Nicotine & Tobacco Research

ObjectivesUptake of evidence-based smoking cessation support remains limited. Digital interventions offer the prospect of scalable and highly accessible support. Smoke Free, a digital mobile application using established behaviour change techniques, has shown promise, but no large-scale randomised controlled efficacy trial has yet been conducted. We assessed its effectiveness for smoking cessation. DesignIn this prospective, randomised, controlled, two-arm, parallel clinical trial with 6-month follow-up, study personnel and patients were blinded. SettingThe trial was conducted nationwide in Germany, utilising a decentralised, fully remote trial design. Enrolment took place digitally after receiving brief advice from a healthcare professional, following guidelines for primary care. ParticipantsOut of a volunteer sample of 1850 patients assessed for eligibility, 1466 adult cigarette smokers who had at least moderate cigarette dependence (F17.2, FTCD[&ge;]3) were recruited between August 2023 and February 2024; 84.1% (1233 participants) completed the primary outcome measure. InterventionsThe intervention group (IG) received the Smoke Free app including behaviour-change missions and gamification elements, while the control group (CG) received a text-only cessation information app. Both groups received brief advice from a healthcare professional. Main outcome measuresThe prespecified primary outcome was self-reported 7-day point-prevalence abstinence from combustible tobacco at 6 months post-randomisation; secondary outcomes included biochemical validation of abstinence in participants providing a saliva sample (59% of eligible participants). ResultsSelf-reported abstinence (primary outcome) was significantly higher in the IG compared with the CG (283 [39.3%] vs. 182 [24.4%], OR=2.01, 95% CI 1.60 to 2.50, p<0.0001). The NNT was 6.7 (5.1 to 9.8). The effect was consistent with biochemical validation (OR=1.76, 95% CI 1.27 to 2.44, p<0.0001) and across secondary outcomes and sensitivity analyses. The 6-month follow-up rates for the primary outcome did not differ between groups (IG: 601 [83.5%]; CG: 632 [84.7%]; p=0.52). Eighty-four serious adverse events were reported by 75 participants (IG: 31, 4.3%; CG: 44, 5.9%; p=0.53); none were treatment-related. ConclusionsThe Smoke Free app is effective for aiding smoking cessation in at least moderately dependent cigarette smokers compared with an informational app when provided as an adjunct to brief advice from a healthcare professional. Trial registrationThe trial was registered with the German Clinical Trials Register (DRKS00031140). FundingSmoke Free 23 GmbH (for-profit company).

Introduction: Monitoring trends in transitions in the use of electronic nicotine delivery systems (ENDS) and cigarettes among youth is important for understanding the potential public health impacts of these products. Methods: Using a weighted Markov multistate transition model accounting for complex survey design, we estimated transition rates and one-year transition probabilities between never, non-current, ENDS-only, and cigarette use (with or without dual use of ENDS) among 26,744 youth aged 12-17 years who participated in at least two consecutive waves from Waves 2-7.5 (approximately 2015-2023) of the nationally representative Population Assessment of Tobacco and Health (PATH) Study. We also estimated transitions stratified by ages 12-14 and 15-17 years. Results. The one-year probability of ENDS-only initiation from never use among youth peaked in 2017-19 (Waves 4-5) at 4.0% (95%CI: 3.6-4.3%) and was higher for 15-17-year-olds at 5.8% (95%CI: 5.2-6.4%) than 12-14-year-olds at 2.2% (95%CI: 1.8-2.6%). In the following years, ENDS-only initiation rates declined and plateaued, with 2.6% (95%CI: 2.3-3.0%) initiation in 2022-23. Cigarette initiation from never use decreased over 2015-23 from 0.8% (95%CI: 0.6-1.0%) in 2015-16 to 0.1% (95%CI: 0.0-0.2%) in 2022-23. There was an increase in the fraction of youth who transitioned from non-current product use to ENDS-only use from 13.7% (95%CI: 7.5-20.0%) in 2015-16 to 35.1% (95%CI: 25.4-44.8%) in 2022-23, paired with a decrease in non-current use to cigarette use from 20.9% (95%CI: 11.8-30.0%) to 6.3% (95%CI: 1.7-10.8%). Transitions from ENDS-only or cigarette use to non-current use remained relatively constant over time at around 25% and 15% per year, respectively. Conclusion. ENDS-only use initiation has changed over time, peaking around 2019 and subsequently decreasing and plateauing, but cessation rates for both ENDS and cigarettes have remained relatively stable. Thus, interruption of tobacco product initiation may be the most effective approach to reducing tobacco product use among youth.

"Dry Hitting" is a unique phenomenon of e-cigarette use that has been shown to produce toxic chemical degradants and byproducts. Although it is widely understood that nicotine exposure during adolescence impacts neurobiological and behavioral function, little is known about how dry hitting may impact users. We hypothesized that subjects repeatedly exposed to nicotine dry hit vapor would exhibit distinct behavioral responses compared with saturated nicotine vapor and would differentially alter the expression of perineuronal nets (PNNs) in the rodent brain. Using a customized system of e-cigarette vapor inhalation, adolescent male Wistar rats (PND 31-40) received vaporized nicotine (30 or 60 mg/mL; [~]2.5-3 mL/cage), nicotine with dry hits (60 mg/mL; 1.75-2 mL/cage), or propylene glycol (PG) vehicle for 30 minutes over 7 daily sessions. Locomotor activity, antinociception, and elevated plus maze testing were used to assess behavioral response to drug intoxication and tolerance. Immunohistochemistry was used to identify Wisteria Floribunda Agglutinin (WFA)-positive PNN structures in the amygdala and insular cortex. Rats exposed to dry hits exhibited behavioral responses (locomotor sensitization, antinociception) similar to those of rats exposed to saturated nicotine vapor, but spent more time in the open arms of the elevated plus maze. Immunohistochemical analyses confirmed significantly greater WFA intensity in the central nucleus of the amygdala, but not the basolateral amygdala or insular cortex, of rats exposed to dry hits. Overall, these data confirm the impact of dry hit vapor on behavioral responses and perineuronal net expression in rats during adolescence.

