Noninvasive tissue adhesive for cardiac implantable electronic device pocket closure: the TAPE pilot study.

PURPOSE: Device infection is a serious complication of cardiac implantable electronic devices (CIED). Ensuring complete pocket closure can be time consuming, but remains vital to prevent infection. The Zip® Surgical Skin Closure (ZIP) is a noninvasive adhesive device applied to the skin as an alternative to subcuticular sutures for skin closure. We hypothesized that using this device would decrease pocket closure times without increasing the risk of pocket infections. This is a single center, retrospective cohort study to compare pocket closure times and infection rates between ZIP and standard suture for CIED pocket closure. METHODS: Two separate groups of consecutive new intravenous implants, upgrades, and pulse generator replacements from October 2015 to April 2017 were included. A total of 175 patients were included, using either ZIP (n = 80) or suture (n = 95). Total procedure time (local anesthetic to dressing application) and pocket closure time (fascial suture to dressing application) were compared. Pocket infections were defined as infections leading to CIED extraction or wound dehiscence requiring repeat procedure. Statistical analysis was performed using chi square test and Student's t test. RESULTS: Pocket closure time and procedure time were significantly shorter for the ZIP group (14.9 ± 6.8 vs 20.1 ± 11.09 min, p = 0.0003) and (65.02 ± 30.4 vs 83.83 ± 40.3 min, p = 0.0008), respectively. No pocket infections occurred in the Zip group, while the suture group had 2:1 wound dehiscence and 1 pocket infection. CONCLUSION: The ZIP device resulted in significantly shorter pocket closure and procedure times without increasing device pocket infections.

The Rap GTPases regulate the migration, invasiveness and in vivo dissemination of B-cell lymphomas.

B-cell lymphomas are common malignancies in which transformed B cells enter the circulation, extravasate into tissues and form tumors in multiple organs. Lymphoma cells are thought to exit the vasculature and enter tissues through the same chemokine- and adhesion molecule-dependent mechanisms as normal B cells. We have previously shown that activation of the Rap GTPases, proteins that control cytoskeletal organization and integrin activation, is critical for chemokine-induced migration and adhesion in B-lymphoma cell lines. Using the A20 murine B-lymphoma cell line as a model, we now show that Rap activation is important for circulating lymphoma cells to enter tissues and form tumors in vivo. In vitro assays showed that Rap activation is required for A20 cells to efficiently adhere to vascular endothelial cells and undergo transendothelial migration. These findings suggest that Rap or its effectors could be novel targets for treating B-cell lymphomas.

Predicting geographical variations in behavioural risk factors: an analysis of physical and mental healthy days.

STUDY OBJECTIVES: To determine the validity of physical and mental unhealthy days as summary measures for county health status and to forward a method for examining county level health trends using a single year of data from the Behavioral Risk Factor Surveillance System (BRFSS). DESIGN: The study analysed geographical variation in physical and mental unhealthy days at the state and county level using the 2000 BRFSS. Whereas state level analyses used individual level data, this research conducted multilevel regression analysis using county level data as independent variables and individual level reports of physical and mental unhealthy days as dependent variables. SETTING: Population based samples of non-institutionalised civilian adult residents from each of the 50 states and the District of Columbia in the United States. MAIN RESULTS: Socioeconomic variables predicted similar mean numbers of physical and mental unhealthy days at both the state and county level, validating the county level analyses. County level disability rates were strongly associated with county mean unhealthy days. Using the regression method we forward, it is possible to analyse county level trends using a single year of BRFSS data. CONCLUSIONS: Physical and mental unhealthy days may be used as valid summary measures of county health status. Regression models may be used to assist local decision makers in assessing the needs of their communities and may be used to improve health resource allocation within states.

T wave alternans for ventricular arrhythmia risk stratification.

Sudden cardiac death remains one of the leading causes of death in Europe and the United States. Accordingly, the ability to identify patients at high risk of sudden cardiac death is important so that appropriate treatments can be used efficiently. Recently, T wave alternans (TWA) has emerged as a promising new test for such risk stratification. TWA is a heart rate dependent measure of arrhythmia vulnerability, with maximal predictive accuracy at sustained, regular heart rates of 100-120 bpm. In the clinical setting these conditions may be achieved by either exercise or atrial pacing. TWA has been shown to predict inducibility of ventricular tachycardia with programmed stimulation and also spontaneous arrhythmic events. TWA has been successfully applied to diverse populations, including patients with coronary artery disease, nonischemic cardiomyopathy, congestive heart failure and those with implantable defibrillators. Despite these encouraging results, the role of TWA to guide clinical therapy still needs to be better elucidated.

