Methods for Comparing Two Means with Application in Adaptive Clinical Trials

In the design of a clinical trial, the study of the effect of an intervention for a given medical condition is frequently of interest to researcher. Also, in recent years, the use of sequential and adaptive design methods in clinical research and development based on accrued data has become very popular due to its flexibility and efficiency. In this thesis, we derive the Behrens-Fisher distribution, and use the distributional result to examine the effect of an intervention by comparing population means of intervention group and control group. Sample size prediction methods proporting to solve the Behrens-Fisher problem are examined. A new method for solving the Behrens-Fisher problem is proposed. Various sequential and adaptive designs are reviewed

THE EFFECT OF BASELINE CLUSTER STRATIFICATION ON THE POWER OF PRE-POST ANALYSIS

The purpose of study is to check whether the power of detecting the effect of intervention versus control in a pre- and post-study can be increased by using a stratified randomized controlled design. A stratified randomized controlled design with two study arms and two time points, where strata are determined by clustering on baseline outcomes of the primary measure, is considered. A modified hierarchical clustering algorithm is developed which guarantees optimality as well as requiring each cluster to have at least one subject per study arm. The power is calculated based on simulated bivariate normal distributed primary measures with mixture normal distributed baseline outcomes. The simulation shows that the power of this approach can be increased compared with using a completely randomized controlled study with no stratification. The difference of the power between with stratification and without stratification increases as the sample size increases or as the correlation of the pre- and post-measures decreases

Tripping Friction Model for Multi-Stage Fracturing and Completion String in Horizontal Well

The structure of multi-stage fracturing completion string in horizontal well is complicated. The downhole tools such as packers and sliding sleeves whose dimensions are very close to the size of the borehole, and the completion string has strong stiffness as well. Thus, it leads to larger frictional restriction when running string. Based on the above reasons, it is essential to calculate the tripping capacity before the strings running into the well in case of sticking off. However, calculation errors of conventional string tripping models are relatively larger. This paper took the structure of multi-stage fracturing completion string into consideration, divided completion string by contact points between string and borehole to establish the stress and bending model of the string between two contact points, and established the tripping friction and hookload model for multi-stage fracturing completion string. An applied example of multi-stage fracturing horizontal well in Hong 90-1 block of Jilin Oil Field shows that the created model in the paper is more accurate. The accuracy of hookload while the string running in form curved section to bottom is 95.80%. The established model is more accurate and reliable. It can be used to estimate the tripping ability of the multi-stage fracturing completion string.Key words: Multistage fracturing; Tripping; Tripping friction; Mechanical mode

Adiponectin Protects Against Cerebral Ischemic Injury Through AdipoR1/AMPK Pathways

Excitotoxicity induced by excessive N-methyl-D-aspartate (NMDA) receptor activation underlies the pathology of ischemic injury. Adiponectin (APN) is an adipocyte-derived protein hormone that modulates a number of metabolic processes. APN exerts a wide range of biological functions in the central nervous system. However, the role of APN and its receptors in cerebral ischemia/reperfusion (I/R)-induced injury and the related mechanisms remain to be clarified. Here, we found that APN and APN receptor agonist AdipoRon (APR) were protective against excitotoxicity induced by oxygen and glucose deprivation/reperfusion (OGD/R) and NMDA in primary neurons. Adiponectin receptor 1 (AdipoR1) knockdown reversed the protection conferred by either APN or APR. Moreover, the protective effects offered by both APN and APR were compromised by compound C, an inhibitor of amp-activated protein kinase (AMPK) phosphorylation. Both APN and APR protected the dissipation of the ΔΨm caused by OGD/R. They also up-regulated the PGC-1α expression, which was reversed by compound C. Furthermore, both APN and APR ameliorated but APN knockout aggravated the infarct volume and neurological deficient induced by transient middle cerebral artery occlusion (tMCAO) in vivo. Taken together, these findings show that APN and APR protect against ischemic injury in vitro and in vivo. The protective mechanism is mainly related to AdipoR1-dependent AMPK phosphorylation and PGC-1α up-regulation

Evaluation of the antibacterial activity of Elsholtzia ciliate essential oil against halitosis-related Fusobacterium nucleatum and Porphyromonas gingivalis

