Bayesian phase II adaptive randomization by jointly modeling efficacy and toxicity as time-to-event outcomes.

The main goals of Phase II trials are to identify the therapeutic efficacy of new treatments and continue monitoring all the possible adverse effects. In Phase II trials, it is important to develop an adaptive randomization (AR) procedure that takes into account both the efficacy and toxicity. In most existing articles, toxicity is modeled as a binary endpoint through an unobservable random effect (frailty) to link the efficacy and toxicity. However, this approach does not capture toxicity profiles that evolve over time. In this article, we propose a new Bayesian adaptive randomization (BAR) procedure using the covariate-adjusted efficacy-toxicity ratio (ETR) index, where efficacy and toxicity are jointly modelled as time-to-event (TTE) outcomes. Furthermore, we also propose early stopping rules for toxicity and futility such that inferior treatments can be dropped at earlier time of trial. Simulation results show that compared to the BAR procedures based solely on the efficacy and that based on TTE efficacy and binary toxicity outcomes, the proposed BAR procedure can better identify the difference in treatment toxicity such that it can assign more patients to the superior treatment arm under some scenarios.

Enantioselective Addition of Diethylzinc to Aldehydes Catalyzed by Chiral O,N,O-tridentate Phenol Ligands Derived From Camphor.

Chiral O,N,O-tridentate phenol ligands bearing a camphor backbone were found to be effective chiral catalysts for the enantioselective addition of diethylzinc to aromatic aldehydes, resulting in high enantioselectivities (80-95% ee) at room temperature.

Ankle reflex stiffness during unperceived perturbation of standing in elderly subjects.

Postural reflex activity during unperceived perturbation of standing was investigated in 38 elderly subjects (70-96 years old) and 10 younger adults (19-48 years old), and it was related in the elderly group to a history of unexplained falling in the 12 months prior to testing. Ankle torque (T) and ankle angle (A) were recorded during unperceived forward pulls to obtain the ankle stiffness (DeltaT/DeltaA), providing a measure of postural reflex activity at the ankle. Elderly nonfallers and younger adults had similar ranges of normalized ankle reflex stiffness. High ankle stiffness was significantly more common in elderly multiple fallers than in elderly nonfallers (p =.018). Furthermore, a majority of unstable elderly subjects who had reported a single unexplained fall also had unusually high ankle stiffness (p =.004). Multiple fallers and unstable subjects tended to overshoot backward on pull release in comparison with nonfallers (p =.003), which is suggestive of an overactive reflex response that might contribute to postural instability.