A randomized comparison of 5 versus 12 hours per day of cardiac contractility modulation treatment for heart failure patients: A preliminary report

Background: Cardiac contractility modulation (CCM) signals are non-excitatory electrical signals delivered during the absolute refractory period intended to improve contraction and cardiac function. Clinical trials have shown that CCM treatment significantly improves exercise tolerance and quality of life in symptomatic heart failure patients. Studies with CCM therapy typically include CCM delivery for 3, 5 or 7 h per day, although other configurations are also commonly used. Each has been associated with improved outcomes in heart failure, but it is not clear whether different application durations are associated with the various degrees of benefit. The purpose of the current pilot evaluation study was to evaluate the quality of life, exercise tolerance, and cardiac function, over a 6-month period when CCM was delivered for 5 h/day vs. 12 h/day. Increasing the daily CCM therapy duration is safe and as good as the standard CCM periods of application per day. Methods: This single center pilot evaluation study involved 19 medically refractory symptomatic patients with heart failure and reduced left ventricular function who underwent implantation of an Optimizer™ system (Impulse Dynamics, Orangeburg, NY, USA). Patients were randomized into one of two treatment groups; 5 h/day CCM treatment or 12 h/day CCM treatment. Subjects and evaluating physicians were blinded to the study group. Subjects returned to the hospital after 12 and 24 weeks. Efficacy evaluations included changes from baseline to 24 weeks in Minnesota Living With Heart Failure Questionnaire score (MLWHFQ), maximal oxygen consumption in the cardio-pulmonary stress test (peak VO2), New York Heart Association classification (NYHA), 6-min walk distance (6MWD), and ejection fraction (EF). Results: At the end of 24 weeks, clinical improvement was observed in the entire cohort in all efficacy measures (mean change from baseline of –17.1 in MLWHFQ, –0.86 in NYHA, and improvement trend of 1.48 mL O2/kg/min in peak VO2, 31.3 m in 6MWD, and 2.25% in EF). There were no significant differences, either clinically or statistically, between the groups receiving CCM for 5 h/day vs. 12 h/day. Three subjects were voluntarily withdrawn before completing the study. One subject died from pneumonia after 125 days, and 6 serious adverse events were reported, none of which was classified as related to either the device or the procedure. Conclusions: Together with previously reported experience with CCM, delivery of CCM therapy is equally safe and appears similarly effective over the range of shorter (5 h) to longer (12 h) daily periods of application. Given the small sample size, further studies are warranted.

Nuclear Factor κB–dependent Gene Expression Profiling of Hodgkin's Disease Tumor Cells, Pathogenetic Significance, and Link to Constitutive Signal Transducer and Activator of Transcription 5a Activity

Constitutive nuclear nuclear factor (NF)-κB activity is observed in a variety of hematopoietic and solid tumors. Given the distinctive role of constitutive NF-κB for Hodgkin and Reed-Sternberg (HRS) cell viability, we performed molecular profiling in two Hodgkin's disease (HD) cell lines to identify NF-κB target genes. We recognized 45 genes whose expression in both cell lines was regulated by NF-κB. The NF-κB–dependent gene profile comprises chemokines, cytokines, receptors, apoptotic regulators, intracellular signaling molecules, and transcription factors, the majority of which maintain a marker-like expression in HRS cells. Remarkably, we found 17 novel NF-κB target genes. Using chromatin immunoprecipitation we demonstrate that NF-κB is recruited directly to the promoters of several target genes, including signal transducer and activator of transcription (STAT)5a, interleukin-13, and CC chemokine receptor 7. Intriguingly, NF-κB positively regulates STAT5a expression and signaling pathways in HRS cells, and promotes its persistent activation. In fact, STAT5a overexpression was found in most tumor cells of tested patients with classical HD, indicating a critical role for HD. The gene profile underscores a central role of NF-κB in the pathogenesis of HD and potentially of other tumors with constitutive NF-κB activation

Left atrial versus bi-atrial maze operation using intraoperatively cooled-tip radiofrequency ablation in patients undergoing open-heart surgery Safety and efficacy

