Investigating the effect of sotalol on the repolarization intervals in healthy young individuals

Background

The dissociation between a drug-induced increase of the QT interval prolongation and an increased risk for ventricular arrhythmias has been suggested by academic investigators and regulatory agencies. Yet, there are no alternative or complimentary electrocardiographic (ECG) techniques available for assessing the cardiotoxicity of novel compounds. In this study, we investigated a set of novel ECG parameters quantifying the morphology of the T-loop. In a group of healthy individuals exposed to sotalol, we compared their drug-induced changes to the drug-induced prolongations of the QTc, QTc apex and T-peak to T-end intervals.

Methods

We implemented a set of parameters describing the morphology of the T loop in its preferential plane. These parameters measure the time interval needed for the heart vector amplitude to change from its maximum value to a time when its amplitude has been reduced by 30%, 50%, and 70%. These measurements are called early repolarization duration (ERD) when they are located before the T-wave apex and late repolarization duration (LRD) when measured after the apex. They depend on both the speed of the repolarization process and the morphology of the T loop. Thirty-nine healthy individuals were exposed to sotalol in a crossover-design study. Sixteen ECGs were recorded per day during 3 days. The first day (day 0) was baseline; a single dose of sotalol (160 mg) was given during day 1, and a double dose was given during day 2 (320 mg). The plasma concentration of the drug was measured just before the ECG recordings.

Results

The values of all investigated parameters revealed a dose-dependent effect of sotalol (in average between parameters, ρ = 0.9, P < .001). Our investigations described profound and statistically significant changes in the morphology of the vectorial T loop for day 1 (peak effect of sotalol: ΔERD_50% = 23 ± 6 msec, P < .05; ΔLRD_50% = 8 ± 3 msec, P = .05) and day 2 (peak effect of sotalol: ΔERD_50% = 51 ± 14 msec, P < .05; ΔLRD_50% = 20 ± 12 msec, P = .05). When investigating the timing of peak drug concentration and peak effect of the drug on the various repolarization parameters, we found asynchrony between ERDs/LRDs (≥3.5 hours after dosing) and QTc/QTc apex profiles (<3.5 hours after dosing), suggesting that the time of maximum prolongation on the repolarization process was not synchronized with the time of maximum drug-induced heterogeneity of repolarization.

Conclusion

This study describes the sotalol-induced changes of the T-loop morphology in healthy individuals based on novel vectocardiographic parameters. These observations might help in improving the next generation of ECG markers for the evaluation of drug cardiotoxicity.     

Time dependence of defibrillator benefit after coronary revascularization in the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II.

OBJECTIVES: The study was designed to assess the effect of elapsed time from coronary revascularization (CR) on the benefit of the implantable cardioverter-defibrillator (ICD) and the risk of sudden cardiac death (SCD) in patients with ischemic left ventricular dysfunction. BACKGROUND: The ICD improves survival in appropriately selected high-risk cardiac patients by 30% to 54%. However, in the Coronary Artery Bypass Graft (CABG)-Patch trial no evidence of improved survival was shown among a similar population of patients in whom an ICD was implanted prophylactically at the time of elective CABG. METHODS: The outcome by time from CR was analyzed in 951 patients in whom a revascularization procedure was performed before enrollment in the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II. RESULTS: The adjusted hazard ratio (HR) of ICD versus conventional therapy was 0.64 (p = 0.01) among patients enrolled more than six months after CR, whereas no survival benefit with ICD therapy was shown among patients enrolled six months or earlier after CR (HR = 1.19; p = 0.76). In the conventional therapy group, the risk of cardiac death increased significantly with increasing time from CR (p for trend = 0.009), corresponding mainly to a six-fold increase in the risk of SCD among patients enrolled more than six months after CR. CONCLUSIONS: In patients with ischemic left ventricular dysfunction, the efficacy of ICD therapy after CR is time dependent, with a significant life-saving benefit in patients receiving device implantation more than six months after CR. The lack of ICD benefit when implanted early after CR may be related to a relatively low risk of SCD during this time period.     

Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT‐CRT): Design and Clinical Protocol

The planned MADIT‐CRT trial is designed to determine if CRT‐D will reduce the risk of mortality and HF events by approximately 25% in subjects with ischemic (NYHA class I‐II) and non‐ischemic (NYHA class II) cardiomyopathy, left ventricular dysfunction (EF ≤ 0.30), and prolonged intraventricular conduction (QRS duration ≥ 130 ms).     

