EVALUATING ORAL, NON-COMBUSTIBLE POTENTIAL REDUCED EXPOSURE PRODUCTS MARKETED TO SMOKERS

Potential reduced exposure products (PREPs) are marketed to reduce smoking’s harm, despite little information concerning their effects. This study adapts previously reported clinical laboratory methods used to evaluate combustible PREPs to investigate the acute effects of four non-combustible PREPs (Ariva, Camel Snus, Marlboro Snus, Commit nicotine lozenge) relative to own brand cigarettes, sham smoking, and one combustible PREP that delivers no measurable nicotine (Quest). Twenty-eight smokers participated in 7 Latin-squared ordered, 2.5-hr sessions in which each product was administered twice (60-minute inter-administration interval). Sessions differed by product and were separated by \u3e 48 hours. Plasma nicotine, heart rate, expired air carbon monoxide (CO), and subjective effects were assessed. Relative to own brand, non-combustible PREPs decreased nicotine and CO exposure, did not suppress abstinence symptoms fully, and were less acceptable. These short-term clinical laboratory methods are reliable and provide valuable information concerning non-combustible PREPs for smokers

EVALUATING THE ACUTE EFFECTS OF CAFFEINATED WATERPIPE TOBACCO IN WATERPIPE USERS

Caffeine and nicotine are the two most commonly consumed licit psychoactive drugs in the world. In addition, they are frequently co-administered with over 86% of cigarette smokers reporting caffeine use versus 77% of non-smokers. Research suggests the combination of nicotine and caffeine produces effects that are more rewarding or pleasurable than either drug alone, and this potential reward enhancement may influence patterns of tobacco use initiation and maintenance. Waterpipe tobacco smoking is an alternative tobacco use method that is increasing in prevalence in the U.S. and offers a novel opportunity for nicotine and caffeine co-administration via a caffeinated tobacco product (Tangiers F-Line). Based on previous work, this caffeinated tobacco product was hypothesized to enhance reward-related and cardiovascular effects in waterpipe users relative to tobacco-only waterpipe preparations. Thirty-two waterpipe tobacco smokers who regularly drank caffeinated beverages participated in a four condition, Latin-square ordered, within-subjects study. In each condition, there was a 45-minute double-blind product administration period that differed by the content of waterpipe product smoked: caffeine and nicotine (Tangiers F-Line), nicotine and no caffeine (Tangiers), reduced (low) nicotine and caffeine (low nicotine Tangiers F-Line), or neither nicotine nor caffeine (Soex). Outcome measures included blood plasma caffeine and nicotine, cardiovascular response, expired air carbon monoxide (CO), puff topography, and subjective ratings. Plasma analyses revealed no detectable levels of caffeine from either caffeinated product, but significant nicotine exposure from all nicotine-containing products. Few differences between conditions were observed for subjective measures. Larger puff volumes were observed for products that contained low or no nicotine, resulting in higher CO concentrations for these conditions. While findings do not address whether caffeine can be delivered via volatilization, they suggest that measurable caffeine exposure was not observed for the products examined and under the conditions explored here. Importantly, study results support continued investigation of the effects of waterpipe tobacco smoking using a placebo-controlled design as well as demonstrate that tobacco dependence and toxicity capabilities are still concerns for these and other waterpipe products

Electronic cigarettes and nicotine dependence: evolving products, evolving problems

Electronic cigarettes (ECIGs) use an electric heater to aerosolize a liquid that usually contains propylene glycol, vegetable glycerin, flavorants, and the dependence-producing drug nicotine. ECIG-induced nicotine dependence has become an important concern, as some ECIGs deliver very little nicotine while some may exceed the nicotine delivery profile of a tobacco cigarette. This variability is relevant to tobacco cigarette smokers who try to switch to ECIGs. Products with very low nicotine delivery may not substitute for tobacco cigarettes, so that ECIG use is accompanied by little reduced risk of cigarette-caused disease. Products with very high nicotine delivery may make quitting ECIGs particularly difficult should users decide to try. For non-smokers, the wide variability of ECIGs on the market is especially troublesome: low nicotine products may lead them to initiate nicotine self-administration and progress to higher dosing ECIGs or other products, and those that deliver more nicotine may produce nicotine dependence where it was not otherwise present. External regulatory action, guided by strong science, may be required to ensure that population-level nicotine dependence does not rise

Electronic cigarettes and nicotine dependence: evolving products, evolving problems