Temporal decline in defibrillation thresholds with an active pectoral lead system.

OBJECTIVES: The objective of this study was to characterize temporal changes in defibrillation thresholds (DFTs) after implantation with an active pectoral, dual-coil transvenous lead system. BACKGROUND: Ventricular DFTs rise over time when monophasic waveforms are used with non-thoracotomy lead systems. This effect is attenuated when biphasic waveforms are used with transvenous lead systems; however, significant increases in DFT still occur in a minority of patients. The long-term stability of DFTs with contemporary active pectoral lead systems is unknown. METHODS: This study was a prospective assessment of temporal changes in DFT using a uniform testing algorithm, shock polarity and dual-coil active pectoral lead system. Thresholds were measured at implantation, before discharge and at long-term follow-up (70 +/- 40 weeks) in 50 patients. RESULTS: The DFTs were 9.2 +/- 5.4 J at implantation, 8.3 +/- 5.8 J before discharge and 6.9 +/- 3.6 J at long-term follow-up (p < 0.01 by analysis of variance; p < 0.05 for long-term follow-up vs. at implantation or before discharge). The effect was most marked in a prespecified subgroup with high implant DFTs (> or =15 J). No patient developed an inadequate safety margin (< 9 J) during follow-up. CONCLUSIONS: The DFTs declined significantly after implantation with an active pectoral, dual-coil transvenous lead system, and no clinically significant increases in DFT were observed. Therefore, routine defibrillation testing may not be required during the first two years after implantation with this lead system, in the absence of a change in the cardiac substrate or treatment with antiarrhythmic drugs.

New views of BCR structure and organization.

Recent work has provided new insights into the stoichiometry of BCR subunits, as well as the organization of the BCR before and after engagement by antigen. On resting cells, the BCR may be pre-assembled into oligomeric receptor complexes that generate a basal level of signaling. After antigen binding, the BCR may be organized into larger receptor arrays that reside in lipid rafts - sites where signaling enzymes are concentrated. The critical role of BCR assembly and organization in B cell function is underscored by the recent findings that this process is altered in many B cell tumors.

Health insurance expansion through states in a pluralistic system.

The United States continues to stand almost alone among developed nations in its lack of universal health care coverage. In this essay, we argue that even though the debate over whether the federal government or states should lead the effort to expand health care coverage under the federal system is relevant in strategizing how to cover the uninsured; the more critical issues stem from the challenge of the mixed and fragmented mode of public-private financing of our pluralistic health care system. We base this argument on (1) an in-depth review of Oregon's and Tennessee's five years of experience with broad coverage reform in the context of the United States health care system and on (2) a more abbreviated review of other state experiences in providing health care coverage. We conclude from our review that when the will exists, states can substantially expand coverage. However, as one moves up the income scale, political support and resources are harder to come by. Further, concerns grow about the interface of public and private coverage, with issues of "crowd out" and other distributional questions dominating the discussion of coverage expansion as policy makers focus less on how to cover people than on how to make sure one kind of coverage doesn't preempt another. Concern for crowd out can then lead to policies that keep out some of the very people policy makers may want to cover. In this context the question whether states or the federal government is more likely to succeed in expanding coverage is eclipsed by the more fundamental challenges raised by pluralism. Neither federal nor state government is likely to be fully successful without first identifying ways of better coordinating public and private activities and resources to provide continuous and affordable coverage.

Provider organizations at risk: a profile of major risk-bearing intermediaries, 1999.

Provider organizations have evolved to function as intermediaries between managed care plans and individual providers. These organizations assume much financial risk and care management responsibilities. We profile the characteristics of these organizations in markets across the country. The data, taken from a 1999 telephone survey of sixty-four entities in twenty markets and from interviews conducted during site visits to four markets, highlight the youth of many of these organizations, the large financial risk and functional responsibilities they bear, and the mixed views they hold about the health plans they contract with in terms of their willingness to delegate the authority, support, and collaboration that accompany risk. Policymakers need to evaluate what this means for oversight of managed care.

The Gab1 docking protein links the b cell antigen receptor to the phosphatidylinositol 3-kinase/Akt signaling pathway and to the SHP2 tyrosine phosphatase.