The broad-spectrum antimicrobial activity of Elsholtzia ciliate essential oil (ECO) has been previously reported, but its effectiveness against halitosis-causing bacteria such as Fusobacterium nucleatum and Porphyromonas gingivalis is not well understood. In this study, we investigated the bacteriostatic activity of ECO against planktonic cells and biofilms of F. nucleatum and P. gingivalis, as well as its ability to inhibit bacterial metabolism and production of volatile sulfur compounds (VSCs) at sub-lethal concentrations. Our findings revealed that ECO exhibited comparable activities to chlorhexidine against these oral bacteria. Treatment with ECO significantly reduced the production of VSCs, including hydrogen sulfide, dimethyl disulfide, and methanethiol, which are major contributors to bad breath. As the major chemical components of ECO, carvacrol, p-cymene, and phellandrene, were demonstrated in vitro inhibitory effects on F. nucleatum and P. gingivalis, and their combined use showed synergistic and additive effects, suggesting that the overall activity of ECO is derived from the cumulative or synergistic effect of multiple active components. ECO was found to have a destructive effect on the bacterial cell membrane by examining the cell morphology and permeability. Furthermore, the application of ECO induced significant changes in the bacterial composition of saliva-derived biofilm, resulting in the elimination of bacterial species that contribute to halitosis, including Fusobacterium, Porphyromonas, and Prevotella. These results provide experimental evidence for the potential clinical applications of ECOs in the prevention and treatment of halitosis

NLRP3 Inflammasome Promotes the Progression of Acute Myeloid Leukemia via IL-1β Pathway

NLRP3 inflammasome has been reported to be associated with the pathogenesis of multiple solid tumors. However, the role of NLRP3 inflammasome in acute myeloid leukemia (AML) remains unclear. We showed that NLRP3 inflammasome is over-expressed and highly activated in AML bone marrow leukemia cells, which is correlated with poor prognosis. The activation of NLRP3 inflammasome in AML cells promotes leukemia cells proliferation, inhibits apoptosis and increases resistance to chemotherapy, while inactivation of NLRP3 by caspase-1 or NF-κB inhibitor shows leukemia-suppressing effects. Bayesian networks analysis and cell co-culture tests further suggest that NLRP3 inflammasome acts through IL-1β but not IL-18 in AML. Knocking down endogenous IL-1β or anti-IL-1β antibody inhibits leukemia cells whereas IL-1β cytokine enhances leukemia proliferation. In AML murine model, up-regulation of NLRP3 increases the leukemia burden in bone marrow, spleen and liver, and shortens the survival time; furthermore, knocking out NLRP3 inhibits leukemia progression. Collectively, all these evidences demonstrate that NLRP3 inflammasome promotes AML progression in an IL-1β dependent manner, and targeting NLRP3 inflammasome may provide a novel therapeutic option for AML

The genome of hibiscus hamabo reveals its adaptation to saline and waterlogged habitat

Hibiscus hamabo is a semi-mangrove species with strong tolerance to salt and waterlogging stress. However, the molecular basis and mechanisms that underlie this strong adaptability to harsh environments remain poorly understood. Here, we assembled a high-quality, chromosome-level genome of this semi-mangrove plant and analyzed its transcriptome under different stress treatments to reveal regulatory responses and mechanisms. Our analyses suggested that H. hamabo has undergone two recent successive polyploidy events, a whole-genome duplication followed by a whole-genome triplication, resulting in an unusually large gene number (107 309 genes). Comparison of the H. hamabo genome with that of its close relative Hibiscus cannabinus, which has not experienced a recent WGT, indicated that genes associated with high stress resistance have been preferentially preserved in the H. hamabo genome, suggesting an underlying association between polyploidy and stronger stress resistance. Transcriptomic data indicated that genes in the roots and leaves responded differently to stress. In roots, genes that regulate ion channels involved in biosynthetic and metabolic processes responded quickly to adjust the ion concentration and provide metabolic products to protect root cells, whereas no such rapid response was observed from genes in leaves. Using co-expression networks, potential stress resistance genes were identified for use in future functional investigations. The genome sequence, along with several transcriptome datasets, provide insights into genome evolution and the mechanism of salt and waterlogging tolerance in H. hamabo, suggesting the importance of polyploidization for environmental adaptation.DATA AVAILABILITY: The data supporting the findings of this work are available within the paper and its Supporting Information files. The data sets generated and analyzed during this study are available from the corresponding author upon request. All the whole-genome raw data generated during this study have been deposited in the SRA database under BioProject number PRJNA759075. Transcriptome clean data have been deposited in the SRA database under BioProject number PRJNA759717. The final chromosome-scale genome assembly and annotation data have been deposited in the Figshare database (https://doi.org/10.6084/m9.figshare.19142558.v1).Six Talent Peaks Project of Jiangsu Province (NY-042); Open Fund of the Jiangsu Key Laboratory for the Research and Utilization of Plant Resources (JSPKLB201928); Talent Training Funds of the Institute of Botany, Jiangsu Province and Chinese Academy of Sciences.https://academic.oup.com/hrBiochemistryGeneticsMicrobiology and Plant Patholog