Electronic cigarettes (ECIGs) use an electric heater to aerosolize a liquid that usually contains propylene glycol, vegetable glycerin, flavorants, and the dependence-producing drug nicotine. ECIG-induced nicotine dependence has become an important concern, as some ECIGs deliver very little nicotine while some may exceed the nicotine delivery profile of a tobacco cigarette. This variability is relevant to tobacco cigarette smokers who try to switch to ECIGs. Products with very low nicotine delivery may not substitute for tobacco cigarettes, so that ECIG use is accompanied by little reduced risk of cigarette-caused disease. Products with very high nicotine delivery may make quitting ECIGs particularly difficult should users decide to try. For non-smokers, the wide variability of ECIGs on the market is especially troublesome: low nicotine products may lead them to initiate nicotine self-administration and progress to higher dosing ECIGs or other products, and those that deliver more nicotine may produce nicotine dependence where it was not otherwise present. External regulatory action, guided by strong science, may be required to ensure that population-level nicotine dependence does not rise

Triangulating Abuse Liability Assessment for Flavoured Cigar Products Using Physiological, Behavioural Economic and Subjective Assessments: A Within-subjects Clinical Laboratory Protocol

Introduction In the USA, Food and Drug Administration regulations prohibit the sale of flavoured cigarettes, with menthol being the exception. However, the manufacture, advertisement and sale of flavoured cigar products are permitted. Such flavourings influence positive perceptions of tobacco products and are linked to increased use. Flavourings may mask the taste of tobacco and enhance smoke inhalation, influencing toxicant exposure and abuse liability among novice tobacco users. Using clinical laboratory methods, this study investigates how flavour availability affects measures of abuse liability in young adult cigarette smokers. The specific aims are to evaluate the effect of cigar flavours on nicotine exposure, and behavioural and subjective measures of abuse liability. Methods and analyses Participants (projected n=25) are healthy smokers of five or more cigarettes per day over the past 3 months, 18–25 years old, naive to cigar use (lifetime use of 50 or fewer cigar products and no more than 10 cigars smoked in the past 30 days) and without a desire to quit cigarette smoking in the next 30 days. Participants complete five laboratory sessions in a Latin square design with either their own brand cigarette or a session-specific Black & Mild cigar differing in flavour (apple, cream, original and wine). Participants are single-blinded to cigar flavours. Each session consists of two 10-puff smoking bouts (30 s interpuff interval) separated by 1 hour. Primary outcomes include saliva nicotine concentration, behavioural economic task performance and response to various questionnaire items assessing subjective effects predictive of abuse liability. Differences in outcomes across own brand cigarette and flavoured cigar conditions will be tested using linear mixed models

Electronic nicotine delivery devices, and their impact on health and patterns of tobacco use: a systematic review protocol

Introduction E-cigarettes or electronic nicotine delivery systems (ENDS) have recently attracted considerable attention. Among some individuals there is strong debate and a polarisation of views about the public health benefits versus harms of ENDS. With little regulation, the ENDS market is evolving, and new products are introduced and marketed constantly. Rapid developments in manufacturing, marketing and consumer domains related to ENDS will warrant frequent re-evaluation, based on the state of the evolving science. The purpose of this article is to describe a protocol for an ongoing comprehensive review of the published scientific literature on ENDS. Methods and analysis We will undertake a systematic review of published empirical research literature on ENDS using the National Library of Medicine\u27s PubMed electronic database to search for relevant articles. Data from included studies will be extracted into a standardised form, tables with study details and key outcomes for each article will be created, and studies will be synthesised qualitatively. Ethics and dissemination This review synthesises published literature and presents no primary data. Therefore, no ethical approval is required for this study. Subsequent papers will provide greater detail on results, within select categories, that represent gaps in the literature base

On Clinical Agreement on the Visibility and Extent of Anatomical Layers in Digital Gonio Photographs

Purpose: To quantitatively evaluate the inter-annotator variability of clinicians tracing the contours of anatomical layers of the iridocorneal angle on digital gonio photographs, thus providing a baseline for the validation of automated analysis algorithms. Methods: Using a software annotation tool on a common set of 20 images, five experienced ophthalmologists highlighted the contours of five anatomical layers of interest: iris root (IR), ciliary body band (CBB), scleral spur (SS), trabecular meshwork (TM), and cornea (C). Inter-annotator variability was assessed by (1) comparing the number of times ophthalmologists delineated each layer in the dataset; (2) quantifying how the consensus area for each layer (i.e., the intersection area of observers\u2019delineations) varied with the consensus threshold; and (3) calculating agreement among annotators using average per-layer precision, sensitivity, and Dice score. Results: The SS showed the largest difference in annotation frequency (31%) and the minimum overall agreement in terms of consensus size ( 3c28% of the labeled pixels). The average annotator\u2019s per-layer statistics showed consistent patterns, with lower agreement on the CBB and SS (average Dice score ranges of 0.61\u20130.7 and 0.73\u20130.78, respectively) and better agreement on the IR, TM, and C (average Dice score ranges of 0.97\u20130.98, 0.84\u20130.9, and 0.93\u20130.96, respectively). Conclusions: There was considerable inter-annotator variation in identifying contours of some anatomical layers in digital gonio photographs. Our pilot indicates that agreement was best on IR, TM, and C but poorer for CBB and SS. Translational Relevance: This study provides a comprehensive description of interannotator agreement on digital gonio photographs segmentation as a baseline for validating deep learning models for automated gonioscopy

