Optimal sequential enrichment designs for phase II clinical trials

In the early phase development of molecularly targeted agents (MTAs), a commonly encountered situation is that the MTA is expected to be more effective for a certain biomarker subgroup, say marker-positive patients, but there is no adequate evidence to show that the MTA does not work for the other subgroup, that is, marker-negative patients. After establishing that marker-positive patients benefit from the treatment, it is often of great clinical interest to determine whether the treatment benefit extends to marker-negative patients. The authors propose optimal sequential enrichment (OSE) designs to address this practical issue in the context of phase II clinical trials. The OSE designs evaluate the treatment effect first in marker-positive patients and then in marker-negative patients if needed. The designs are optimal in the sense that they minimize the expected sample size or the maximum sample size under the null hypothesis that the MTA is futile. An efficient, accurate optimization algorithm is proposed to find the optimal design parameters. One important advantage of the OSE design is that the go/no-go interim decision rules are specified prior to the trial conduct, which makes the design particularly easy to use in practice. A simulation study shows that the OSE designs perform well and are ethically more desirable than the commonly used marker-stratified design. The OSE design is applied to an endometrial carcinoma trial

Cross-linked CoMoO4/rGO nanosheets as oxygen reduction catalyst

Development of inexpensive and robust electrocatalysts towards oxygen reduction reaction (ORR) is crucial for the cost-affordable manufacturing of metal-air batteries and fuel cells. Here we show that cross-linked CoMoO4 nanosheets and reduced graphene oxide (CoMoO4/rGO) can be integrated in a hybrid material under one-pot hydrothermal conditions, yielding a composite material with promising catalytic activity for oxygen reduction reaction (ORR). Cyclic voltammetry (CV) and linear sweep voltammetry (LSV) were used to investigate the efficiency of the fabricated CoMoO4/rGO catalyst towards ORR in alkaline conditions. The CoMoO4/rGO composite revealed the main reduction peak and onset potential centered at 0.78 and 0.89 V (vs. RHE), respectively. This study shows that the CoMoO4/rGO composite is a highly promising catalyst for the ORR under alkaline conditions, and potential noble metal replacement cathode in fuel cells and metal-air batteries

Electrical Probing of Field-Driven Cascading Quantized Transitions of Skyrmion Cluster States in MnSi Nanowires

Magnetic skyrmions are topologically stable whirlpool-like spin textures that offer great promise as information carriers for future ultra-dense memory and logic devices1-4. To enable such applications, particular attention has been focused on the skyrmions properties in highly confined geometry such as one dimensional nanowires5-8. Hitherto it is still experimentally unclear what happens when the width of the nanowire is comparable to that of a single skyrmion. Here we report the experimental demonstration of such scheme, where magnetic field-driven skyrmion cluster (SC) states with small numbers of skyrmions were demonstrated to exist on the cross-sections of ultra-narrow single-crystal MnSi nanowires (NWs) with diameters, comparable to the skyrmion lattice constant (18 nm). In contrast to the skyrmion lattice in bulk MnSi samples, the skyrmion clusters lead to anomalous magnetoresistance (MR) behavior measured under magnetic field parallel to the NW long axis, where quantized jumps in MR are observed and directly associated with the change of the skyrmion number in the cluster, which is supported by Monte Carlo simulations. These jumps show the key difference between the clustering and crystalline states of skyrmions, and lay a solid foundation to realize skyrmion-based memory devices that the number of skyrmions can be counted via conventional electrical measurements

Investigating word length effects in Chinese reading

A word’s length in English is fundamental in determining whether readers fixate it, and how long they spend processing it during reading. Chinese is unspaced and most words are two characters long: Is word length an important cue to eye guidance in Chinese reading? Eye movements were recorded as participants read sentences containing a one-, two-, or three-character word matched for frequency. Results showed that longer words took longer to process (primarily driven by refixations). Furthermore, skips were fewer, incoming saccades longer and landing positions further to the right of long than short words. Additional analyses of a three-character region (matched stroke number) showed an incremental processing cost when character(s) belonged to different, rather than the same, word. These results demonstrate that word length affects both lexical identification and saccade target selection in Chinese reading

A Real-Time Video-based Eye Tracking Approach for Driver Attention Study

nowing the driver's point of gaze has significant potential to enhance driving safety, eye movements can be used as an indicator of the attention state of a driver; but the primary obstacle of integrating eye gaze into today's large scale real world driving attention study is the availability of a reliable, low-cost eye-tracking system. In this paper, we make an attempt to investigate such a real-time system to collect driver's eye gaze in real world driving environment. A novel eye-tracking approach is proposed based on low cost head mounted eye tracker. Our approach detects corneal reflection and pupil edge points firstly, and then fits the points with ellipse. The proposed approach is available in different illumination and driving environment from simple inexpensive head mounted eye tracker, which can be widely used in large scale experiments. The experimental results illustrate our approach can reliably estimate eye position with an accuracy of average 0.34 degree of visual angle in door experiment and 2--5 degrees in real driving environments

A Bayesian phase I/II clinical trial design in the presence of informative dropouts

A phase I/II trial design utilizes both toxicity and efficacy outcomes to make the decision of dose assignment for patients. Because assessing the efficacy endpoint often requires a relatively long follow-up time, phase I/II trials are more susceptible to the missing data problem caused by informative dropouts that are correlated with treatment efficacy and toxicity. In addition, patient outcomes may not be scored quickly enough to apply decision rules that choose treatments or doses for newly accrued patients. To address these issues, we propose a Bayesian phase I/II design that jointly models efficacy, toxicity, and dropout as time-to-event data. Correlations among the three time-to-event outcomes are taken into account by a shared frailty. This joint model strategy accounts for the informative dropouts and has an additional advantage of accommodating a high accrual rate without suspending patient enrollment when toxicity or efficacy outcomes require a long follow-up. Under the Bayesian paradigm, we continuously update the posterior estimate of the model and assign incoming patients to the most desirable dose based on an efficacy-toxicity trade-off utility. Simulation studies show that the proposed design has good operating characteristics with a high probability of selecting the target dose and assigning the most patients to the target dose