Electronic cigarettes (e-cigarettes) continue to gain popularity globally. Jurisdictions with comprehensive tobacco control policies, which limit the use and availability of combustible tobacco ...products but do not regulate e-cigarettes (as in Russia), may be vulnerable to the expansion of the e-cigarette market.
Using McNemar's test conducted in STATA, this observational study assessed changes between 2014 and 2016 in the availability of e-cigarettes across 239 retail outlets in Moscow and St Petersburg. Also, this study characterized the presence of retail advertising and promotion of e-cigarettes in 2016.
Between 2014 and 2016, the availability and display of e-cigarettes increased within traditional tobacco product retail venues (27.6% in 2014 vs 51.9% in 2016; p<0.01).
Observations indicate that there has been an increase in the proportion of retailers selling and displaying e-cigarettes.
Jizanpeptins A–E (1–5) are micropeptin depsipeptides isolated from a Red Sea specimen of a Symploca sp. cyanobacterium. The planar structures of the jizanpeptins were established using NMR ...spectroscopy and mass spectrometry and contain 3-amino-6-hydroxy-2-piperidone (Ahp) as one of eight residues in a typical micropeptin motif, as well as a side chain terminal glyceric acid sulfate moiety. The absolute configurations of the jizanpeptins were assigned using a combination of Marfey’s methodology and chiral-phase HPLC analysis of hydrolysis products compared to commercial and synthesized standards. Jizanpeptins A–E showed specific inhibition of the serine protease trypsin (IC50 = 72 nM to 1 μM) compared to chymotrypsin (IC50 = 1.4 to >10 μM) in vitro and were not overtly cytotoxic to HeLa cervical or NCI-H460 lung cancer cell lines at micromolar concentrations.
ObjectivesSmoke-free policies not only reduce harm to non-smokers, they may also reduce harm to smokers by decreasing the number of cigarettes smoked and increasing the likelihood of a successful ...quit attempt. However, little is known about the impact of exposure to smoking on patios on smoking behaviour.Design and participantsSmokers from the Ontario Tobacco Survey, a longitudinal population representative cohort of smokers (2005–2011). There were 3460 current smokers who had completed one to six follow-ups and were asked at each follow-up whether or not they had been exposed to smoking on patios in the month.Main outcome measuresGeneralised estimating equations and survival analysis were used to examine the association between exposure to patio smoking and smoking behaviour changes (making a quit attempt and time to relapse after a quit attempt), controlling for potential confounders.ResultsSmokers who were exposed to smoking on patios (adjusted incident rate ratio (aIRR) = 0.89; 95% CI 0.81 to 0.97) or had been to a patio (aIRR = 0.86; 95% CI 0.74 to 0.99) were less likely to have made a quit attempt than smokers who had not visited a patio. Smokers who were exposed to smoking on patios were more likely to relapse (adjusted HR=2.40; 95% CI 1.07 to 5.40)) after making a quit attempt than those who visited a patio but were not exposed to smoking.ConclusionsExposure to smoking on patios of a bar or restaurant is associated with a lower likelihood of success in a quit attempt. Instituting smoke-free patio regulations may help smokers avoid relapse after quitting.
This article provides evidence for implicit change detection and for the contribution of multiple memory sources to online representations. Multiple eye-movement measures distinguished original from ...changed scenes, even when college students had no conscious awareness for the change. Patients with amnesia showed a systematic deficit on 1 class of eye-movement measures of change detection, even though conscious awareness was not required for the effect to be observed. The authors' findings suggest that online representations of scenes are (a) built up across viewings, (b) composed of activated information from both long-term and working memory, and (c) directly compared with currently processed information regarding the external world. Subsequent online processing is influenced by these representations even when the results of the comparison are not accessible for verbal report.
Herein the discovery of potent IDO1 inhibitors with low predicted human dose is discussed. Metabolite identification (MetID) and structural data were used to strategically incorporate cyclopropane ...rings into this tetrahydronaphthyridine series of IDO1 inhibitors to improve their metabolic stability and potency. Enabling synthetic chemistry was developed to construct these unique fused cyclopropyl compounds, leading to inhibitors with improved pharmacokinetics and human whole blood potency and a predicted human oral dose as low as 9 mg once daily (QD).
