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Patients with relapsed/refractory (R/R) higher-risk myelodysplastic syndromes (MDS) have a dismal median overall survival (OS) after failing hypomethylating agent (HMA) treatment. There is no standard of care for patients after HMA therapy failure; hence, there is a critical need for effective therapeutic strategies. Herein, we present the safety and efficacy of venetoclax + azacitidine in patients with R/R MDS. This phase 1b, open-label, multicenter study enrolled patients ≥18 years. Patients were treated with escalating doses of oral venetoclax: 100, 200, or 400 mg daily for 14 days every 28-day cycle. Azacitidine was administered on Days 1-7 every cycle at 75 mg/m

Small cell lung cancer (SCLC) is a leading cause of cancer death worldwide, with few treatment options. Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate that targets delta-like 3 on SCLC cells to deliver a cytotoxic payload directly to tumor cells. In this study, the cardiac safety profile of Rova-T was assessed by evaluating changes in QT interval, electrocardiogram (ECG) waveform, heart rate, and proarrhythmic adverse events (AEs) after treatment with Rova-T in patients with previously treated extensive-stage SCLC. Patients underwent ECG monitoring for 2 weeks after each of 2 i.v. infusions of 0.3 mg/kg Rova-T over 30 minutes, administered 6 weeks apart. Forty-six patients received at least one dose of Rova-T. At the geometric mean Rova-T maximum serum concentration of 7,940 ng/mL, ECG monitoring showed no significant changes in the Fridericia-corrected QT (QTcF) interval; the upper limit of the 2-sided 90% confidence interval did not exceed 10 msec for any time point. There were no clinically significant changes in QRS or PR intervals, ECG waveforms, or heart rate after Rova-T administration. All patients experienced a treatment-emergent AE (TEAE); 78% had a grade ≥ 3 TEAE, 59% had a serious TEAE, and 41% had a cardiac-related TEAE. The TEAEs that might signal proarrhythmia tendencies were uncommon. Confirmed partial responses were observed in 24% of patients. Based on the evaluation of ECG data collected in this study from patients treated with Rova-T at 0.3 mg/kg i.v. administered every 6 weeks, a QTcF effect of clinical concern can be excluded.

This article describes how a frequentist model averaging approach can be used for concentration-QT analyses in the context of thorough QTc studies. Based on simulations, we have concluded that starting from three candidate model families (linear, exponential, and Emax) the model averaging approach leads to treatment effect estimates that are quite robust with respect to the control of the type I error in nearly all simulated scenarios; in particular, with the model averaging approach, the type I error appears less sensitive to model misspecification than the widely used linear model. We noticed also few differences in terms of performance between the model averaging approach and the more classical model selection approach, but we believe that, despite both can be recommended in practice, the model averaging approach can be more appealing because of some deficiencies of model selection approach pointed out in the literature. We think that a model averaging or model selection approach should be systematically considered for conducting concentration-QT analyses. Copyright © 2016 John Wiley & Sons, Ltd.

Mafic rocks in the Chipman domain of the Athabasca granulite terrane, western Canadian Shield, provide the first well-documented record of two distinct high-P granulite facies events in the same domain in this region. Textural relations and the results of petrological modelling (NCFMASHT system) of mafic granulites are interpreted in terms of a three-stage tectonometamorphic history. Stage 1 involved development of the assemblage Grt + Cpx + Qtz ± Pl (M1) from a primary Opx-bearing igneous precursor at conditions of 1.3 GPa, 850–900 °C. Field and microstructural observations suggest that M1 developed synchronously with an early S1 gneissic fabric. Stage 2 is characterized by heterogeneous deformation (D2) and synkinematic partial retrogression of the peak assemblage to an amphibole-bearing assemblage (M2). Stage 3 involved a third phase of deformation and a return to granulite facies conditions marked by the prograde breakdown of amphibole (Amph2) to produce matrix garnet (Grt3a) and the coronitic assemblage Cpx3b + Opx3b + Ilm3b + Pl3b (M3b) at 1.0 GPa, 800–900 °C. M1 and M3b are correlated with 2.55 and 1.9 Ga metamorphic generations of zircon, respectively, which were dated in a separate study. Heterogeneous strain played a crucial role in both the development and preservation of these rare examples of multiple granulite facies events within single samples. Without this fortuitous set of circumstances, the apparent reaction history could have incorrectly led to an interpretation involving a single-cycle high-grade event. The detailed P–T–t–D history constructed for these rocks provides the best evidence to date that much of the east Lake Athabasca region experienced long-term lower crustal residence from 2.55 to 1.9 Ga, and thus the region represents a rare window into the reactivation and ultimate stabilization processes of cratonic lithosphere.

Two series of xerogels (desiccated hydrogels), one consisting of single phases and the other of two phases, were prepared from organic and inorganic precursors in the system Al2o3-Sio2. The effect of these nanostructural differences in the xerogel powders on the energy content and behavior on heating were studied using DTA, powder X-ray diffraction, and ultrafast heating on a strip furnace. The results demonstrate that diphasic xerogels are substantially different materials from single-phase xerogels of the same composition.

Assessment of the time needed to attain steady state is a key pharmacokinetic objective during drug development. Traditional approaches for assessing steady state include ANOVA-based methods for comparing mean plasma concentration values from each sampling day, with either a difference or equivalence test. However, hypothesis-testing approaches are ill suited for assessment of steady state. This paper presents a nonlinear mixed effects modelling approach for estimation of steady state attainment, based on fitting a simple nonlinear mixed model to observed trough plasma concentrations. The simple nonlinear mixed model is developed and proposed for use under certain pharmacokinetic assumptions. The nonlinear mixed modelling estimation approach is described and illustrated by application to trough data from a multiple dose trial in healthy subjects. The performance of the nonlinear mixed modelling approach is compared to ANOVA-based approaches by means of simulation techniques. Copyright © 2005 John Wiley & Sons, Ltd.

Traditional techniques for calculating control limits for processes with discrete responses are based on the Poisson distribution. However, for many processes, the assumption of a Poisson distribution is violated. In such cases, use of traditional Poisson control limits may result in an inflated risk of Type I error. The negative binomial distribution is a natural extension of the Poisson distribution and allows for over-dispersion relative to the Poisson distribution. A simple approach to calculating exact and approximate control limits for count data based on the negative binomial distribution is described. The approach is illustrated by application to water bacteria count data taken from a water purification system. Copyright © 2003 John Wiley & Sons, Ltd.

One of the obligations of offerors in the preparation of proposed standards for the Consumer Product Safety Commission is to include consumer representatives on the standards-writing committee. This report describes Underwriters Laboratories Inc.'s problems in identifying consumer representatives and its experience with consumer representation on the committee preparing a proposed television receiver safety standard.