Background The clinical safety profile of e-cigarette use for smoking reduction remains poorly characterized. This study compared the relative safety and tolerability of nicotine e-cigarette use with non-nicotine e-cigarettes or a non-aerosol cigarette substitute (CS) among adults interested in reducing their smoking. Methods We conducted a secondary analysis of adverse events (AEs) reported in a 6-month, double-blind RCT involving 520 participants assigned to either e-cigarettes with 0, 8, or 36 mg/mL nicotine or a CS. AEs were coded using CTCAE V4.0 and assessed for frequency, severity, seriousness and relatedness across groups. Cumulative incidence was calculated over 24 weeks. We estimated risk differences (RDs) and 95% confidence intervals (CIs) for frequently reported AEs (>=1% of participants overall) comparing e-cigarette vs. CS and nicotine versus non-nicotine e-cigarette groups. Fisher's exact test, with adjustment for multiple comparisons, was used to assess statistical significance. Results Most study-related AEs (those rated as possibly, probably, or definitely related by medical monitor) were mild in severity and none were classified as serious. At 24 weeks, cumulative incidence of first study-related AE was highest in the 36 mg/mL (37.0%) and 8 mg/mL (35.2%) e-cigarette groups, followed by 0 mg/mL (23.4%), and lowest in CS group (2.5%). E-cigarette users experienced significantly greater risks of cough (RD [95%CI]: 8.5% [5.6-11.3]), headache (RD [95%CI]: 5.4% [3.3-7.6]) and sore throat (RD [95%CI]: 5.4% [3.2-7.6]) as compared with the CS group. Cough was also more common in those randomized to nicotine versus non-nicotine e-cigarettes (RD [95%CI]: 8.1% [3.4-12.8]). Conclusion All study products were generally well-tolerated; however, AEs were more common in e-cigarette groups, especially with nicotine. Findings highlight the need to monitor common symptoms such as cough, headache, and sore throat in clinical and regulatory evaluations of e-cigarette safety.

BackgroundDespite their potential to serve as a reduced-harm alternative to combustible tobacco, e-cigarette take-up remains low among older (45+) adult smokers, especially in the U.S. While social media is a known driver of vaping attitudes and behaviors in younger populations, its influence on older smokers is poorly understood. This paper provides the first focused analysis of e-cigarette-related social media exposure in this population, documenting its prevalence, characteristics, and attitudinal correlates. MethodsData come from an opt-in survey of U.S. adults (N = 974) recruited via Prolific, comprising three groups: (i) non-vaping smokers aged 45+ (N = 484), (ii) former-smoking vapers aged 45+ (N = 149), and (iii) any-vaping-status smokers aged 18-35 (N = 341). Descriptive statistics, weighted to U.S. population benchmarks, characterize self-reported exposure to e-cigarette-related content on social media. Logistic regressions estimate associations between exposure and intentions for future e-cigarette use, e-cigarette harm perceptions, and related attitudes. ResultsOlder smokers (35.3%) reported exposure to e-cigarette-related content on social media less frequently than both older vapers (44.0%) and younger smokers (72.0%). For older smokers, e-cigarette health risks were the most frequently reported topic of content viewed, followed by youth vaping and e-cigarette addiction. Among this group, exposure was positively associated with stated intentions for future e-cigarette use. Exposure was not significantly associated with perceived e-cigarette harms for any group. ConclusionsFindings provide suggestive evidence that social media exposure may promote e-cigarette adoption among older smokers. However, the cross-sectional design limits causal inference, and the observed associations may reflect selection bias or reverse causality. If a causal relationship exists, the patterns observed suggest that exposure influences e-cigarette adoption through mechanisms other than updating beliefs about e-cigarette risks. While these results tentatively support the potential of social media as a channel for older-smoker harm reduction, any policy applications must carefully weigh privacy concerns and risks to youth. Rigorous experimental studies are needed to confirm these findings and clarify how social media might be leveraged to improve public health outcomes among older smokers.

