A landscape of methodology and implementation of adaptive designs in cancer clinical trials.

BACKGROUND: The use of adaptive designs in cancer trials has considerably increased worldwide in recent years, along with the release of various guidelines for their application. This systematic review aims to comprehensively summarize the key methodological and executive features of adaptive designs in cancer clinical trials. METHODS: A comprehensive search from PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials was conducted to screen eligible clinical trials that employed adaptive designs and were conducted in cancer patients. The methodological and executive characteristics of adaptive designs were the main measurements extracted. Descriptive analyses, primarily consisting of frequency and percentage, were employed to analyzed and reported the data. RESULTS: A total of 180 cancer clinical trials with adaptive designs were identified. The first three most common type of adaptive design was the group sequential design (n=114, 63.3 %), adaptive dose-finding design (n=22, 12.2 %), and adaptive platform design (n=16, 8.9 %). The results showed that 4.4 % (n=8) of trials conducted post hoc modifications, and around 29.4 % (n=53) did not provide the methods for controlling type I errors. Among phase II or above trials, 79.9 % (112/140) applied the surrogate endpoint as the primary outcome in these trials. Importantly, 27.2 % (49/180) of trials did not report clear information on the independent data monitoring committee (iDMC), and 13.3 % (n=24) without clear information on interim analyses. Interim analyses suggested 34.4 % (62/180) of trials being stopped for futility, 10.6 % (n=19) for efficacy, and 2.2 % (n=4) for safety concerns in the early stage. CONCLUSIONS: This study emphasizes adaptive designs in cancer trials face significant challenges in their design or strict implementation according to protocol, which might significantly compromise the validity and integrity of trials. It is thus important for researchers, sponsors, and policymakers to actively oversee and guide their application.

Long-Term Impact of COVID-19 on Hospital Visits of Rural Residents in Guangdong, China: A Controlled Interrupted Time Series Study.

To date, there is a lack of comprehensive understanding regarding the effect of coronavirus disease 2019 (COVID-19) on the healthcare-seeking behavior and utilization of health services in rural areas where healthcare resources are scarce. We aimed to quantify the long-term impact of COVID-19 on hospital visits of rural residents in China. We collected data on the hospitalization of all residents covered by national health insurance schemes in a county in southern China from April 2017 to March 2021. We analyzed changes in residents' hospitalization visits in different areas, i.e., within-county, out-of-county but within-city, and out-of-city, via a controlled interrupted time series approach. Subgroup analyses based on gender, age, hospital levels, and ICD-10 classifications for hospital visits were examined. After experiencing a significant decline in hospitalization cases after the COVID-19 outbreak in early 2020, the pattern of rural residents' hospitalization utilization differed markedly by disease classification. Notably, we found that the overall demand for hospitalization utilization of mental and neurological illness among rural residents in China has been suppressed during the pandemic, while the utilization of inpatient services for other common chronic diseases was redistributed across regions. Our findings suggest that in resource-poor areas, focused strategies are urgently needed to ensure that people have access to adequate healthcare services, particularly mental and neurological healthcare, during the COVID-19 pandemic.

Fuzzy-approximation-based prescribed performance control of air-breathing hypersonic vehicles with input constraints.

In this article, aiming at the longitudinal dynamics model of air-breathing hypersonic vehicles, a fuzzy-approximation-based prescribed performance control scheme with input constraints is proposed. First, this article presents a novel prescribed performance function, which does not depend on the sign of initial tracking error. And combining prescribed performance control method with backstepping control, the control scheme can ensure that system can converge at a prescribed rate of convergence, overshoot, and steady-state error. In order to solve the problem that backstepping control method needs to be differentiated multiple times, fuzzy approximators are used to estimate the unknown functions, and norm estimation approach is used to simplify the computation of fuzzy approximator. Aiming at the problem of input saturation of actuator in subsystem of air-breathing hypersonic vehicle, the new auxiliary system is designed to ensure the stability and robustness of air-breathing hypersonic vehicle system under input constraints. Finally, the effectiveness of the proposed control strategy is verified by simulation analysis.

Higher NADH Availability of Lager Yeast Increases the Flavor Stability of Beer.

Flavor stability is a significant concern to brewers as the staling compounds impart unpleasant flavor to beer. Thus, yeasts with antistaling ability have been engineered to produce beer with improved flavor stability. Here, we proposed that increasing the NADH availability of yeast could improve the flavor stability of beer. By engineering endogenous pathways, we obtained an array of yeast strains with a higher reducing activity. Then, we carried out beer fermentation with these strains and found that the antistaling capacities of the beer samples were improved. For a better understanding of the underlying mechanism, we compared the flavor profiles of these strains. The production of staling components was significantly decreased, whereas the content of antistaling components, such as SO2, was increased, in line with the increased antistaling ability. The other aroma components were marginally changed, indicating that this concept was useful for improving the antistaling stability without changing the flavor of beer.