Predictive Value of QT Dispersion for Ventricular Tachyarrhythmias in Patients with Implantable Cardioverter Defibrillator

Background: QT dispersion, measured as interlead variability of QT intervals in the surface electrocardiogram, has been demonstrated to provide an indirect measurement of the inhomogeneity of myocardial repolarization as a potential substrate for ventricular arrhythmias. Methods: QT dispersion was measured in the standard 12-lead ECG in 51 patients at the time of implantation of a third generation implantable cardioverter defibrillator (ICD) with automatic electrogram storage capability for electrical events triggering device therapy. In addition, QT dispersion was measured in 100 age- and sex-matched healthy controls. All 5 1 study patients with ICD were prospectively followed to determine possible associations between QT dispersion at implant and subsequent spontaneous ICD shocks for ventricular tachyarrhythmias (VT). Results: Rate-corrected QT dispersion and adjusted QTc dispersion, which takes account of the number of leads measured, were significantly greater in ICD patients compared to controls (76 ± 25 ms vs 46 ± 11 ms, and 24 ± 7 ms vs 14 ± 3 ms respectively, P < 0.0 1). During 15 ± 8 months follow-up, ventricular tachyarrhythmias occurred in 23 (45%) of 51 ICD patients. QTc dispersion and adjusted QTc dispersion were not significantly different between ICD patients with ventricular tachyarrhythmias and ICD patients without ventricular tachyarrhythmias during follow-up (74 ± 19 ms versus 77 ± 29 ms, and 23 ± 6 ms vs 25 ± 8 ms respectively). Conclusion: Increased QT dispersion measured in the 12-lead standard ECG does not appear to be a useful marker for future arrhythmic events in a mixed patient population with ICD.     

Copolymerization of CO2 and epoxides mediated by zinc organyls

Herein we report the copolymerization of CHO with CO₂ in the presence of various zinc compounds R₂Zn (R = Et, Bu, iPr, Cy and Ph). Several zinc organyls proved to be efficient catalysts for this reaction in the absence of water and co-catalyst. Notably, readily available Bu₂Zn reached a TON up to 269 and an initial TOF up to 91 h⁻¹. The effect of various parameters on the reaction outcome has been investigated. Poly(ether)carbonates with molecular weights up to 79.3 kg mol⁻¹ and a CO₂ content of up to 97% were obtained. Under standard reaction conditions (100 °C, 2.0 MPa, 16 h) the influence of commonly employed co-catalysts such as PPNCl and TBAB has been investigated in the presence of Et₂Zn (0.5 mol%). The reaction of other epoxides (e.g. propylene and styrene oxide) under these conditions led to no significant conversion or to the formation of the respective cyclic carbonate as the main product.

Simple zinc organyls (R₂Zn) efficiently catalyze the copolymerization of CO₂ and cyclohexene oxide. The effect of various reaction parameters has been studied. The reaction proceeds under halogen-free conditions and no co-catalyst is required.     

Preoperative anemia and extensive transfusion during stay-in-hospital are critical for patient`s mortality: A retrospective multicenter cohort study of oncological patients undergoing radical cystectomy

Background

Preoperative anemia and allogeneic blood transfusions (ABTs) may affect outcomes in cancer surgery. The prevalence of anemia, the use of ABTs, the risks of transfusions, lengths of stay and mortality of oncological patients undergoing radical cystectomy were investigated in three University Hospitals in Germany.

Rivaroxaban versus standard anticoagulation for acute venous thromboembolism in childhood. Design of the EINSTEIN-Jr phase III study

Background

Venous thromboembolism (VTE) is a relatively rare condition in childhood with treatment mainly based on extrapolation from studies in adults. Therefore, clinical trials of anticoagulation in children require novel approaches to deal with numerous challenges. The EINSTEIN-Jr program identified pediatric rivaroxaban regimens commencing with in vitro dose finding studies followed by evaluation of children of different ages through phase I and II studies using extensive modeling to determine bodyweight-related doses. Use of this approach resulted in drug exposure similar to that observed in young adults treated with rivaroxaban 20?mg once-daily.