Abstract Importance: The overall prevalence of youth nicotine and tobacco product use has declined over recent years, but the product landscape continues to evolve rapidly, particularly with new disposable e-cigarettes and oral nicotine pouches. Objective: To examine changes between 2024 and 2025 in the prevalence of nicotine and tobacco product use among US middle and high school students and describe shifts in product characteristics among current e-cigarette and nicotine pouch users. Design, Setting, and Participants: Repeated cross-sectional study using nationally representative data from the 2024 and 2025 National Youth Tobacco Survey (NYTS), a school-based survey of US students in grades 6-12 (approximately ages 11-18). The analytic sample included 29,678 students in 2024 and 23,557 students in 2025. Exposures: Survey year (2025 vs 2024). Main Outcomes and Measures: Past 30-day use of nicotine/tobacco products, including e-cigarettes, nicotine pouches, cigarettes, and other combustible and non-combustible products. Among current e-cigarette and nicotine pouch users, frequency of use, device type, brands, and flavors were assessed. Results: In 2025, 7.2% (95% CI, 6.4-8.2%) of US middle and high school students reported past 30-day use of any nicotine/tobacco product, compared with 8.1% (7.4-8.9%) in 2024. E-cigarettes remained the most commonly used product (5.2%, 4.5-5.9%); 1.7% (1.4-2.1%) used nicotine pouches, 1.7% (1.4-1.9%) smoked cigarettes, and 2.7% (2.4-3.1%) smoked any combustible tobacco product. Among current e-cigarette users, 40.7% (36.7-44.9%) reported frequent use and 27.0% (24.0-30.2%) reported daily use in 2025. Disposable e-cigarette use increased from 55.8% (52.6-59.0%) in 2024 to 66.7% (62.5-70.7%) in 2025, while pod/cartridge device use declined. Flavored product use was reported by 90.0% of e-cigarette users and 88.0% of nicotine pouch users. The most commonly reported brands were Geek Bar among e-cigarette users (61.1%) and ZYN among nicotine pouch users (69.4%). Conclusions and Relevance: Overall youth nicotine and tobacco use remains relatively low, but the product landscape is evolving rapidly, with increasing disposable device use and shifting brand preferences. These findings highlight the importance of ongoing, product-specific surveillance to inform public health strategies and regulatory policies.

ABSTRACT Background and aims: Mental and behavioral disorders due to use of tobacco (MBDT) present a critical challenge to global health, yet modifiable lifestyle factors for reducing its risk remain poorly understood. Given that dietary fibre can affect mental health through gut-brain communication, we sought to explore how fibre intake relates to MBDT risks in smokers. Methods: We specifically evaluated the link between dietary fibre intake and MBDT within a smoking population. Utilizing the UK Biobank (UKB) database, we performed cross-sectional (N=19,943) and prospective cohort (N=19,885) evaluations applying logistic and Cox proportional hazards models, respectively. To determine potential causality, two-sample Mendelian randomization (MR) was applied, relying on GWAS summary data derived from the IEU Open GWAS Project and FinnGen repositories. Results: Cross-sectional findings indicated that individuals in the top quartile (Q4) of fibre intake exhibited decreased MBDT risks relative to the bottom quartile (Q1) (OR: 0.32, 95% CI: 0.13-0.79). Over a median observation time of 12.84 years, the prospective evaluation demonstrated a notable inverse correlation (Q4 HR: 0.46, 95% CI: 0.40-0.54). Non-linear modeling via restricted cubic splines uncovered an L-shaped dose-response curve. Furthermore, MR results confirmed a genetically predicted protective causality (IVW OR: 0.68, 95% CI: 0.49-0.95), which remained consistent across sensitivity validations. Conclusions: Among smokers, higher dietary fibre intake is robustly associated with a reduced risk of mental and behavioral disorders due to the use of tobacco, offering a modifiable dietary target for public health interventions.

IntroductionAlthough prior studies suggest e-cigarette use is associated with worse mental health, it remains unclear whether these associations persist independent of diagnosed depression and how tobacco use and depression jointly affect health-related quality of life. Although the long-term health risks of vaping are still unknown, self-reported health is a reliable measure of quality of life. This study provides the first health utility estimates of the independent and combined effects of cigarette use, e-cigarette use, and depression on health-related quality of life. MethodsWe analyzed 2022-2023 Behavioral Risk Factor Surveillance System data on health-related quality of life as measured by self-reported physically or mentally unhealthy days in the past 30 days. The average number of unhealthy days was estimated by age, gender, smoking status (current versus non-smoking), depression status (received a prior diagnosis), and current e-cigarette use status (every day or some day use). We converted the number of overall healthy days into EQ-5D utility scores by age-specific percentile matching of BRFSS and MEPS distributions, a method developed by Jia and Lubetkin. ResultsCigarette use, e-cigarette use, and depression were each associated with worse health-related quality of life. Mentally unhealthy days increased with the accumulation of these conditions. Associations with physically unhealthy days followed a similar pattern, particularly among younger adults, although the magnitude of association was smaller. E-cigarette use alone was associated with 2.0-4.2 (95% CI: 2.0-4.6) additional mentally unhealthy days per month across all age groups. Notably, e-cigarette use was independently associated with poorer mental health among adults aged 18-64 with or without diagnosed depression. After accounting for smoking and depression status, e-cigarette use was associated with disutility scores of 0.011 in men and 0.015 in women among young adults, with the largest losses observed when multiple conditions co-occurred. ConclusionE-cigarette use is associated with poorer health-related quality of life, particularly among younger adults, and these effects are amplified when combined with cigarette use and depression. Quantifying these joint impacts as health utility losses highlights the importance of addressing e-cigarette use within integrated tobacco control and mental health policies, especially for young populations.

