25 research outputs found
Microvolt T-Wave Alternans and the Risk of Death or Sustained Ventricular Arrhythmias in Patients With Left Ventricular Dysfunction
ObjectivesThis study hypothesized that microvolt T-wave alternans (MTWA) improves selection of patients for implantable cardioverter-defibrillator (ICD) prophylaxis, especially by identifying patients who are not likely to benefit.BackgroundMany patients with left ventricular dysfunction are now eligible for prophylactic ICDs, but most eligible patients do not benefit; MTWA testing has been proposed to improve patient selection.MethodsOur study was conducted at 11 clinical centers in the U.S. Patients were eligible if they had a left ventricular ejection fraction (LVEF) ≤0.40 and lacked a history of sustained ventricular arrhythmias; patients were excluded for atrial fibrillation, unstable coronary artery disease, or New York Heart Association functional class IV heart failure. Participants underwent an MTWA test and then were followed for about two years. The primary outcome was all-cause mortality or non-fatal sustained ventricular arrhythmias.ResultsIschemic heart disease was present in 49%, mean LVEF was 0.25, and 66% had an abnormal MTWA test. During 20 ± 6 months of follow-up, 51 end points (40 deaths and 11 non-fatal sustained ventricular arrhythmias) occurred. Comparing patients with normal and abnormal MTWA tests, the hazard ratio for the primary end point was 6.5 at two years (95% confidence interval 2.4 to 18.1, p < 0.001). Survival of patients with normal MTWA tests was 97.5% at two years. The strong association between MTWA and the primary end point was similar in all subgroups tested.ConclusionsAmong patients with heart disease and LVEF ≤0.40, MTWA can identify not only a high-risk group, but also a low-risk group unlikely to benefit from ICD prophylaxis
Institutional Conflict Settlement in Divided Societies: The Role of Subgroup Identities in Self-Government Arrangements
Effect of spatial uncertainty of masker on masked detection for nonspeech stimuli
Research on informational masking for nonspeech stimuli has focused on the effects of spectral uncertainty in the masker. In this letter, results are presented from some preliminary probe experiments in which the spectrum of the masker is held fixed but the spatial properties of the masker are randomized. In addition, in some tests, the overall level of the stimulus is randomized. These experiments differ from previous experiments that have measured the effect of spatial uncertainty on masking in that the only attributes (aside from level) that distinguish the target from the masker are the spatial attributes; in all of the tests, the target and masker were statistically identical, statistically independent, narrowband noise signals. In general, the results indicate that detection performance is degraded by spatial uncertainty in the masker but that compared both to the effects of spectral uncertainty and to the effects of overall-level uncertainty, the effects of spatial uncertainty are relatively small
Identification of Clinically Used Drugs That Activate Pregnane X ReceptorsS⃞
The pregnane X receptor (PXR) binds xenobiotics and regulates the expression of
several drug-metabolizing enzymes and transporters. Human PXR (hPXR) activation and
CYP3A4 induction can be involved in drug-drug interactions, resulting in reduced
efficacy or increased toxicity. However, there are known species-specific differences
with regard to PXR activation that should be taken into account when animal PXR data
are extrapolated to humans. We profiled 2816 clinically used drugs from the National
Institutes of Health Chemical Genomics Center Pharmaceutical Collection for their
ability to activate hPXR and rat PXR (rPXR) at the cellular level, induce human
CYP3A4 at the cellular level, and bind human PXR at the protein level. From 6 to 11%
of drugs were identified as active across the four assays, which included
assay-specific and pan-active compounds. The lowest concordance was observed between
the hPXR and rPXR assays, and many compounds active in both assays nonetheless
demonstrated significant potency differences between species. Analysis based on
clustering potency values demonstrated the greatest activity correlation between the
hPXR activation and CYP3A4 induction assays. Structure-activity relationship analysis
identified chemical scaffolds that were pan-active (e.g., dihydropyridine calcium
channel blockers) and others that were uniquely active in individual assays (e.g.,
steroids and fatty acids). These results provide important information on PXR
activation by clinically used drugs, highlight the species specificity of PXR
activation by xenobiotics, and provide a means of prioritizing compounds for
follow-up studies and optimization efforts
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Response to Letter Regarding Article, "Predictors of Response to Cardiac Resynchronization Therapy in The Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT)"
Predictors of Response to Cardiac Resynchronization Therapy in the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT)
Background— We hypothesized that combined assessment of factors that are associated with favorable reverse remodeling after cardiac resynchronization-defibrillator therapy (CRT-D) can be used to predict clinical response to the device. Methods and Results— The study population comprised 1761 patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT). Best-subset regression analysis was performed to identify factors associated with echocardiographic response (defined as percent reduction in left ventricular end-diastolic volume 1 year after CRT-D implantation) and to create a response score. Cox proportional hazards regression analysis was used to evaluate the CRT-D versus defibrillator-only reduction in the risk of heart failure or death by the response score. Seven factors were identified as associated with echocardiographic response to CRT-D and made up the response score (female sex, nonischemic origin, left bundle-branch block, QRS ≥150 milliseconds, prior hospitalization for heart failure, left ventricular end-diastolic volume ≥125 mL/m 2 , and left atrial volume <40 mL/m 2 ). Multivariate analysis showed a 13% ( P <0.001) increase in the clinical benefit of CRT-D per 1-point increment in the response score (range, 0–14) and a significant direct correlation between risk reduction associated with CRT-D and response score quartiles: Patients in the first quartile did not derive a significant reduction in the risk of heart failure or death with CRT-D (hazard ratio=0.87; P =0.52); patients in the second and third quartiles derived 33% ( P =0.04) and 36% ( P =0.03) risk reductions, respectively; and patients in the upper quartile experienced a 69% ( P <0.001) risk reduction ( P for trend=0.005). Conclusion— Combined assessment of factors associated with reverse remodeling can be used for improved selection of patients for cardiac resynchronization therapy. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00180271
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Predictors of Response to Cardiac Resynchronization Therapy in the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT)
Background— We hypothesized that combined assessment of factors that are associated with favorable reverse remodeling after cardiac resynchronization-defibrillator therapy (CRT-D) can be used to predict clinical response to the device. Methods and Results— The study population comprised 1761 patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT). Best-subset regression analysis was performed to identify factors associated with echocardiographic response (defined as percent reduction in left ventricular end-diastolic volume 1 year after CRT-D implantation) and to create a response score. Cox proportional hazards regression analysis was used to evaluate the CRT-D versus defibrillator-only reduction in the risk of heart failure or death by the response score. Seven factors were identified as associated with echocardiographic response to CRT-D and made up the response score (female sex, nonischemic origin, left bundle-branch block, QRS ≥150 milliseconds, prior hospitalization for heart failure, left ventricular end-diastolic volume ≥125 mL/m 2 , and left atrial volume <40 mL/m 2 ). Multivariate analysis showed a 13% ( P <0.001) increase in the clinical benefit of CRT-D per 1-point increment in the response score (range, 0–14) and a significant direct correlation between risk reduction associated with CRT-D and response score quartiles: Patients in the first quartile did not derive a significant reduction in the risk of heart failure or death with CRT-D (hazard ratio=0.87; P =0.52); patients in the second and third quartiles derived 33% ( P =0.04) and 36% ( P =0.03) risk reductions, respectively; and patients in the upper quartile experienced a 69% ( P <0.001) risk reduction ( P for trend=0.005). Conclusion— Combined assessment of factors associated with reverse remodeling can be used for improved selection of patients for cardiac resynchronization therapy. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00180271