Methods

EINSTEIN-Jr phase III is a randomized, open-label, study comparing the efficacy and safety of rivaroxaban 20?mg-equivalent dose regimens with those of standard anticoagulation for the treatment of any types of acute VTE in children aged 0–18?years.A total of approximately 500 children are expected to be included during the 4-year study window. Flexibility of treatment duration is allowed with study treatment to be given for 3?months with the option to continue treatment in 3-month increments, up to a total of 12?months. However, based on most common current practice, children younger than 2?years with catheter-related thrombosis will have a main treatment period of 1?month with the option to prolong treatment in 1-month increments, up to a total of 3?months.

Conclusions

EINSTEIN-Jr will compare previously established 20?mg-equivalent rivaroxaban dosing regimens with standard anticoagulation for the treatment of VTE in children. Demonstration of similarity of disease, as well as equivalent rivaroxaban exposure and exposure-response will enable extrapolation of efficacy from adult trials, which is critical given the challenges of enrollment in pediatric anticoagulation trials.

Trial registration

Clinicaltrials.gov NCT02234843, registered on 9 September 2014.

     

Powerful Set‐Based Gene‐Environment Interaction Testing Framework for Complex Diseases

Identification of gene‐environment interaction (G × E) is important in understanding the etiology of complex diseases. Based on our previously developed Set Based gene EnviRonment InterAction test (SBERIA), in this paper we propose a powerful framework for enhanced set‐based G × E testing (eSBERIA). The major challenge of signal aggregation within a set is how to tell signals from noise. eSBERIA tackles this challenge by adaptively aggregating the interaction signals within a set weighted by the strength of the marginal and correlation screening signals. eSBERIA then combines the screening‐informed aggregate test with a variance component test to account for the residual signals. Additionally, we develop a case‐only extension for eSBERIA (coSBERIA) and an existing set‐based method, which boosts the power not only by exploiting the G‐E independence assumption but also by avoiding the need to specify main effects for a large number of variants in the set. Through extensive simulation, we show that coSBERIA and eSBERIA are considerably more powerful than existing methods within the case‐only and the case‐control method categories across a wide range of scenarios. We conduct a genome‐wide G × E search by applying our methods to Illumina HumanExome Beadchip data of 10,446 colorectal cancer cases and 10,191 controls and identify two novel interactions between nonsteroidal anti‐inflammatory drugs (NSAIDs) and MINK1 and PTCHD3.     

Second malignancies after treatment of childhood non-Hodgkin lymphoma – a report of the Berlin-Frankfurt-Muenster study group

Second malignant neoplasms (SMN) pose a concern for survivors of childhood cancer. We evaluated incidence, type and risk factors for SMN in patients included in Berlin-Frankfurt-Muenster protocols for childhood non-Hodgkin lymphoma.3,590 patients <15 years of age at diagnosis, registered between 01/1981 and 06/2010, were analyzed. SMN were reported by the treating institutions and the German Childhood Cancer Registry. After a median follow-up of 9.4 years (quartile [Q] range, Q1 6.7 and Q3 12.1) 95 SMN were registered (26 carcinomas including nine basal cell carcinomas, 21 acute myeloid leukemias/myelodysplastic syndromes, 20 lymphoid malignancies, 12 central nervous system [CNS]-tumors, and 16 others). Cumulative incidence at 20 years was 5.7±0.7%, standard incidence ratio, excluding basal cell carcinomas, was 19.8 (95% Confidence Interval [CI]: 14.5-26.5). Median time from initial diagnosis to second malignancy was 8.7 years (range, 0.2-30.3 years). Acute-lymphoblasticleukemia- type therapy, cumulative anthracycline dose, and cranial radiotherapy for brain tumor-development were significant risk factors in univariate analysis only. In multivariate analysis including risk factors significant in univariate analysis, female sex (hazard ratio [HR] 1.87, 95% CI: 1.23-2.86, P=0.004), CNS-involvement (HR 2.24, 95% CI: 1.03-4.88, P=0.042), lymphoblastic lymphoma (HR 2.60, 95% CI: 1.69-3.97, P<0.001), and cancer-predisposing condition (HR 11.2, 95% CI: 5.52-22.75, P<0.001) retained an independent risk. Carcinomas were the most frequent SMN after non-Hodgkin lymphoma in childhood followed by acute myeloid leukemia and lymphoid malignancies. Female sex, lymphoblastic lymphoma, CNS-involvement, or/and known cancer-predisposing condition were risk factors for SMN-development. Our findings set the basis for individualized long-term follow-up and risk assessment of new therapies.