Ran Wu

Background Aldehydes are common e-liquid flavourants that undergo chemical reactions with the e-liquid solvents propylene glycol (PG) and glycerol (G) to form acetals. Some flavour aldehyde PG acetals are respiratory irritants and may have negative user effects. Water—a byproduct of acetal formation—can shift the chemical equilibrium back towards the flavour aldehydes. This study combined chemical and human experiments to assess effects of water addition on acetal formation in laboratory-made e-liquids, commercial products and user experience. Methods Acetal content was monitored in laboratory-made e-liquids containing PG and one flavour aldehyde (benzaldehyde, cinnamaldehyde, ethylvanillin and vanillin) and commercial e-liquids based on PG/G with corresponding flavours (Cherry, Cinnamon, Vanilla and Grape as non-aldehyde-containing control) containing 0%–20% water over 28 days. E-cigarette users (n=30, 35.3 years (10.4), 51.7% female) assessed sensory and appeal outcomes of the diluted commercial e-liquids (no-added-water, 5%, 10% and 20%). Mixed-effects models assessed main effects of water, flavour and interactions. Results Water addition reduced PG-acetal buildup in laboratory-made e-liquids 1.3–38-fold depending on water content (more water was more effective) and flavour aldehyde (vanillin>ethylvanillin>cinnamaldehyde>benzaldehyde). Water addition to commercial e-liquids reversed combined PG/G-acetal content up to 26-fold. Among e-cigarette users, 20% water content (but not 5% and 10%) significantly lowered liking and reward (vs no-added-water). Water addition did not impact sensory outcomes. Conclusions Water appears to have a limited effect on appeal at ≤10%, while reducing flavour aldehyde acetal formation. Therefore, water addition to e-liquids may be an elegant regulatory approach to reduce exposure to potentially harmful flavour aldehyde acetals in e-cigarettes. Trial registration number NCT05257109.

Oral nicotine pouches may have potential for smoking cessation, but scientific evidence on the effects of pouches and their constituents on smoking behaviour is limited.Design: This study was a 4-week, open-label, randomised pilot trial of nicotine pouches in 3 mg (low) or 6 mg (high) nicotine strength.Subjects: US outpatient research clinic with non-treatment seeking adults who smoke cigarettes (N=30).Interventions: Participants selected two flavours and were instructed to switch to using nicotine pouches in place of cigarettes.Main outcome measures: We compared groups on cigarettes smoked per day, pouch use and urinary levels of a tobacco-specific carcinogen (NNAL) over 4 weeks, biochemically verified 7-day point prevalence smoking abstinence at week 4, and willingness to continue pouch use.Results: Nearly all participants completed the trial (29/30). Participants in both groups significantly reduced their cigarettes smoked per day (log-transformed) over time (F_{3, 74.4}=3.8, p=0.01). The 6 mg group reported numerically greater, but non-significant, reductions in smoking than the 3 mg group (least-square mean difference (LSMD) at week 1=0.008; 95% CI −0.42–0.44; LSMD at week 4=0.38; 95% CI −0.06–0.81). The 6 mg group also reported numerically higher, but non-significant, likelihood of complete smoking abstinence (13% vs 0%) and willingness to continue pouch use (67% vs 40%). There were no differences by group or time for NNAL.Conclusions: Results provide preliminary support for nicotine pouches for cigarette substitution. Compared with lower nicotine strength pouches, higher nicotine strength pouches may have a greater impact on smoking behaviour and adults who smoke may be more willing to use them.Trial registration number: NCT04250727.

Background: This study is the first to examine longitudinal posttreatment outcomes of a placebo‐controlled trial of varenicline for alcohol use disorder (AUD) with comorbid cigarette smoking.Methods: Participants were 131 adults (n = 39 female) seeking alcohol treatment in a randomized, double‐blind, parallel group, placebo‐controlled, 16‐week multisite trial of varenicline combined with medical management (MM). Timeline follow‐back assessments of alcohol and smoking behavior were conducted at the end of treatment (4 months), with follow‐ups at 6, 9, and 12 months. Outcomes were percentage of heavy drinking days (PHDD), percent of participants with no heavy drinking days (NHDD), cotinine‐confirmed prolonged smoking abstinence (PA), and good clinical outcome on either NHDD or PA.Results: Treatment improvements were maintained posttreatment. For the sample overall, PHDD or NHDD did not differ significantly by treatment condition (ps > 0.13), but varenicline produced higher rates of PA versus placebo at 4, 9, and 12 months (p < 0.05). Significant differences were observed by sex: Males had higher rates of NHDD with varenicline (28.9%) versus placebo (6.4%) at the end of treatment (p = 0.004), and these effects were maintained at 12 months (varenicline: 40.0% vs. placebo: 19.2%, p = 0.03). Higher rates of PA were seen for varenicline in both males (8.9%) and females (21.1%) versus placebo (males/females: 0%) at the end of treatment (p = 0.05), and this effect was maintained at 12 months for females (varenicline: 21.1% vs. placebo, 0.0%, p = 0.05).Conclusions: Varenicline treatment combined with MM appears to have enduring benefits for patients with co‐occurring AUD and cigarette smoking, and these effects may differ by sex.