AbstractObjectivesWe sought to determine whether limited left atrial Maze surgery encircling each of the pulmonary veins, using cooled-tip radiofrequency (RF) ablation, is as effective as the bi-atrial approach?BackgroundThe original Cox/Maze operation effectively restores sinus rhythm (SR) in patients with atrial fibrillation (AF). Ablation procedures aimed at eliminating pulmonary vein foci have produced promising short-term success.MethodsThis was a prospective analysis of patients with chronic AF undergoing open-heart surgery in addition to the Maze operation, using intraoperatively cooled-tip RF ablation either in the left atrium alone (group A) or in both atria (group B).ResultsPatients in group A (n = 21) and group B (n = 49) did not differ in terms of their baseline characteristics. Concomitant open-heart surgical procedures included mitral valve replacement (3 vs. 25), mitral valve plasty (0 vs. 2), mitral and aortic valve replacement (1 vs. 1), aortic valve replacement (4 vs. 6) and coronary artery bypass grafting (13 vs. 15) in groups A and B, respectively. Follow-up ranged from 1 to 50 months. The overall cumulative rates of SR were 82% in group A and 75% in group B, without a statistically significant difference (p = 0.571). Bi-atrial contraction was revealed in 92.3% of patients in SR in group A and in 79.2% in group B. The cumulative survival rates were 90.5% in group A and 77.9% in group B (p = 0.880).ConclusionsA left or bi-atrial Maze operation using intraoperatively cooled-tip RF ablation can safely be combined with open-heart surgery. A left atrial Maze procedure seems to be as effective as the bi-atrial procedure and restores SR in 82% of patients

Non-invasive Determination of the Optimized Atrioventricular Delay in Patients with Implanted Biventricular Pacing Devices

Background: Biventricular (BiV) is extensively used in the treatment of congestive heart failure but so far no recommendations for optimized programming of atrioventricular-delay (AVD) settings have been proposed. Can AVD optimization be performed using a simple formula based on non-invasive doppler-echocardiography?Methods: 25 patients (ejection fraction 30±8%) received BiV ICDs. Doppler-echocardiographic evaluation of diastolic and systolic flow was performed for different AVDs (30ms to 150ms) and different stimulation sites (left ventricular (LV), right ventricular and BiV). The optimal atrioventricular delay was calculated applying a simple formula based on systolic and diastolic mechanical delays determined during doppler-echocardiography.Results: The mean optimal AVD was calculated to be 112±29ms (50 to 180ms) for BiV, 95±30ms (65 to 150ms) for LV and 75±28ms (40 to 125ms) for right ventricular pacing with wide interindividual variations. Compared to suboptimal AVDs diastolic optimization improved preejection and ejection intervals independent to pacing site. Optimization of the AVD significantly increased ejection time during BiV pacing (279ms versus 266ms; p<0.05). Compared to LV or right ventricular pacing BiV pacing produced the shortest mean pre-ejection and longest ejection intervals as parameters of improved systolic ventricular contractile synchrony. Diastolic filling times were longest during BiV pacing compared to LV or RV pacing.Conclusions: Individual programming of BiV pacing devices increases hemodynamic benefit when implementing the inter-individually widely varying electromechanical delays. Optimization applying a simple formula not only improves diastolic ventricular filling but also increases systolic functional parameters

Continuous optimization of cardiac resynchronization therapy reduces atrial fibrillation in heart failure patients: Results of the Adaptive Cardiac Resynchronization Therapy Trial

