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E-6375 (4-butoxy-2-[4-(2-cyanobenzoyl)-1-piperazinyl] pyrimidine hydrochloride) is a new intravenous general anaesthetic with an anaesthetic potency, in mice, comparable to propofol, or etomidate. Here, we examined the effect of E-6375 upon the GABAA receptor, a putative target of intravenous anaesthetic action. E-6375 reversibly enhanced GABA-evoked currents mediated by recombinant GABAA (α1β2γ2L) receptors expressed in Xenopus laevis oocytes, with little effect on NMDA- and kainate-evoked currents mediated by NR1a/NR2A and GluR1o/GluR2o glutamate receptors, respectively. E-6375 prolonged the decay of GABA-evoked miniature inhibitory postsynaptic currents recorded from rat Purkinje neurones demonstrating the anaesthetic also enhanced the activity of synaptic GABAA receptors. The GABA enhancing action of E-6375 on recombinant GABAA receptors was unaffected by the subtype of the α isoform (i.e. αxβ2γ2L; x=1–3) within the receptor, but was increased by the omission of the γ2L subunit. Receptors incorporating β2, or β3, subunits were more sensitive to modulation by E-6375 than those containing the β1 subunit. The selectivity of E-6375 was largely governed by the identity (serine or asparagine) of a single amino acid residue within the second transmembrane domain of the β-subunit. The various in vivo actions of general anaesthetics may be mediated by GABAA receptor isoforms that have a differential distribution within the CNS. The identification of agents, such as E-6375, that discriminate between GABAA receptor subtypes may augur the development of general anaesthetics with an improved therapeutic profile. [Copyright &y& Elsevier]

To compare efficacy of first-line bevacizumab-bases therapy in advanced non-squamous, Non Small-Cell Lung Cancer (aNSCLC) between two unbalanced populations when we have access to individual patient (IPD) data for only one study. We performed an Matching-Adjusted Indirect Comparison (MAIC) by matching IPD baseline for EOLE non-interventional study were matched to published aggregated data for SAiL trial (phase IV) to adjust for key baseline characteristics including age, sex, tumor histology, ECOG score, smoking status and stage of tumor. After adjusting for difference in baseline characteristics, this indirect comparison seems to show consistent results of bevacizumab in aNSCLC patients in real world (RWD) setting with those observed in Clinical Trial (CT). [Extracted from the article]

Classical methods to estimate CI are biased when used with IPTW due to induced pseudo sample size inflation. Naïve estimations provided too small CI SB 95% sb while bootstrap provided a robust confidence interval in the context of PS weighting. [Extracted from the article]

TREE TECHNIQUE Identical groups of pts were shown for the factors associated to PFS: disease stage IV-M1c (or missing; n=118 pts) was shown to be associated with a shorter median PFS compared to other pts (n=67): 4.5 mo and 12.0 mo, respectively. Using survival decision trees, disease stage IV-M1c was shown to be the factor associated with shorter OS and PFS. [Extracted from the article]