B cell antigen receptor (BCR) signaling causes tyrosine phosphorylation of the Gab1 docking protein. This allows phosphatidylinositol 3-kinase (PI3K) and the SHP2 tyrosine phosphatase to bind to Gab1. In this report, we tested the hypothesis that Gab1 acts as an amplifier of PI3K- and SHP2-dependent signaling in B lymphocytes. By overexpressing Gab1 in the WEHI-231 B cell line, we found that Gab1 can potentiate BCR-induced phosphorylation of Akt, a PI3K-dependent response. Gab1 expression also increased BCR-induced tyrosine phosphorylation of SHP2 as well as the binding of Grb2 to SHP2. We show that the pleckstrin homology (PH) domain of Gab1 is required for BCR-induced phosphorylation of Gab1 and for Gab1 participation in BCR signaling. Moreover, using confocal microscopy, we show that BCR ligation can induce the translocation of Gab1 from the cytosol to the plasma membrane and that this requires the Gab1 PH domain as well as PI3K activity. These findings are consistent with a model in which the binding of the Gab1 PH domain to PI3K-derived lipids brings Gab1 to the plasma membrane, where it can be tyrosine-phosphorylated and then act as an amplifier of BCR signaling.

Implantable cardiac defibrillators.

The implantable cardioverter defibrillator (ICD) represents an important development in the effort to reduce the incidence of sudden cardiac death (almost 400,000 yearly in the United States). Early generation ICDs, which required epicardial lead systems and abdominal placement of the pulse generator, have been replaced by transvenous leads and pectoral implants. Other important refinements, which include biphasic waveforms, extensive memory capability, antitachycardia pacing, and enhanced sensing algorithms, have greatly improved patient tolerance. Ongoing trials and those in the planning stages will continue to expand the indications for ICDs and will focus on cost-effectiveness.

Clinical predictors and efficacy of antitachycardia pacing in patients with implantable cardioverter defibrillators: the importance of the patient's sex.

The ICD has become accepted as primary therapy for malignant ventricular arrhythmias. The incorporation of antitachycardia pacing into ICDs has provided a better tolerated alternative to shocks but has the potential disadvantage of delaying definitive therapy. Accordingly, we sought to delineate the characteristics of patients likely to experience unsuccessful termination of pacing and to identify ineffective pacing strategies. Of 519 patients who received ICDs, 11 clinical and tachycardia characteristics in the 162 who received antitachycardia pacing therapy for sustained ventricular arrhythmias were evaluated. Tachycardia episodes were grouped according to outcome of pacing (successful, unsuccessful, acceleration). Of 1,946 episodes, 1,502 (77.2%) were successfully reverted with pacing, 322 (16.5%) were unsuccessful, and 121 (6.2%) were accelerated. Antitachycardia pacing was less successful in women, patients with a history of myocardial infarction, those with more severe left ventricular dysfunction, those who received antiarrhythmic drugs, and those programmed to ramp pacing. Tachycardia acceleration was inversely related to tachycardia cycle length and was more frequent in patients programmed to more aggressive ramp pacing protocols. Women had an almost threefold incidence of tachycardia acceleration compared with men (14% vs 5%, P < 0.001). Antitachycardia pacing is generally successful in terminating ventricular tachycardia and has a low incidence of tachycardia acceleration. Caution should be used with rapid tachycardias and aggressive ramp pacing protocols because of an increased risk of acceleration. Antitachycardia pacing appears less successful and has a higher incidence of complications in women.

Using the years-of-healthy-life measure to calculate QALYs.

BACKGROUND: The quality-adjusted life year (QALY) is an attractive outcome measure because it captures both health-related quality of life (HRQL) and life expectancy in a single metric. We present a method for calculating QALYs that is simple, utilizes data that are free of charge, and may improve consistency in burden-of-disease investigations. METHODS: For purposes of illustration, we calculated the burden of disease due to stroke using two abridged life tables, each adjusted for HRQL. The first life table was generated using all-cause mortality and morbidity data (a reference cohort) and the second was generated using all diseases except stroke (a stroke-free cohort). The difference in total QALYs and in quality-adjusted life expectancy (QALE) was determined by subtraction. RESULTS: Approximately 61,328 (95% CI=60,272, 62,383) QALYs were lost to stroke in the life-table cohort. Stroke is responsible for a decrement of 0.03 years of life expectancy and 0.61 years of QALE in the United States. CONCLUSIONS: The "years of health life"measure affords a rapid, inexpensive, and sensitive means for estimating the burden of disease for local health priorities and may assist research efforts in including QALYs as an outcome measure.