BackgroundData from randomized trials have suggested a modest or no effect of conventional cardiac resynchronization therapy (convCRT) on the incidence of atrial fibrillation (AF). AdaptivCRT (aCRT, Medtronic, Mounds View, MN) is a recently described algorithm for synchronized left ventricular (LV) pacing and continuous optimization of cardiac resynchronization therapy (CRT).ObjectiveWe compared the long-term effects of aCRT with convCRT pacing on the incidence of AF.MethodsThe Adaptive CRT trial randomized CRT-defibrillator (CRT-D)–indicated patients (2:1) to receive either aCRT or convCRT pacing. The aCRT algorithm evaluates intrinsic conduction every minute, providing LV-only pacing during normal atrioventricular (AV) conduction and AV and ventriculoventricular timing adjustments during prolonged AV conduction. The primary outcome of this subanalysis was an episode of AF >48 consecutive hours as detected by device diagnostics.ResultsOver a follow-up period with a mean and standard deviation of 20.2 ± 5.9 months, 8.7% of patients with aCRT and 16.2% with convCRT experienced the primary outcome (hazard ratio [HR] = 0.54; 95% confidence interval [CI] = 0.31–0.93; P = .03). In patients with prolonged baseline AV, the incidence of the primary outcome was 12.8% in patients randomized to aCRT compared with 27.4% in convCRT patients (HR = 0.45; 95% CI = 0.24–0.85; P = .01). Also, patients with AF episodes adjudicated as clinical adverse events were less common with aCRT (4.3%) than with convCRT (12.7%) (HR = 0.39; 95% CI = 0.19–0.79; P = .01).ConclusionPatients receiving aCRT had a reduced risk of AF compared with those receiving convCRT. Most of the reduction in AF occurred in subgroups with prolonged AV conduction at baseline and with significant left atrial reverse remodeling

GERBIL: General Entity Annotator Benchmarking Framework

We present GERBIL, an evaluation framework for semantic entity annotation. The rationale behind our framework is to provide developers, end users and researchers with easy-to-use interfaces that allow for the agile, fine-grained and uniform evaluation of annotation tools on multiple datasets. By these means, we aim to ensure that both tool developers and end users can derive meaningful insights pertaining to the extension, integration and use of annotation applications. In particular, GERBIL provides comparable results to tool developers so as to allow them to easily discover the strengths and weaknesses of their implementations with respect to the state of the art. With the permanent experiment URIs provided by our framework, we ensure the reproducibility and archiving of evaluation results. Moreover, the framework generates data in machine-processable format, allowing for the efficient querying and post-processing of evaluation results. Finally, the tool diagnostics provided by GERBIL allows deriving insights pertaining to the areas in which tools should be further refined, thus allowing developers to create an informed agenda for extensions and end users to detect the right tools for their purposes. GERBIL aims to become a focal point for the state of the art, driving the research agenda of the community by presenting comparable objective evaluation results

The influence of left ventricular ejection fraction on the effectiveness of cardiac resynchronization therapy: MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy).

OBJECTIVES: The goal of this study was to evaluate the influence of left ventricular (LV) lead position on the risk of ventricular tachyarrhythmia in patients undergoing cardiac resynchronization therapy (CRT). BACKGROUND: Left ventricular ejection fraction (LVEF) is a surrogate marker of heart failure (HF) status and associated risk. Data on the effectiveness of cardiac resynchronization therapy with defibrillator (CRT-D) in patients with mild HF and better LVEF are limited. METHODS: In the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy) study, the echocardiography core laboratory assessed baseline LVEF independent of the enrolling centers and identified a range of LVEFs, including those >30% (i.e., beyond the eligibility criteria). Echocardiographic response with CRT, defined as percent change in left ventricular end-diastolic volume (LVEDV), was analyzed in 3 prespecified LVEF groups: >30%, 26% to 30%, and 30% (in the range of 30.1% to 45.3%); 914 patients (50.5%) with LVEF 26% to 30%; and 199 patients with LVEF 30%: 22.3%; LVEF 26% to 30%: 20.1%; and LVEF 30% (hazard ratio [HR]: = 0.56 [95% confidence interval (CI): 0.39 to 0.82], p = 0.003), LVEF 26% to 30% (HR: 0.67: [95% CI: 0.50 to 0.90], p = 0.007), and LVEF 0.1). CONCLUSIONS: In MADIT-CRT, the clinical benefit of CRT was evident regardless of baseline LVEF, including those with LVEF >30%, whereas the echocardiographic response was increased with increasing LVEF, indicating that CRT might benefit patients with better LVEF. (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy [MADIT-CRT]; NCT00180271)

Delineating the GRIN1 phenotypic spectrum: a distinct genetic NMDA receptor encephalopathy