Pharmacogenetics of the local thrombolysis in patients with deep vein thrombosis

Thrombophilia, the state of increased tendency for blood clotting, is considered the disorder of a complex etiology, caused by both environmental and genetic factors. As gene variants predisposing to thrombophilia and influencing the increased risk of vein thrombosis might influence response to local thrombolysis, the aim of the work was to characterize the pharmacogenetic conditions for local streptokinase treatment in patients with a deep vein thrombosis (DVT) of lower extremities based on the following polymorphism analyses: G1691A polymorphism of factor V (FV), G20210A polymorphism of prothrombin (PT), A4250G (Thr312Ala) polymorphism of fibrinogen-alpha (FGA), G(-455)A polymorphism of fibrinogen-beta (FGB), 4G/5G polymorphism of plasminogen activator inhibitor type 1(PAI-1) and insertion/deletion (I/D) polymorphism of tissue plasminogen activator (t-PA). The study included 40 DVT patients who underwent a local thrombolytic treatment within 14-day period from diagnosis. Full recanalization was achieved in 20 subjects (50%) [group R(+)], whereas incomplete or total lack of recanalization was identified in the remaining 20 patients [group R(-)]. No major complications of thrombolytic treatment occurred in the studied group. In the case of prothrombin gene all individuals carried homozygous wild type genotype (GG). Prevalence of the genotypes and alleles of the remaining five polymorphisms did not differ significantly between the groups R(+) and R(-). Neither sex nor age, smoking or time period from diagnosis to introduction of the thrombolytic treatment significantly influenced treatment efficacy. The results of the study suggest that a local thrombolysis with streptokinase introduced within two week period from the diagnosis is a safe and efficient method of treatment for deep vein thrombosis of lower extremities. However, size of the group is insufficient to clearly determine the association between investigated polymorphisms and efficacy of local treatment with streptokinase.     

Variance stabilization for computing and comparing grand mean waveforms in MEG and EEG

Grand means of time‐varying signals (waveforms) across subjects in magnetoencephalography (MEG) and electroencephalography (EEG) are commonly computed as arithmetic averages and compared between conditions, for example, by subtraction. However, the prerequisite for these operations, homogeneity of the variance of the waveforms in time, and for most common parametric statistical tests also between conditions, is rarely met. We suggest that the heteroscedasticity observed instead results because waveforms may differ by factors and additive terms and follow a mixed model. We propose to apply the asinh‐transformation to stabilize the variance in such cases. We demonstrate the homogeneous variance and the normal distributions of data achieved by this transformation using simulated waveforms, and we apply it to real MEG data and show its benefits. The asinh‐transformation is thus an essential and useful processing step prior to computing and comparing grand mean waveforms in MEG and EEG.     

Inhibitor kinazy Brutona u chorych z nawrotowym lub opornym na leczenie chłoniakiem z komórek płaszcza – wyniki międzynarodowego,wieloośrodkowego,badania II fazy z ibrutynibem (PCI-32765) – EHA Encore

Bruton's tyrosine kinase (BTK) is a central mediator of B-cell receptor (BCR) signaling essential for normal B-cell development. Ibrutinib is an oral BTK inhibitor that induces apoptosis and inhibits migration and adhesion of malignant B-cells. Updated results of this international, multicenter, phase 2 study of single agent ibrutinib in relapsed or refractory MCL will be presented.Ibrutinib 560 mg PO QD was administered continuously until disease progression. Tumor response was assessed every 2 cycles (one cycle = 28 days). The study enrolled 115 patients (65 bortezomib-naïve, 50 bortezomib-exposed); 111 patients were treated; 110 were evaluable for response. Baseline characteristics included: median age 68 years, time since diagnosis 42 months, number of prior treatments 3; bulky disease (>10 cm) 13%, prior stem cell transplant 10%, high risk MIPI 49%.Median time on treatment was 9.2 months; 53% of patients remain on therapy. Median PFS was 13.9 months and DOR has not yet been reached. Responses increased with longer treatment: comparing to previous data described at ASH 2011, the CR rate increased from 16% to 39%, and the ORR increased from 69% to 75%.     

Prediction of eye color in the Slovenian population using the IrisPlex SNPs

Aim

To evaluate the accuracy of eye color prediction based on six IrisPlex single nucleotide polymorphisms (SNP) in a Slovenian population sample.