An asymmetric synthesis of HCV NS5B nucleoside polymerase inhibitor (1) is described. This novel route features several remarkably diastereoselective and high-yielding transformations, including ...construction of the all-carbon quaternary stereogenic center at C-2 via a thermodynamic aldol reaction. A subsequent glycosylation reaction with activated uracil via C-1 phosphate and installation of the cyclic phosphate group using an achiral phosphorus(III) reagent followed by oxidation provides 1.
This essay represents the collective vision of a group of scholars in vocational psychology who have sought to develop a research agenda in response to the massive global unemployment crisis that has ...been evoked by the COVID-19 pandemic. The research agenda includes exploring how this unemployment crisis may differ from previous unemployment periods; examining the nature of the grief evoked by the parallel loss of work and loss of life; recognizing and addressing the privilege of scholars; examining the inequality that underlies the disproportionate impact of the crisis on poor and working class communities; developing a framework for evidence-based interventions for unemployed individuals; and examining the work-family interface and unemployment among youth.
The development of a safe, robust, and efficient manufacturing route for the synthesis of diaminopyrimidine 1, a key intermediate to gefapixant citrate (MK-7264), is described. A full mechanistic ...understanding of the cyclization step in the presence of guanidine was established by performing isotopic labeling experiments and identification of impurities. Guided by the mechanistic understanding, further attempts to modify the cyclization reaction by employing additives to reduce the triazine (9) formation and guanidine loading will also be presented. This newly developed method delivered compound 1 in 88–94% yield on a commercial scale and addressed the shortcomings of the early synthetic route including high PMI, low atom economy, long cycle-time, and multiple purifications to achieve the desired quality.
To describe first-dose and steady state pharmacokinetics (PKs) of dolutegravir (DTG) in blood plasma (BP), seminal fluid (SF), colorectal tissue (RT), and rectal mucosal fluid (RF) of healthy ...HIV-negative men.
A phase 1, open-label, PK study that enrolled 12 healthy men taking 50 mg DTG daily for 8 days.
Eleven paired BP samples and 3 SF and RF samples were collected over 24 hours after first (PK1) and multiple (PK2) dosing. RT biopsies were collected at 1 of 6 time points at PK1 and PK2 to generate composite PK profiles. DTG concentrations were analyzed by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). Noncompartmental PK analysis was conducted with Phoenix WinNonlin v6.3, and Spearman rank correlations were determined using SAS v9.3.
BP area under the concentration-time curves (AUCs) were similar to previous reports, and concentrations at 24 hours (C24 h) were 6- to 34-fold greater than the protein-adjusted concentration required for 90% viral inhibition (PA-IC90) of 64 ng/mL. SF exposures were <7% of BP and below the PA-IC90. RT exposures were 17% of BP and ∼2-fold greater than the PA-IC90. RF AUCs were ∼2%-5% of RT and did not correlate with RT (rho = 0.43, P = 0.17). Accumulation of DTG with multiple dosing was observed in BP, SF, and RT.
DTG BP PKs were consistent with previously published values. SF concentrations were <7% BP, with SF C24 h below the PA-IC90. However, SF protein binding was not measured. Although the AUC of DTG in RT was <20% BP, RT C24 h remained ∼2-fold higher than the PA-IC90. RF was not a strong surrogate for RT concentrations.
Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as an attractive target for cancer immunotherapy. An automated ligand identification system screen afforded the tetrahydroquinoline class of novel ...IDO1 inhibitors. Potency and pharmacokinetic (PK) were key issues with this class of compounds. Structure-based drug design and strategic incorporation of polarity enabled the rapid improvement on potency, solubility, and oxidative metabolic stability. Metabolite identification studies revealed that amide hydrolysis in the D-pocket was the key clearance mechanism for this class. Strategic survey of amide isosteres revealed that carbamates and N-pyrimidines, which maintained exquisite potencies, mitigated the amide hydrolysis issue and led to an improved rat PK profile. The lead compound 28 is a potent IDO1 inhibitor, with clean off-target profiles and the potential for quaque die dosing in humans.
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