Birchegholm2949

Detecting safety signals in clinical trial safety data is known to be challenging due to high dimensionality, rare occurrence, weak signal, and complex dependence. We propose a new hierarchical testing approach for analyzing safety data from a typical randomized clinical trial. This approach accounts for the hierarchical structure of adverse events (AEs), that is, AEs are categorized by system organ class (SOC). Our approach contains two steps the first step tests, for each SOC, whether any AEs within this SOC are differently distributed between treatment arms; and the second step identifies signal AEs from SOCs passing the first step tests. We show the superiority, in terms of power of detecting safety signals given controlled false discovery rate, of the new approach comparing with currently available approaches through simulation studies. We also demonstrate this approach with two real data examples. © 2020 John Wiley & Sons, Ltd.The expression levels of many cell-surface proteins vary with the time of day. Glycoprotein 2 (Gp2), specifically expressed on the apical surface of M cells in Peyer's patches, functions as a transcytotic receptor for mucosal antigens. We report that cAMP response element-binding protein (CREB) regulates the transcription of the Gp2 gene, thereby generating the circadian change in its expression in mouse Peyer's patches. The transcytotic receptor activity of Gp2 was increased during the dark phase when the Gp2 protein abundance increased. Rhythmic expression of clock gene mRNA was observed in mouse Peyer's patches, and expression levels of Gp2 mRNA also exhibited circadian oscillation, with peak levels during the early dark phase. The promoter region of the mouse Gp2 gene contains several cAMP response elements (CREs). Chromatin immunoprecipitation assays revealed that CREB bound to the CREs in the Gp2 gene in Peyer's patches. Importazole compound library inhibitor Forskolin, which promotes CREB phosphorylation, increased the transcription of the Gp2 gene in Peyer's patches. As phosphorylation of CREB protein was increased when Gp2 gene transcription was activated, CREB may regulate the rhythmic expression of Gp2 mRNA in Peyer's patches. These findings suggest that intestinal immunity is controlled by the circadian clock system. © 2020 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.Development of efficient and selective C-N bond-forming reactions from abundant feedstock chemicals remains a central theme in organic chemistry, due to the key roles of amines in synthesis, drug discovery and materials science. Here, we present a dual catalytic system for N -alkylation of diverse aromatic carbocyclic and heterocyclic amines directly with carboxylic acids, by-passing preactivation as redox-active esters. The reaction that is enabled by visible light-driven, acridine-catalyzed decarboxylation provides access to N -alkylated secondary and tertiary anilines, and N -heterocycles. Additional N -functionalization modes, including dual alkylation, installation of metabolically robust deuterated methyl groups and tandem ring formation further demonstrate the potential of the direct decarboxylative alkylation (DDA) reaction. © 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.A new, transformative methodology for the preparation of diketopyrrolopyrroles from aldehydes, primary amines, nitriles and diethyl oxalacetate has been developed. It is now possible to prepare diketopyrrolopyrroles bearing an ordered arrangement of three different substituents from abundant and commercially available materials allowing the independent regulation of all desired physicochemical properties. For the first time very electron-rich (carbazo-3-yl, dimethylaminophenyl, pyrrolo[3,2- b ]pyrrolyl) and sterically hindered substituents (naphthalen-1-yl, quinolin-4-yl, acridin-9-yl, imidazo[1,5- a ]pyridin-1-yl, 2-bromophenyl, etc.) can be appended to the diketopyrrolopyrrole core via condensation of an appropriate nitrile with a pyrrolidin-2-one intermediate. Even greater synthetic possibilities are related to the fact that such demanding substituents as 4-dimethylaminophenyl, indol-3-yl and 2-methoxyphenyl can be incorporated from aldehyde precursors, bypassing problems with the nitriles reactivity. Starting from terephthaldehyde, previously inaccessible bis-diketopyrrolopyrroles can also be obtained. The ability to incorporate an unprecedented variety of substituents translates to a comprehensive method for the modulation of photophysical properties such as shifting the absorption and emission across almost the entire visible spectrum, reaching the highest recorded Stokes shift for a diketopyrrolopyrrole (5800 cm -1 ) and switching-on/off solvatofluorochromism. © 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.DNA encoded libraries (DEL) have shown promise as a valuable technology for democratizing the hit discovery process. Although DEL provides relatively inexpensive access to libraries of unprecedented size, their production has been hampered by the idiosyncratic needs of the encoding DNA tag relegating DEL compatible chemistry to dilute aqueous environments. Recently reversible adsorption to solid support (RASS) has been demonstrated as a promising method to expand DEL reactivity using standard organic synthesis protocols. Here we demonstrate a suite of on-DNA chemistries to incorporate medicinally relevant and C-S, C-P and N-S linkages into DELs, which are underrepresented in the canonical methods. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.RATIONALE Some drugs can only be dispensed in multiple-dose containers. Multiple-dose packaging may pose a problem for hospitals in terms of drug wastage and cost. Oral inhalers, such as fluticasone propionate and salmeterol combination inhalers, are only available as multiple-dose formats in Canada. OBJECTIVES The objectives of this study are to quantify the amount of fluticasone propionate and salmeterol combination inhaler waste and to assess possible factors that could be contributing to waste. METHODS A retrospective chart review of 189 patients was conducted. Patients were included if they had received an order for fluticasone propionate and salmeterol combination inhaler at one of the 12 acute hospital sites of Fraser Health Authority. The primary outcome was the proportion of patients who were dispensed one or more inhalers unnecessarily. The number of inhalers dispensed was compared with the number of inhalers needed to complete a patient's order duration. The chart was also reviewed for possible factors that could have contributed to extra inhalers being dispensed unnecessarily.