Methods

Six IrisPlex predictor SNPs (HERC2 – rs12913832, OCA2 – rs1800407, SLC45A2 – rs16891982 and TYR – rs1393350, SLC24A4 – rs12896399, and IRF4 – rs12203592) of 105 individuals were analyzed using single base extension approach and SNaPshot chemistry. The IrisPlex multinomial regression prediction model was used to infer eye color probabilities. The accuracy of the IrisPlex was assessed through the calculation of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and the area under the receiver characteristic operating curves (AUC).

Results

Blue eye color was observed in 44.7%, brown in 29.6%, and intermediate in 25.7% participants. Prediction accuracy expressed by the AUC was 0.966 for blue, 0.913 for brown, and 0.796 for intermediate eye color. Sensitivity was 93.6% for blue, 58.1% for brown, and 0% for intermediate eye color. Specificity was 93.1% for blue, 89.2% for brown, and 100% for intermediate eye color. PPV was 91.7% for blue and 69.2% for brown color. NPV was 94.7% for blue and 83.5% for brown eye color. These values indicate prediction accuracy comparable to that established in other studies.

Conclusion

Blue and brown eye color can be reliably predicted from DNA samples using only six polymorphisms, while intermediate eye color defies prediction, indicating that more research is needed to genetically predict the whole variation of eye color in humans.Prediction of human visible characteristics by genotyping informative polymorphisms in DNA opens up a new perspective in the forensic field. Multiple genes including HERC2, OCA2, MC1R, SLC24A5, SLC45A2, TYR, TYRP1, ASIP, SLC24A4, TPCN2, KITLG, and IRF4 have been associated with eye, hair, and skin color in European populations and they have been used in studies dealing with eye color prediction (1-14). Variation of iris color depends on the content of eumelanine, a brown light-absorbing biopolymer, which is present in higher concentrations in brown-eyed individuals (15,16). Although eye color is evidently a continuous variable, it has been often classified into three categories – blue, brown, and intermediate (4,14). Eye color variability is particularly striking in European populations, constituting a highly differentiating trait of potential use in forensic investigations (7,14,17). Recent studies have shown that a significant fraction of human iris color variation can be explained by polymorphisms within a single region in the human genome, comprising the evolutionary conserved HERC2 gene and the neighboring OCA2 gene located on the chromosome 15. It is assumed that the level of expression of the known pigmentation gene – OCA2 – is controlled by polymorphism rs12913832 on HERC2 locus (18,19). The remaining genes that have been shown to contribute to eye color variation are SLC24A4, SLC45A2, TYR, and IRF4 (4,20,21). However, their impact on eye color prediction is lower and it seems to vary between populations (8,14,22,23). Since such differences may potentially affect accuracy of prediction in various populations, we further addressed this issue and analyzed a population sample of individuals with defined eye color from Slovenia.Several prediction models have already been proposed to be useful in eye color prediction (4,8,9,17,23,24). Here we used six IrisPlex predictors, which were selected by Liu et al (4) from a larger set of polymorphisms potentially influencing pigmentation in humans and included into the IrisPlex prediction system (4,13,17). The IrisPlex prediction model is based on a multinomial logistic regression method and uses phenotype and genotype data from 3804 Dutch individuals. Based on these data the model gives three probabilities for blue, brown, and intermediate eye color (13). From the obtained probabilities, the most probable iris color is predicted based on recommendations given in Walsh et al (13).     

Dangerous liaisons: Bacteria,antimicrobial therapies,and allergic diseases

Microbiota composition and associated metabolic activities are essential for the education and development of a healthy immune system. Microbial dysbiosis, caused by risk factors such as diet, birth mode, or early infant antimicrobial therapy, is associated with the inception of allergic diseases. In turn, allergic diseases increase the risk for irrational use of antimicrobial therapy. Microbial therapies, such as probiotics, have been studied in the prevention and treatment of allergic diseases, but evidence remains limited due to studies with high heterogeneity, strain-dependent effectiveness, and variable outcome measures. In this review, we sketch the relation of microbiota with allergic diseases, the overuse and rationale for the use of antimicrobial agents in allergic diseases, and current knowledge concerning the use of bacterial products in allergic diseases. We urgently recommend 1) limiting antibiotic therapy in pregnancy and early childhood as a method contributing to the reduction of the allergy epidemic in children and 2) restricting antibiotic therapy in exacerbations and chronic treatment of allergic diseases, mainly concerning asthma and atopic dermatitis. Future research should be aimed at antibiotic stewardship implementation strategies and biomarker-guided therapy, discerning those patients that might benefit from antibiotic therapy.