (EES) in patients with coronary artery disease and a high risk of restenosis.Design: COMPARE ABSORB is designed to enroll 2100 patients at up to 45 European sites. Enrolled patients will possess high risk for restenosis due to clinical profile or coronary lesion complexity and will undergo elective or emergent PCI. Once included in the study, patients will receive either Absorb BVS or Xience EES. Specific advice on implantation technique including mandatory pre-dilatation, sizing and post-dilatation (PSP), will be used in the Absorb BVS arm. The primary endpoint is target lesion failure (TLF), a device-oriented composite endpoint (cardiac death, target vessel myocardial infarction and clinically- indicated target lesion revascularization). The trial is powered to assess non-inferiority of Absorb BVS compared with Xience EES with a predetermined non-inferiority margin of 4.5% at 1 year after index procedure. The clinical follow-up will continue for 7 years.Conclusions: The prospective COMPARE ABSORB randomized trial (ClinicalTrials.gov NCT02486068) will help to assess the long-term safety and efficacy of Absorb BVS compared with Xience EES in the treatments of patients with complex coronary artery disease and a high attendant risk of restenosis

Clinical Outcomes With a Repositionable Self-Expanding Transcatheter Aortic Valve Prosthesis: The International FORWARD Study

Background Clinical outcomes in large patient populations from real-world clinical practice with a next-generation self-expanding transcatheter aortic valve are lacking. Objectives This study sought to document the clinical and device performance outcomes of transcatheter aortic valve replacement (TAVR) with a next-generation, self-expanding transcatheter heart valve (THV) system in patients with severe symptomatic aortic stenosis (AS) in routine clinical practice. Methods The FORWARD (CoreValve Evolut R FORWARD) study is a prospective, single-arm, multinational, multicenter, observational study. An independent clinical events committee adjudicated safety endpoints based on Valve Academic Research Consortium-2 definitions. An independent echocardiographic core laboratory evaluated all echocardiograms. From January 2016 to December 2016, TAVR with the next-generation self-expanding THV was attempted in 1,038 patients with symptomatic, severe AS at 53 centers on 4 continents. Results Mean age was 81.8 ± 6.2 years, 64.9% were women, the mean Society of Thoracic Surgeons Predicted Risk of Mortality was 5.5 ± 4.5%, and 33.9% of patients were deemed frail. The repositioning feature of the THV was applied in 25.8% of patients. A single valve was implanted in the proper anatomic location in 98.9% of patients. The mean aortic valve gradient was 8.5 ± 5.6 mm Hg, and moderate or severe aortic regurgitation was 1.9% at discharge. All-cause mortality was 1.9%, and disabling stroke occurred in 1.8% at 30 days. The expected-to-observed early surgical mortality ratio was 0.35. A pacemaker was implanted in 17.5% of patients. Conclusions TAVR using the next-generation THV is clinically safe and effective for treating older patients with severe AS at increased operative risk. (CoreValve Evolut R FORWARD Study [FORWARD]; NCT02592369

Catalyst composition and impurity-dependent kinetics of nanowire heteroepitaxy.

The mechanisms and kinetics of axial Ge-Si nanowire heteroepitaxial growth based on the tailoring of the Au catalyst composition via Ga alloying are studied by environmental transmission electron microscopy combined with systematic ex situ CVD calibrations. The morphology of the Ge-Si heterojunction, in particular, the extent of a local, asymmetric increase in nanowire diameter, is found to depend on the Ga composition of the catalyst, on the TMGa precursor exposure temperature, and on the presence of dopants. To rationalize the findings, a general nucleation-based model for nanowire heteroepitaxy is established which is anticipated to be relevant to a wide range of material systems and device-enabling heterostructures.S.H. acknowledges funding from ERC grant InsituNANO (No. 279342). A.D.G. acknowledges funding from the Marshall Aid Commemoration Commission and the National Science Foundation. C.D. acknowledges funding from the Royal Society. A portion of the research was also performed using EMSL, a national scientific user facility sponsored by the Department of Energy’s (DOE) Office of Biological and Environmental Research and located at Pacific Northwest National Laboratory (PNNL). PNNL is operated by Battelle for the U.S. DOE under Contract DE-AC05-76RL01830. We gratefully acknowledge the use of facilities within the LeRoy Eyring Center for Solid State Science at Arizona State University. This work was performed in part at CINT, a U.S. DOE, Office of Science User Facility. The research was funded in part by the Laboratory Directed Research and Development Program at LANL, an affirmative action equal opportunity employer operated by Los Alamos National Security, LLC, for the National Nuclear Security Administration of the U.S. DOE under Contract DE-AC52-06NA25396.This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Nano, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/nn402208p. Gamalski AD, Perea DE, Yoo J, Li N, Olszta MJ, Colby R, Schreiber DK, Ducati C, Picraux ST, Hofmann S, ACS Nano 2013, 7 (9), 7689–7697, doi:10.1021/nn402208