Effective interventions for reducing co-occurring health risks, such as heavy alcohol use and smoking, have the potential to benefit patients and reduce health care costs.^1,2 Quiz Ref ID Cigarette smoking, the leading cause of disability and death, is more than twice as common among individuals with alcohol use disorder (AUD) than among the general population,^3,4 and combined smoking and heavy drinking has negative synergistic effects on health.^5,6 Cigarette smoking also predicts poorer treatment outcome among patients seeking alcohol treatment.^7-10 Neither naltrexone hydrochloride nor acamprosate calcium, which are approved pharmacotherapies for AUD, promotes reductions in smoking during treatment of AUD.^11,12 Thus, identifying pharmacotherapies to treat both AUD and smoking represents an important step in integrating addiction treatment into mainstream health care.¹³

Objectives: Menthol is often added to cigarettes and e-cigarette solutions for its cooling and anti-irritant effects, and may contribute to development of nicotine dependence, particularly in vulnerable populations such as adolescents, and among African Americans. Menthol is rapidly metabolized to menthol glucuronide (MG) with little or no unconjugated menthol measurable in venous blood. Human challenge studies of the effects of inhaled menthol, and of its interactions with nicotine, would benefit from a quantitative measure of acute menthol exposure. Our objective was to determine whether plasma MG concentrations might be a suitable quantitative biomarker of acute menthol exposure following its inhalation. Methods: We performed a secondary analysis of plasma MG concentrations obtained during a study of the effects of inhaled menthol on behavioral responses to intravenous nicotine. MG concentrations were followed over time in venous plasma from 48 participants following inhalation of aerosols from e-cigarettes employing solutions containing either of 2 menthol concentrations or placebo. Results: Whereas plasma MG concentrations were variable, they showed a dose-dependent increase following menthol inhalation. Conclusions: Measurement of plasma MG may be useful to assess inter-individual differences in acute menthol exposure in human challenge studies involving menthol inhalation.

Neovascularization is a key role of renal cell carcinoma (RCC) and the status of neovascularization in RCC is closely correlated with the tumor development and patient prognosis. Endothelial progenitor cells (EPCs) are considered as important building blocks for neovascularization. However, the role of mobilized EPCs in RCC remains unknown. In this study, the orthotopic RCC model was established to investigate the distribution, frequency, and significance of mobilized EPCs. We found that circulating endothelial progenitor cell (CEPC) levels and plasma angiogenic factors (vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1 (SDF-1) were higher in peripheral blood (PB) of the RCC than those in the normal group and positively correlated with each other. EPC levels in adjacent nonmalignant kidney tissue (AT) were significantly higher than those in tumor tissue (TT) and normal kidney tissue (NT), which were positively correlated with CEPC levels. VEGF, VEGF receptor-2 (Flk), and SDF-1 and its SDF-1 receptor (CXCR4) expression in AT was significantly higher than that in TT and NT. Levels of these angiogenic factors in AT were positively correlated with those in PB. Mean microvessel density (MVD) was higher in AT than in TT, and that in TT was slightly lower than that in NT. Our findings propose that mobilized EPCs play an important role in RCC neovascularization. EPCs in PB and AT can be used as a biomarker for predicting RCC progression.

Lower concentrations of serum bilirubin, an endogenous antioxidant, have been associated with risk of many smoking-related diseases, including lung cancer and cardiovascular disease, and current smokers are reported to have lower bilirubin levels than nonsmokers and past smokers. This study evaluates the effects of smoking cessation on bilirubin levels. In a secondary analysis of a 6-week placebo-controlled trial of naltrexone for smoking cessation, indirect and total bilirubin concentrations were evaluated at baseline and following smoking cessation. Individuals who were continuously abstinent for 6 weeks (n = 155) were compared to those who were not (n = 193). Participants reported smoking ≥20 cigarettes daily at baseline and received smoking cessation counseling, 21mg nicotine patch daily, and either placebo or 1 of 3 doses of naltrexone (25, 50, or 100mg) for 6 weeks. Change in indirect and total bilirubin following the quit date was measured at Weeks 1, 4, and 6 compared to baseline. Individuals who were continuously abstinent from smoking, independent of naltrexone condition, showed a significantly greater mean increase in indirect (~unconjugated) bilirubin (0.06mg/dl, SD = 0.165) compared to those who did not (mean = 0.02, SD = 0.148, p = .015). Similar results were obtained for total bilirubin (p = .037). Smoking cessation is followed by increases in bilirubin concentration that have been associated with lower risk of lung cancer and cardiovascular disease.