Objective:To determine the phenotypic spectrum caused by mutations in GRIN1 encoding the NMDA receptor subunit GluN1 and to investigate their underlying functional pathophysiology.Methods:We collected molecular and clinical data from several diagnostic and research cohorts. Functional consequences of GRIN1 mutations were investigated in Xenopus laevis oocytes.Results:We identified heterozygous de novo GRIN1 mutations in 14 individuals and reviewed the phenotypes of all 9 previously reported patients. These 23 individuals presented with a distinct phenotype of profound developmental delay, severe intellectual disability with absent speech, muscular hypotonia, hyperkinetic movement disorder, oculogyric crises, cortical blindness, generalized cerebral atrophy, and epilepsy. Mutations cluster within transmembrane segments and result in loss of channel function of varying severity with a dominant-negative effect. In addition, we describe 2 homozygous GRIN1 mutations (1 missense, 1 truncation), each segregating with severe neurodevelopmental phenotypes in consanguineous families.Conclusions:De novo GRIN1 mutations are associated with severe intellectual disability with cortical visual impairment as well as oculomotor and movement disorders being discriminating phenotypic features. Loss of NMDA receptor function appears to be the underlying disease mechanism. The identification of both heterozygous and homozygous mutations blurs the borders of dominant and recessive inheritance of GRIN1-associated disorders.Johannes R. Lemke (32EP30_136042/1) and Peter De Jonghe (G.A.136.11.N and FWO/ESF-ECRP) received financial support within the EuroEPINOMICS-RES network (www.euroepinomics.org) within the Eurocores framework of the European Science Foundation (ESF). Saskia Biskup and Henrike Heyne received financial support from the German Federal Ministry for Education and Research (BMBF IonNeurONet: 01 GM1105A and FKZ: 01EO1501). Katia Hardies is a PhD fellow of the Institute for Science and Technology (IWT) Flanders. Ingo Helbig was supported by intramural funds of the University of Kiel, by a grant from the German Research Foundation (HE5415/3-1) within the EuroEPINOMICS framework of the European Science Foundation, and additional grants of the German Research Foundation (DFG, HE5415/5-1, HE 5415/6-1), German Ministry for Education and Research (01DH12033, MAR 10/012), and grant by the German chapter of the International League against Epilepsy (DGfE). The project also received infrastructural support through the Institute of Clinical Molecular Biology in Kiel, supported in part by DFG Cluster of Excellence "Inflammation at Interfaces" and "Future Ocean." The project was also supported by the popgen 2.0 network (P2N) through a grant from the German Ministry for Education and Research (01EY1103) and by the International Coordination Action (ICA) grant G0E8614N. Christel Depienne, Caroline Nava, and Delphine Heron received financial support for exome analyses by the Centre National de Genotypage (CNG, Evry, France)

Evaluation of presumably disease causing SCN1A variants in a cohort of common epilepsy syndromes

Objective: The SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are more likely to be classified as pathogenic if they have already been identified previously in a patient with epilepsy. Here, we critically re-evaluate the pathogenicity of this class of variants in a cohort of patients with common epilepsy syndromes and subsequently ask whether a significant fraction of benign variants have been misclassified as pathogenic. Methods: We screened a discovery cohort of 448 patients with a broad range of common genetic epilepsies and 734 controls for previously reported SCN1A mutations that were assumed to be disease causing. We re-evaluated the evidence for pathogenicity of the identified variants using in silico predictions, segregation, original reports, available functional data and assessment of allele frequencies in healthy individuals as well as in a follow up cohort of 777 patients. Results and Interpretation: We identified 8 known missense mutations, previously reported as path

Pivoting in Linear Complementarity: Two Polynomial-Time Cases

We study the behavior of simple principal pivoting methods for the P-matrix linear complementarity problem (P-LCP). We solve an open problem of Morris by showing that Murty’s least-index pivot rule (under any fixed index order) leads to a quadratic number of iterations on Morris’s highly cyclic P-LCP examples. We then show that on K-matrix LCP instances, all pivot rules require only a linear number of iterations. As the main tool, we employ unique-sink orientations of cubes, a useful combinatorial abstraction of the P-LCP