Tobacco use disorder is a chronic condition characterized by compulsive nicotine use, withdrawal, and relapse following abstinence. Impulsivity contributes to persistent nicotine use and poor cessation outcomes. This study examined whether nicotinic acetylcholine receptor (nAChR) modulators alter impulsive action in a nicotine self-administration Go/No-Go task in male and female rats. Rats acquired intravenous nicotine self-administration and were then trained in a Go/No-Go procedure in which active lever presses were reinforced during Go periods but not during No-Go periods. We then assessed the effects of varenicline (0.1-3 mg/kg), nicotine (0.1-0.6 mg/kg), and the nAChR antagonist mecamylamine (0.5-2 mg/kg) in the Go/No-Go procedure. Varenicline and nicotine pretreatment reduced active responding during both Go and No-Go periods, whereas mecamylamine selectively reduced responding during No-Go periods. Mecamylamine decreased the percentage of active responses during No-Go trials, indicating reduced bias toward the nicotine-associated lever. In contrast, nicotine and varenicline did not alter response allocation, suggesting that their effects reflected nonspecific reductions in responding rather than changes in impulsive action. No sex differences were observed. Substituting saline for nicotine during self-administration did not alter active responding during Go periods, but rats in the saline group had fewer active responses during No-Go periods than rats in the nicotine group. These results show that chronic nicotine self-administration increases impulsive action and that nAChR antagonism, but not agonism or partial agonism, reduces nicotine-related impulsive action. This work supports the utility of the Go/No-Go self-administration task for investigating nAChR-dependent mechanisms underlying nicotine-induced impulsivity.

Importance: Understanding patterns of substance use and environmental exposures to tobacco, cannabis, and electronic nicotine delivery systems (ENDS) among youth is critical for developing targeted prevention strategies, particularly as co-use of tobacco, ENDS, and cannabis becomes more prevalent. Objective: To identify latent classes of tobacco, ENDS, and cannabis use, and environmental exposures to these products among adolescents and emerging adults. Design, Setting, and Participants: Data from the Environmental influences on Child Health Outcomes (ECHO) consortium (3rd data release, 2018 to 2022) were analyzed from March 2025 to January 2026. The sample (N=2,786) included early adolescents (ages 11 to 13; n=226, 7.9%), middle adolescents (ages 14 to 17; n=1,248, 43.4%), and late adolescents/emerging adults (ages 18 to 24; n=1,402, 48.7%) from 19 ECHO cohorts. Main Outcomes and Measures: The Youth Risk Behavior Survey, Substance Use module measured experimental and current use of cannabis, ENDS, and tobacco products, as well as daily environmental exposure to tobacco smoke, nicotine aerosols, and cannabis smoke within home and social contexts. A multiple group latent class analysis was used to identify distinct latent classes of substance use and environmental exposure to tobacco smoke, nicotine aerosols, and cannabis smoke and compared class prevalences across early, middle, and late adolescence. Results: Four latent classes were identified, including: No Use/No Exposure (53%), No Use, Polyexposure (10%), Experimental Use/Low Exposure (22%), and Polysubstance Use/High Polyexposure (14%). Cannabis was the most used substance (34% experimental or current use) and the most common source of environmental exposure (20%), followed by ENDS use (26% experimental or current use; 19% environmental exposure) and combustible tobacco (15% use; 19% environmental exposure). The No Use/No Exposure and No Use/Polyexposure classes were primarily made up of early and middle-aged adolescents, whereas the Experimental Use/Low Exposure and Polysubstance Use/High Polyexposure classes primarily consisted of late adolescents and emerging adults. Conclusions: Our study revealed distinct, developmentally patterned groupings of substance use and environmental exposure among US adolescents and emerging adults, highlighting the need for developmentally tailored interventions, messaging, and policies that address both active use and environmental exposure across adolescence.

Background and AimsOn April 1st, 2024, Germany implemented the Act on the Handling of Cannabis for Non-Medical Use (KCanG), allowing adults to cultivate and possess recreational cannabis. We assessed whether this policy shift was associated with a change in the prevalence of cannabis use in the general population and in daily or almost daily cannabis use. DesignA series of 21 repeated cross-sectional surveys conducted between April/May 2022 and October/November 2025 (covering the period approximately two years before and one and a half years after the KCanG). SettingPopulation of Germany. ParticipantsA total of 32,991 people aged 14-64 years, including 2,092 (6.3%) people who used cannabis in the past 12 months. MeasurementsPast 12-month cannabis use (at least once). In past 12-month users: daily or almost daily use. To test a potential change in prevalence following the KCanG, we used piecewise binomial logistic regression models using the exact date of each wave as the predictor variable, allowing for a change in the slope at the first full wave after implementation of the KCanG in April 2024, with a random effect for wave. We conducted this analysis for the total sample as well as stratified by gender (male vs. female), age (14-24 vs. 25-64 years), and for daily or almost daily cannabis use in the subgroup of people who used cannabis in the past 12 months. Sensitivity analyses used alternate intervention dates (in-time placebo tests). FindingsThe prevalence of cannabis use and the share of (almost) daily users among 12-month users remained largely stable before and after the law reform. None of the slope coefficients before the introduction of the KCanG were statistically significant (all p [&ge;] .08), and none of the coefficients for the change in the slope were statistically significant (all p [&ge;] .31). Results of sensitivity analyses confirmed the stable trends for both outcomes. ConclusionsThe legislation of cannabis introduced in Germany in April 2024 was not associated with a change in trends of 12-month cannabis use prevalence early (1.5 years) after implementation, and also not with a change in the proportion of heavy users among past-12-month users. We recommend continued close monitoring of trends using multiple data sources and over a longer post-implementation period, as the effects of the legislation may not have fully unfolded yet.