Evaluation of LOXL1 gene polymorphisms in exfoliation syndrome and exfoliation glaucoma

Purpose: To evaluate genetic susceptibility of lysyl oxidase-like 1 (LOXL1) gene polymorphisms to exfoliation syndrome (XFS) and exfoliation glaucoma (XFG) in a case-control cohort of American and European patients. Methods: DNA from a total of 620 individuals including 287 exfoliation patients and 333 healthy control subjects were extracted by standard methods. Three single nucleotide polymorphisms (SNPs) of rs1048661 (R141L), rs3825942 (G153D), and rs2165241 were genotyped in these individuals by SNaPshot Assay. The seven coding exons of the LOXL1 gene and their immediate flanking regions were directly sequenced in 95 affected patients. Data management and case-control association studies were performed with SNP-STAT and PLINK programs. The obtained DNA sequences were evaluated with the STADEN package. Results: The 287 unrelated exfoliation cases comprised of 171 American patients (mostly of European background) and 116 patients from 12 European countries. This phenotype was further divided into patients with exfoliation only and no glaucoma (XFO; n=95), exfoliation with glaucoma (XFG; n=133), and exfoliation unclassified (XFU; n=59). Genotypic data were analyzed separately for XFO, XFG, XFU, and XFS (all exfoliations; n=287) and for Americans and Europeans. The observed genotypic frequencies for each exfoliation phenotype or population were tabulated separately and tested for deviation from the Hardy–Weinberg equilibrium (HWE) using a standard Χ2 test. There were no HWE deviations and no significant genotypic differences between these subcategories for the three studied SNPs. For the combined exfoliation cohort, homozygote genotypes of G/G (rs1048661), G/G (rs3825942), and T/T (rs2165241) were significantly overrepresented. Likewise, case-control allelic association for rs1048661 (p=7.74x10−9), rs3825942 (p=3.10x10−17), and rs2165241 (p=4.85x10−24) were highly significant. The corresponding two-locus haplotype frequencies of GG for rs1048661-rs3825942 (p=1.47x10−27), GT for rs1048661-rs2165241 (p=1.29x10−24), and GT for rs3825942-rs2165241 (p=2.02x10−24) were highly associated with exfoliation phenotypes. The combined effect of these three SNPs revealed that the GGT haplotype is overrepresented by 66% in exfoliation cases, and this deviation from controls is highly significant (p=1.93x10−24). This haplotype constituted a major risk factor for development of exfoliation in both XFS and XFG. By contrast, the GAC haplotype was significantly underrepresented (p=4.99x10−18) in exfoliation cases by 83% and may potentially have a protective effect for this condition with an estimated attributable risk percent reduction of 457%. The only other haplotype that was significantly different between cases and controls was TGC (p=5.82x10−9). No observation was made for the GAT haplotype. The combined three haplotypes of GGT, GAC, and TGC were associated with 91% of the exfoliation syndrome cases in the studied populations. Seven coding exons of LOXL1 were also sequenced in 95 affected cases. In addition to the three above-mentioned SNPs, 12 other variations were also observed in these patients(G240G, D292D, A320A, V385V, rs2304719, IVS3+23C>T, IVS3–155G>A, IVS3–101G>A, IVS4+49G>A, rs2304721, IVS5–121C>T, and rs2304722). None were considered a disease-causing mutation. Conclusions: We confirmed a strong association with LOXL1 variants in our patients. For the LOXL1 gene, individual alleles of rs1048661 (G), rs3825942 (G), and rs2165241 (T) are highly associated with XFS and XFG in American and European populations. The GGT haplotype constitutes a major risk haplotype for exfoliation, and GAC may have a protective role. DNA sequencing of 95 affected patients did not show any mutations in this gene. The LOXL1 SNPs are located in the 15q24.1 band and within a genetic locus (GLC1N) that is associated with primary open-angle glaucoma (POAG). However, the LOXL1 genetic predisposition is only limited to exfoliation with or without glaucoma and does not include the POAG phenotype