Clinical experience with a dual-chamber implantable cardioverter defibrillator to treat atrial tachyarrhythmias.

INTRODUCTION: This study evaluated the safety and efficacy of a new dual-chamber implantable cardioverter defibrillator (ICD) to detect and treat atrial tachyarrhythmias in patients with drug-refractory atrial fibrillation (AF) and no indication for a ventricular ICD. METHODS AND RESULTS: A dual-chamber ICD (Medtronic 7250 Jewel AF) was implanted in 144 of 146 patients. The device discriminates atrial tachycardia from AF based on cycle length and regularity, and uses atrial overdrive pacing as well as shocks to terminate tachyarrhythmia episodes. Patients were followed for an average of 12.6+/-6.2 months. Use of antiarrhythmic drugs was 63% at baseline and did not change over time. Kaplan-Meier estimates of 12-month complication-free survival, device therapy survival, and patient survival were 85%, 91%, and 98%, respectively. Positive predictive accuracy of spontaneous atrial tachyarrhythmia detection was 99%, while atrial overdrive pacing and shocks terminated 40% and 87% of treated episodes, respectively. Median duration of successfully treated episodes was 8.9 minutes versus 144 minutes for the therapy failures. There was no reduction in the use of patient-activated shock therapy over time; at the 12-month follow-up evaluation, 94% of patients were in sinus rhythm. Ventricular tachyarrhythmias (67 episodes) were detected and appropriately treated in 7.6% of patients. CONCLUSION: This dual-chamber ICD appears to be safe and well tolerated in patients with drug-refractory symptomatic atrial tachyarrhythmias. The device, used in combination with drugs, effectively treats atrial tachyarrhythmias with pacing and/or shock therapies and decreases the median episode duration. In addition, the device protects from ventricular tachyarrhythmias in patients with AF and structural heart disease.

Activation and function of the Rap1 GTPase in B lymphocytes.

Rap1 is a monomeric GTPase that is closely related to Ras. In this review, we summarize our recent work showing that the B cell antigen receptor (BCR), as well as chemokine receptors, activate Rap1 via a pathway that involves phospholipase C-dependent production of diacylglycerol (DAG). The possible identities of the DAG-regulated guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) that regulate the activation of Rap1 by the BCR and chemokine receptors will be discussed. Although initially thought to be an antagonist of Ras-mediated signaling, Rap1 does not appear to modulate the ability of the BCR to activate downstream targets of Ras. Instead, activation of Rap1 promotes B cell adhesion as well as B cell migration toward chemokines. Thus, Rap1 may play a key role in a number of processes that are essential for B cell development and activation.

A comparison of T-wave alternans, signal averaged electrocardiography and programmed ventricular stimulation for arrhythmia risk stratification.

OBJECTIVES: The goal of this study was to compare T-wave alternans (TWA), signal-averaged electrocardiography (SAECG) and programmed ventricular stimulation (EPS) for arrhythmia risk stratification in patients undergoing electrophysiology study. BACKGROUND: Accurate identification of patients at increased risk for sustained ventricular arrhythmias is critical to prevent sudden cardiac death. T-wave alternans is a heart rate dependent measure of repolarization that correlates with arrhythmia vulnerability in animal and human studies. Signal-averaged electrocardiography and EPS are more established tests used for risk stratification. METHODS: This was a prospective, multicenter trial of 313 patients in sinus rhythm who were undergoing electrophysiologic study. T-wave alternans, assessed with bicycle ergometry, and SAECG were measured before EPS. The primary end point was sudden cardiac death, sustained ventricular tachycardia, ventricular fibrillation or appropriate implantable defibrillator (ICD) therapy, and the secondary end point was any of these arrhythmias or all-cause mortality. RESULTS: Kaplan-Meier survival analysis of the primary end point showed that TWA predicted events with a relative risk of 10.9, EPS had a relative risk of 7.1 and SAECG had a relative risk of 4.5. The relative risks for the secondary end point were 13.9, 4.7 and 3.3, respectively (p < 0.05). Multivariate analysis of 11 clinical parameters identified only TWA and EPS as independent predictors of events. In the prespecified subgroup with known or suspected ventricular arrhythmias, TWA predicted primary end points with a relative risk of 6.1 and secondary end points with a relative risk of 8.0. CONCLUSIONS: T-wave alternans is a strong independent predictor of spontaneous ventricular arrhythmias or death. It performed as well as programmed stimulation and better than SAECG in risk stratifying patients for life-threatening arrhythmias.