Background: Our group previously reported that lung cancer (LC) screening history results and subsequent timing of diagnosis are associated with significant differences in survival outcomes. As a follow-up study, we sought to develop novel personalized risk models that considered screening history for incidence cancers, interval LCs, and prevalence LCs. Methods: Using data from the CT-arm of the NLST, four independent case-control analyses were conducted to develop parsimonious risk models. Controls (n=26,038) were those never diagnosed with LC. The four LC case groups were 270 prevalence LCs, 44 interval LCs, 206 screen-detected LCs (SDLCs) that had a baseline positive screen, and 164 SDLCs that had a baseline negative screen. For each case-control analysis, univariable analyses identified statistically significant covariates from 48 variables and then significant covariates were included into a stepwise backward selection approach to identify a model with the most informative covariates. Results: For prevalence LCs, the model (AUC=0.711) included age, pack-years smoked, BMI, smoking status, smoking onset age, personal history of cancer, family history of LC, alcohol consumption, and milling occupation. For interval LCs, the model (AUC=0.734) included age, smoking status, smoking onset age, cigar smoking, marital status, and asbestos occupation. For baseline positive SDLCs, the model (AUC=0.685) included age, pack-years smoked, BMI, emphysema, chemicals/plastics exposure, and milling occupation. For baseline negative SDLCs, the model (AUC=0.701) included age, pack-years smoked, BMI, smoking status, emphysema, sarcoidosis, and sandblasting occupation. Conclusions: Besides smoking and age, which are inclusion criteria for screening, these models identified other important risk factors which could be used to provide personalized LC risk assessment and screening management.

ObjectiveNicotinic acetylcholinergic receptors (nAChRs), comprising of and {beta} subunits are present in the brain and whole body. The less abundant 2-subunit is a fast-acting receptor subtype and plays an important role in cognition and learning. To understand cellular functional consequences, this study evaluated glucose metabolism using [18F]FDG PET/CT in 2 knockout (2KO) and 2 hypersensitive (2HS) mice. MethodsControl (CN; 4M, 4F), 2 knockout (2KO; 4M, 4F) and 2 hypersensitive (2HS; 4M,4F), 12-16 month old mice were used. Mice were fasted and injected with [18F]FDG (3-5 MBq) while awake. After 40 minutes they underwent whole body PET/CT. On a separate day, nicotine challenge [18F]FDG studies were done. Reconstructed images were analyzed to obtain standard uptake values (SUV) of [18F]FDG in brain and interscapular brown adipose tissue (IBAT). Statistical analysis was performed. ResultsThe 2HS male mice exhibited the largest brain increase in [18F]FDG compared to 2KO male mice. The rank order of brain [18F]FDG uptake in the 3 groups: 2HS[male]> CN[male]> 2KO[male]> CN[female]= 2KO[female][&ge;] 2HS[female]. Nicotine treatment reduced brain [18F]FDG uptake in all mice. Females had lower [18F]FDG uptake compared to males and were less sensitive to 2 nAChR. In the case of IBAT, 2KO mice had significantly higher baseline [18F]FDG uptake compared to the other two groups: 2KO[male]> 2KO[female]> 2HS[female]> 2HS[male]> CN[female]> CN[male]. Nicotine decreased IBAT in 2KO mice rather than increase as observed in CN and 2HS mice. Conclusions2 nAChRs plays a significant role in brain activation as exhibited by the increase in [18F]FDG in 2HS mice. In the absence of regulatory control by the 2 nAChR, the 2KO mice IBAT exhibited higher [18F]FDG IBAT compared to controls and 2HS mice. Female mice were less affected by nicotine compared to the male mice. Overall, 2 nAChRs played a significant role in glucose metabolism in the brain and IBAT.

BackgroundWe explored the efficacy of AS01E-adjuvanted respiratory syncytial virus prefusion F protein-based vaccine (adjuvanted RSVPreF3) in subpopulations of participants with underlying medical conditions in the multi-country, phase 3 AReSVi-006 trial (conducted May/2021-May/2024). MethodsMedically stable [&ge;]60-year-olds were 1:1-randomised to receive one adjuvanted RSVPreF3 or placebo dose pre-RSV season 1. In exploratory post-hoc analyses in subgroups of participants with underlying conditions (including COPD, asthma, diabetes, obesity [BMI[&ge;]30 kg/m2]), we evaluated efficacy of one vaccine dose against RSV-related lower respiratory tract disease (RSV-LRTD), acute respiratory illness (RSV-ARI), and RSV-ARI-related complications (e.g., pneumonia, COPD/asthma exacerbation, cardiovascular events). We also evaluated (post-hoc) RSV-ARI-related systemic corticosteroid and antibiotics use in participants with COPD or asthma. ResultsThe efficacy analyses comprised 12,468 vaccine and 12,498 placebo recipients. Efficacy against RSV-LRTD over three RSV seasons was similar among participants with COPD (75.1%, 95% CI: 40.2-91.4), asthma (65.8%, 31.0-84.7), diabetes (69.8%, 37.5-87.1), and obesity (74.1%, 56.4-85.5) as in the overall study population (62.9%, 97.5% CI: 46.7-74.8). Efficacy was also observed against RSV-ARI in these subgroups. Efficacy against RSV-ARI-related complications was 74.4% (95% CI: 11.2-95.2) in participants with COPD and 60.8% (-9.9-88.7) in those with asthma. Among participants with COPD, 15.4% (1.9-45.4) of RSV-ARI episodes in vaccine vs 22.4% (12.5-35.3) in placebo recipients were treated with systemic corticosteroids, and 46.2% (19.2-74.9) vs 56.9% (43.2-69.8) with antibiotics. ConclusionsPost-hoc analyses of the AReSVi-006 trial suggest that adjuvanted RSVPreF3 may help prevent RSV-ARI, RSV-LRTD, and RSV-related complications in medically stable older adults with underlying medical conditions like COPD and asthma. Trial registrationClinicalTrials.gov: NCT04886596 SummaryPost-hoc analyses of the AReSVi-006 trial suggest that 1 dose of adjuvanted RSVPreF3 may help prevent RSV-related illness and complications over 3 consecutive RSV seasons in subgroups of [&ge;]60-year-olds with chronic medical conditions, e.g., COPD and asthma.

