Enhancing phase I dose-finding trials design through dynamic borrowing information and handling late-onset toxicity

Introduction: In recent years, there has been a growing trend among regulatory agencies to consider the use of historical controls in clinical trials as a means of improving the efficiency of trial design. In this paper, to enhance the statistical operating characteristic of Phase I dose-finding trials, we propose a novel model-assisted design method named “MEM-Keyboard”.Methods: The proposed design is based on the multisource exchangeability models (MEMs) that allows for dynamic borrowing of information from multiple supplemental data sources, including historical trial data, to inform the dose-escalation process. Furthermore, with the frequent occurrence of delayed toxicity in novel anti-cancer drugs, we extended our proposed method to handle late-onset toxicity by incorporating historical data. This extended method is referred to as “MEM-TITE-Keyboard” and aims to improve the efficiency of early clinical trials.Results: Simulation studies have indicated that the proposed methods can improve the probability of correctly selecting the maximum tolerated dose (MTD) with an acceptable level of risk, compared to designs that do not account for information borrowing and late-onset toxicity.Discussion: The MEM-Keyboard and MEM-TITE-Keyboard, easy to implement in practice, provide a useful tool for identifying MTD and accelerating drug development

Stroke Risk among Patients with Type 2 Diabetes Mellitus in Zhejiang: A Population-Based Prospective Study in China

Objective. This study aimed to explore the incidence of stroke and stroke subtypes among patients with type 2 diabetes mellitus (T2DM) based on the long-term surveillance data in Zhejiang, China, during 2007 to 2013. Materials and Methods. During January 1, 2007, and December 31, 2013, a total of 327,268 T2DM and 307,984 stroke patients were registered on Diabetes and Stroke Surveillance System, respectively. Stroke subtypes were classified according to standard definitions of subarachnoid hemorrhage, intracerebral hemorrhage, and ischemic stroke. The incidence of stroke and stroke subtypes was calculated by standardized incidence ratio (SIRs) with 95% confidence intervals (CIs) compared with general population. Results. The incidence of stroke and stroke subtypes among patients with T2DM was significantly higher than in general population. Stroke risk was found significantly increased with an SIR of 3.87 (95% CI 3.76–3.99) and 3.38 (95% CI 3.27–3.48) in females and males, respectively. The excess risk of stroke was mainly attributable to the significantly higher risk of cerebral infarctions with the risk for T2DM being four times that for general population. Conclusions. The relationship between stroke and T2DM was strong, especially in female. The incidence of stroke and stroke subtypes among patients with T2DM was up to 3-fold higher than in general population in Zhejiang province, especially the subtype of cerebral infarctions

Electronic Cigarettes Use and Intention to Cigarette Smoking among Never-Smoking Adolescents and Young Adults: A Meta-Analysis

Electronic cigarettes (e-cigarettes) use is becoming increasingly common, especially among adolescents and young adults, and there is little evidence on the impact of e-cigarettes use on never-smokers. With a meta-analysis method, we explore the association between e-cigarettes use and smoking intention that predicts future cigarette smoking. Studies were identified by searching three databases up to January 2016. The meta-analysis results were presented as pooled odds ratio (OR) with 95% confidence interval (CI) calculated by a fixed-effects model. A total of six studies (91,051 participants, including 1452 with ever e-cigarettes use) were included in this meta-analysis study. We found that never-smoking adolescents and young adults who used e-cigarettes have more than 2 times increased odds of intention to cigarette smoking (OR = 2.21, 95% CI: 1.86–2.61) compared to those who never used, with low evidence of between-study heterogeneity (p = 0.28, I2 = 20.1%). Among never-smoking adolescents and young adults, e-cigarettes use was associated with increased smoking intention

Modifying temperature-related cardiovascular mortality through green-blue space exposure.

Green-blue spaces (GBS) are pivotal in mitigating thermal discomfort. However, their management lacks guidelines rooted in epidemiological evidence for specific planning and design. Here we show how various GBS types modify the link between non-optimal temperatures and cardiovascular mortality across different thermal extremes. We merged fine-scale population density and GBS data to create novel GBS exposure index. A case time series approach was employed to analyse temperature-cardiovascular mortality association and the effect modifications of type-specific GBSs across 1085 subdistricts in south-eastern China. Our findings indicate that both green and blue spaces may significantly reduce high-temperature-related cardiovascular mortality risks (e.g., for low (5%) vs. high (95%) level of overall green spaces at 99th vs. minimum mortality temperature (MMT), Ratio of relative risk (RRR) = 1.14 (95% CI: 1.07, 1.21); for overall blue spaces, RRR = 1.20 (95% CI: 1.12, 1.29)), while specific blue space types offer protection against cold temperatures (e.g., for the rivers at 1st vs MMT, RRR = 1.17 (95% CI: 1.07, 1.28)). Notably, forests, parks, nature reserves, street greenery, and lakes are linked with lower heat-related cardiovascular mortality, whereas rivers and coasts mitigate cold-related cardiovascular mortality. Blue spaces provide greater benefits than green spaces. The severity of temperature extremes further amplifies GBS's protective effects. This study enhances our understanding of how type-specific GBS influences health risks associated with non-optimal temperatures, offering valuable insights for integrating GBS into climate adaptation strategies for maximal health benefits

Analysis of differential expression profile of miRNA in peripheral blood of patients with lung cancer.

PurposeTo identify potential molecular targets for lung cancer intervention and diagnosis, we analyzed the differential miRNA expression of peripheral blood between lung cancer patients and healthy controls.MethodsThree pairs of cases' and controls' peripheral blood samples were evaluated for miRNA expression by microarray. 12 miRNAs were selected for RT-PCR validation and target genes prediction. In addition, 4 miRNAs were selected for future validation by RT-PCR in a large sample of 145 cases and 55 frequency-matched healthy controls.ResultsA total of 338 differentially expressed miRNAs were screened and identified by microarray. According to the fold changes, the top ten upregulated miRNAs were hsa-miR-124-3p, hsa-miR-379-5p, hsa-miR-3655, hsa-miR-450b-5p, hsa-miR-29a-5p, hsa-miR-200a-3p, hsa-miR-542-3p, hsa-miR-138-5p, hsa-miR-219a-2-3p, and hsa-miR-4701-3p, and the top ten downregulated miRNAs were hsa-miR-34c-5p, hsa-miR-135a-5p, hsa-miR-132-3p, hsa-miR-3178, hsa-miR-4449, hsa-miR-4999-3p, hsa-miR-1246, hsa-miR-4424, hsa-miR-1252-5p, and hsa-miR-24-2-5p. RT-PCR verification of the 12 miRNAs revealed that 5 of 8 upregulated miRNAs, 2 of 4 downregulated miRNAs showed a significant difference between the cases and controls (P < .05). A large number of target genes and their functional set showed overlapping among the 453 predicted target genes of the 12 miRNAs (P < .01). RT-PCR in the large sample confirmed the significant differential expression level of hsa-miR-29a-5p, hsa-miR-135a-5p, hsa-miR-542-3p, and hsa-miR-4491 between cases and controls (P < .05), and three of these microRNA, except hsa-miR-29a-5p, were significant after Bonferroni correction for adjustment of multiple comparisons.ConclusionThere was a significant difference in miRNAs expression in the peripheral blood between lung cancer patients and healthy controls, and 4 miRNAs were validated by a large-size sample