BackgroundLoss of control over drinking is a hallmark feature of alcohol use disorder (AUD) that is modeled preclinically through escalation of ethanol consumption and aversion-resistant drinking. Prior work with other reinforcers suggests that within-session unpredictable, intermittent access (uIntA) promotes loss of control over intake. However, the effect of uIntA on voluntary ethanol consumption is unknown. MethodsMale and female Long-Evans rats (n=9-10/group) underwent seven weeks of daily voluntary ethanol (20% v/v) drinking sessions under either a continuous access (ContA) or uIntA schedule. Following four weeks of baseline, rats were rendered dependent using a two-week chronic intermittent ethanol vapor exposure procedure. Daily testing was maintained through one week into withdrawal from vapor exposure. On the final day of testing, ethanol was adulterated with quinine (30 mg/L) to assess aversion-resistant drinking. ResultsRats drinking under ContA and uIntA exhibited similar levels of average daily ethanol consumption at baseline. However, uIntA elicited a more robust dependence-induced escalation of ethanol consumption compared to ContA, with uIntA sustaining escalation through early protracted withdrawal. Additionally, while rats with ContA to ethanol remained sensitive to quinine even after chronic ethanol vapor exposure, uIntA promoted aversion-resistant drinking in ethanol dependent rats. ConclusionsThese results demonstrate that, compared to ContA, uIntA maintains ethanol drinking and exacerbates AUD-related symptomatology while also providing researchers with the ability to capture additional measures of motivation and drinking patterns without increasing experimental burden. This work positions uIntA as a powerful tool to assess psychological and neurobiological factors underlying loss of control over drinking.

AimWe examined associations between smoking and HbA1c among U.S. adults, and whether these associations vary by diabetes status. MethodsWe analyzed NHANES data from 2015-2018 for adults aged [&ge;]20 years. Smoking was assessed by self-report and serum cotinine. Survey-weighted multivariable linear regression was used to evaluate the association between smoking and HbA1c in the full population (N=9,214) and in adults without diabetes (N=7,328), adjusting for demographics, blood pressure, waist circumference, lipids, and C-reactive protein. ResultsAfter adjustment for cardiometabolic covariates, there was no significant association between smoking and HbA1c in the full population (former: {beta}=0.029%, p=0.30; current: {beta}=0.053%, p=0.13). Among adults without diabetes, former smoking was not associated with HbA1c, whereas current smoking remained significantly associated (former: {beta}=-0.001%, p=0.923; current: {beta}=0.067%, p<0.001). These findings were similar when cotinine was used as the exposure measure, with active smoking ([&ge;]3.0 ng/mL) associated with higher HbA1c among non-diabetic adults (p<0.001), but not in the full population. ConclusionsAmong adults without diabetes, current but not former smoking was associated with higher HbA1c. The absence of an association in former smokers suggests that this effect may attenuate following cessation. These findings support early cessation interventions and may inform cessation counseling and diabetes screening.

In rats, cue-induced opioid craving intensifies (incubates) during abstinence from opioid self-administration and then remains high for a prolonged period. The prolonged plateau models persistent vulnerability to cue-induced craving and relapse in humans recovering from opioid use disorder. However, a very significant contributor to relapse vulnerability in these individuals is the presence of negative affective states that can persist for months to years, far beyond physical dependence. The goal of this study was to determine if the incubation of craving model recapitulates this aspect of relapse vulnerability. We began by comparing rats trained to self-administer oxycodone using a regimen leading to persistent elevation of cue-induced craving (6 h/d x 10 d) and rats trained to self-administer saline. We assessed somatic withdrawal signs in early abstinence and conducted behavioral tests modeling negative affect (open field, social preference, sucrose preference, and elevated plus maze) in late abstinence. Some somatic withdrawal signs were greater in oxycodone rats on abstinence day (AD)1, but cumulative scores did not differ between groups on AD1-3. On AD41-46, no group differences were found in behavioral tests modeling negative affect. To compare early and late abstinenceperiods, a second cohort of rats self-administered saline and oxycodoneand then received two cue-induced seeking tests (AD1 and AD40; oxycodone rats exhibited incubation of craving) and two series of negative affect tests (AD2-7 and AD41-48). While some time-dependent changes in affect were observed within each group, they were suggestive of reduced anxiety-like behavior in oxycodone rats. Finally, because rats are single-housed during our incubation studies, we compared drug-naive rats after 8-9 weeks of single vs pair housing and found no difference in behavioral tests modeling negative affect. We conclude that the persistence of elevated cue-induced craving observed after a standard opioid incubation regimen is not accompanied by negative affective states, probably due to lower drug intake during the intravenous regimen compared to non-contingent escalating dose regimens typically used to study withdrawal signs. This does not negate the utility of the incubation model for studying cue-induced opioid craving and its neurobiological basis.

BackgroundSubstance use initiation in adolescence is influenced by both genetic and environmental factors; however, large-scale genetic studies often treat initiation as a binary outcome and underuse longitudinal timing information. MethodsWe conducted time-to-event (survival) genome-wide association analyses (GWAS) of initiation for four outcomes--alcohol, nicotine, cannabis, and any substance use--using longitudinal follow-up data from the Adolescent Brain Cognitive Development (ABCD) Study. We performed ancestry-stratified GWAS within European (EUR), African (AFR), and Hispanic (HISP) groups, applying consistent quality control and covariate adjustment. Summary statistics were harmonized across ancestries and meta-analyzed using inverse-variance weighted fixed-effects and DerSimonian-Laird random-effects models. We evaluated genomic inflation and heterogeneity (Cochrans Q and I2), identified independent lead variants at genome-wide and suggestive significance thresholds, and assessed cross-trait overlap of associated loci. ResultsIn the multi-ancestry meta-analysis, we observed suggestive association signals across traits (minimum p-values: alcohol [~] 1 x 10-7, any [~] 1 x 10-7, cannabis [~] 5 x 10-8, nicotine [~] 1 x 10-8). Nicotine initiation showed one genome-wide significant variant in both fixed- and random-effects meta-analyses (p < 5 x 10-8). Across traits, suggestive loci demonstrated limited overlap, with the strongest concordance between alcohol and any substance use, consistent with shared liability. Heterogeneity statistics indicated that some loci exhibited cross-ancestry variation in effect estimates. ConclusionsSurvival GWAS leveraging initiation timing can identify genetic signals that may be missed by binary designs and enables principled multi-ancestry synthesis. Our results highlight both shared and trait-specific genetic contributions to early substance initiation and provide a foundation for downstream functional annotation and integrative modeling with environmental risk factors. These findings demonstrate the value of incorporating developmental timing into genetic discovery and provide a framework for integrating longitudinal risk modeling with genomic analyses.

Objectives: This meta-review compares methodological and reporting approaches between systematic reviews examining alcohol dose and cardiovascular disease (CVD) and assesses whether alcohol industry involvement is associated with divergent conclusions. Methods: KSR Evidence was searched 6 May 2025 to update a cohort of 60 systematic reviews from previous review. Reviews were included if they examined any dose-response relationship between alcohol consumption and CVD. Two reviewers independently screened records and extracted data on review characteristics, and citations. Methodological quality was appraised using AMSTAR 2. For a matched sample of reviews with and without known alcohol industry funding, the overlap of included primary studies was compared using Corrected Covered Area (CCA) analysis. Results: Thirty additional systematic reviews met the inclusion criteria, yielding 90 systematic reviews (1996-2025). Most (60.0%, 54/90) concluded that alcohol had a cardioprotective effect, whereas 31.1% (28/90) concluded no evidence of protection, and 8.9% (8/90) were inconclusive. Twenty reviews (22.0%) had declared or inferred alcohol industry funding or author connection; all but one reported a protective effect at lower doses, the other was inconclusive. Industry-connected reviews were cited more often (mean 575.9 vs 193.0, p=0.0002) and more commonly examined overall CVD rather than specific conditions (such as hypertension or stroke). Study overlap was low (CCA 2.59%) and 99% of reviews were rated as critically low quality. Conclusions: The fragmented evidence base is of poor methodological quality with selective inclusion of studies. Alcohol industry connections are strongly associated, with conclusions favouring alcohol consumption, highlighting the need for independent high-quality systematic reviews.

Purpose: We systematically reviewed the evidence for three questions on screening for lung cancer with computed tomography (CT): benefits (from randomized trials) and harms of screening versus no screening/minimal intervention or alternative screening approaches (e.g., selection criteria, screening intervals); relative importance that informed patients place on the potential benefits and harms of screening (patient preferences); and comparative effects from observational studies of different screening selection criteria (using risk prediction models) or nodule classification systems compared with those used in the screening trials. Methods: A working group of primary care and specialist clinicians (previously members of Canadian Task Force on Preventive Health Care) and topic experts provided input into the eligibility criteria and key potential effect moderators, rated outcomes for their importance to decision making, and developed decision thresholds for use when making conclusions and assessing certainty of the evidence. Critical outcomes of screening effects included all-cause mortality, lung-cancer mortality, and overdiagnosis (via excess cancer incidence from screening). For patient preferences, we sought direct preference data via (i) disutilities of relevant health states (measuring their impact on ones health-related quality of life on a scale of 0 [perfect health] to 1 [death], mainly using EQ-5D), and (ii) other preference-based data, such as outcome trade-offs, as well as indirect preference data via (iii) the relative importance of benefits versus harms inferred from attitudes, intentions, and behaviors towards screening among eligible patients informed with estimates of the outcomes. For screening benefits and harms and for patient preferences, we searched three databases (MEDLINE, Embase, and Central & MEDLINE, Scopus, and EconLit, respectively) to July 11, 2025. For screening studies published prior to 2015 we relied on searches for other reviews, and for patient preferences our search was limited to 2012-onwards. For comparative effects, we searched MEDLINE and Embase from 2019 to September 23, 2025, with reliance on other reviews for studies published 2012-2018. Reference lists were scanned and trial registries searched. For the main searches, two independent reviewers screened titles and abstracts and then full texts; for search updates we applied AI to assist with title and abstract screening. Data extraction and analysis were undertaken by single reviewers, with verification; risk of bias and GRADE certainty assessments were undertaken independently by at least two reviewers. Data were pooled where suitable using random effects methods appropriate to the outcome metric and prevalence. Subgroup analyses explored heterogeneity (e.g., sex, number of rounds, type of comparator, sensitivity of nodule management, type of utility measurement). When not pooled (e.g., patient preferences based on screening intentions) data were analyzed by grouping studies based on factors such as population, setting, exposure, and outcomes, with consideration of study size and risk of bias. Conclusions and certainty assessments for screening effects were based on estimates of absolute effects. Results: We included 85 studies (N=640,537; 13 trials) on screening benefits and harms, 59 on patient preferences (33 [N=42,219] on disutilities and 26 [N=10,829] other studies), and 16 for comparing trial (National Lung Screening Trial [NLST]) and LungRADs nodule management, either directly (2 studies, N=26,978) or indirectly (14 studies, N=1,102,285). Screening benefits and harms: Findings from nine trials (N=94,530) examining low-dose CT (LDCT) screening on all-cause (RR 0.97, 95% CI 0.93 to 1.01; 3.7 fewer [8.5 fewer to 1.2 more] per 1000) and lung-cancer mortality (RR 0.87, 95% CI 0.79 to 0.96; 4.0 fewer [1.2 to 6.4 fewer] per 1000) offered low and moderate certainty, respectively, that screening previous/current 20-30 pack-year smokers 50-74 years old 3-4 times will probably result in at least 1 (all-cause) and 2 (cause-specific) fewer deaths per 1000 screened after 10-12 years. The absolute effects may not apply to participants at the lowest baseline risk for lung-cancer incidence (e.g., <1.5% over 6 years) or death. Seven trials (N=35,161) contributed to meta-analysis for overdiagnosis (RR 1.19, 95% CI 1.03 to 1.37; 8.4 [1.3 to 16.3] per 1000), and our certainty was moderate that LDCT screening 3-4 times will probably result in at least 2.5 cases of overdiagnosis per 1000 screened over 10 years. For important outcomes, we had high certainty that screening 3-4 times results in at least 75 people per 1000 screened (and probably at least 225) having at least one benign biopsy/false positive, 150 having one or more incidental findings (likely at least 450), and 50 (probably at least 100) having a clinically significant/actionable incidental finding, but probably does not have an important impact on major complications or death from invasive testing among those without cancer. Though undergoing a LDCT scan probably causes little-to-no psychosocial harm, having a positive screening result likely causes at least a small degree of harm (i.e., 4-8% change from baseline), especially for the 10-15% having to undergo invasive procedures where some may experience moderate harm. Among those without cancer, these effects may last for several months while the diagnostic process is underway, though moderate certainty evidence found little-to-no effects remaining after 6 months from diagnostic resolution. Comparative effects: Findings from applying different baseline predicted risks for lung-cancer incidence or mortality to the trial populations (i.e., alternative selection criteria) were considered with the effects from screening benefits and harms. Using LungRADs instead of NLST nodule management (among NLST eligible people) probably reduces the false positive rate substantially (about half), though the number of false positives still exceeded the decision threshold of 75 per 1000 and the effects for benefits or other harm outcomes are not known. Patient preferences: Findings showed little-to-no disutility (i.e., <0.04) from a positive screening test (moderate certainty) or a false positive result (low certainty). Low-certainty evidence found there may be little-to-no disutility from a stage I-IIIA cancer diagnosis (before treatment) but small but important disutilities from a stage IIIB/IV diagnosis, during first-line treatment of any stage (though possibly moderate disutility of about 0.09 for stage IIIB/IV), and after treatment for stage IIIB/IV but not stage I-IIIA (without progression) where effects were inconsistent but indicated that any disutility may not be long-lasting. Findings for stage I-IIIA are likely most relevant for understanding the consequences of overdiagnosis. For stated preferences between outcomes, there was low certainty evidence that a small majority (51-75%) of people may accept 69-122 false positives and at least 1.3 cases of overdiagnosis per prevented lung-cancer death, and think that the reduction in lung-cancer mortality is more important than experiencing one of the relevant harms. After being informed about anticipated benefits and harms from screening (with the largest screening effects shown to those at higher baseline risk), progressively more people preferred screening (mainly via intentions) as the net benefit of screening improved from low [25-50% preferred] to moderate [51-75%] to high [>75%]. Conclusions: This review provides contemporary data on the benefits and harms of LDCT screening after at least a decade of follow-up and makes conclusions based on absolute effects while considering thresholds for decision making. Across the reviews, findings indicate that screening those aged 50-74 years with 3-4 rounds of LDCT will lead to benefits and harms for which a majority, but not all, eligible people probably find acceptable and worthwhile. While current nodule management using LungRADs likely reduces false positives, whether it impacts the benefits of screening is less certain and worth further research. Further, comparative prospective studies are lacking to determine the effects from screening for those not meeting the minimum age (50 years) and smoking history criteria in the trials, despite having an equivalent risk for lung cancer.