Nicotine & Tobacco Research

BackgroundThe initiation of tobacco and nicotine product use often occurs in adolescents. This necessitates monitoring of this behaviour in this population, particularly in countries such as the Democratic Republic of the Congo (DRC) where approximately 58% of the population is under 19 years of age. Our study assessed the prevalence of, and factors associated with use in the DRC. MethodsWe conducted a nationally representative, cross-sectional, household survey between March and May 2024 among adolescents aged 10 to 17 years. We estimated the prevalence of use of smoked and smokeless tobacco products, heated tobacco products, and nicotine products (i.e., electronic cigarettes and nicotine pouches). We used logistic regression to identify factors associated with current use of any tobacco product, smoked tobacco, and smokeless tobacco using adjusted odd ratios. All analyses included 95% confidence intervals (CI). ResultsOf the 4,675 adolescents who completed the survey, the prevalence of current use of any tobacco or nicotine product was 11.87% (95% CI: 6.93-19.58). This was 7.98% (95% CI: 4.23-14.55) for smoked tobacco products, 5.86% (95% CI: 3.42-9.87) for smokeless tobacco products, 0.11% (95% CI: 0.11-0.11) for heated tobacco products and 0.60% (95% CI: 0.10-3.40) for nicotine products. Boys were more likely to use tobacco than girls. Being enrolled in school and having both parents alive were protective from tobacco use. Having a male household head, a household head education level of at least secondary school, and exposure to tobacco smoking in public places increased the odds of being a tobacco user. ConclusionsThe DRC should strengthen policies that make tobacco and nicotine products less accessible or appealing to adolescents. This includes raising excise taxes; banning the sale of single cigarette sticks, small packets and flavoured products; and comprehensive smoke-free laws. Policies should account for factors that make adolescents more vulnerable product use. Key messagesO_ST_ABSWhat is already known on the topicC_ST_ABSO_LIThe last survey on tobacco use among adolescents in the DRC was a school-based survey among 13-15-year-olds conducted in 2008, and only covered Kinshasa and Lubumbashi. C_LI What this study addsO_LIThis survey provided national-level estimates that cover adolescents aged 10-17years, includes out-of-school adolescents, and covers both tobacco and nicotine products. C_LIO_LIIt also identifies individual-, household-, and environmental-level factors that are associated with tobacco and nicotine product use among adolescents in the DRC. C_LI How this study might affect research, practice or policyO_LIBy providing current and more comprehensive data, our study enhances policymakers ability to design evidence-based tobacco control interventions that are aimed at preventing the initiation and use of tobacco and nicotine products among adolescents in the DRC and other similar settings. C_LI

E-cigarettes have attracted significant attention as a safer substitute for conventional tobacco smoking. However, they have introduced new inhalable toxicants, including benzaldehyde-propylene glycol acetal (BPGA)--a chemical adduct produced by cherry-flavoured e-cigarettes. The health risks associated with such flavour-derived acetals remain insufficiently elucidated at the cellular level. This study investigated the role of BPGA in the progression of epithelial-to-mesenchymal transition (EMT)-like changes in alveolar epithelial cells (A549 cells). A549 cells exposed to various concentrations of BPGA were analysed for cell viability, morphology, mitochondrial function, lysosomal health, and cytoskeletal integrity using viability assays and fluorescence imaging. Intracellular reactive oxygen species (ROS) production was quantified using the 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA) assay. Antioxidant enzyme expression, inflammatory responses, and EMT-associated phenotypic alterations were evaluated using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunofluorescence (IF) assays. Exposure of alveolar epithelial cells to BPGA caused a concentration-dependent decrease in cell viability. BPGA exposure resulted in mitochondrial membrane depolarisation, lysosomal damage, cytoskeletal changes, and stress fibre formation, which altered cell morphology. It significantly increased intracellular ROS production. As a result, antioxidant enzyme levels were upregulated as a protective response. However, during severe oxidative stress, this response was overwhelmed. Excess ROS disrupted cellular homeostasis and initiated apoptosis, though not completely. ROS also acted as a signalling molecule, promoting the upregulation of inflammatory mediators. These changes were associated with altered EMT marker expression, suggesting that BPGA might drive EMT-like remodelling. In conclusion, BPGA, a chemical adduct from e-cigarette vapour, induces alveolar injury by promoting oxidative stress, inflammation, and EMT-related changes, which may explain a mechanism by which e-cigarette exposure could lead to lung injury and pulmonary fibrosis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=169 SRC="FIGDIR/small/724520v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@f7739dorg.highwire.dtl.DTLVardef@1c74f11org.highwire.dtl.DTLVardef@180aeeorg.highwire.dtl.DTLVardef@75ae14_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG

Abstract Aims To examine which demographic groups nicotine pouch advertisers chose to target on social media, and which groups Meta's algorithms actually delivered the adverts to. Design Cross-sectional analysis of advert-level data from the Meta Ad Library. Setting Meta social media platforms (including Facebook and Instagram) in the UK. Cases A random sample of 741 nicotine pouch adverts shown in the 12 months up to December 2025, and a comparison sample of 1,125 general adverts. Analyses of reach were restricted to adverts eligible for all genders and adult ages (444 pouch adverts; 674 general). Measurements Outcomes were advertiser-set gender and age-group targeting criteria (i.e., groups eligible to be shown each advert) and estimated advert reach to each group (i.e., number of people who saw each advert). Male-to-female reach ratios within age groups, and reach ratios comparing age groups, were calculated per advert and summarised using geometric means. To assess whether patterns were pouch-specific, comparisons with general adverts were made using ratios of reach ratios (RRR). Findings Advertisers of nicotine pouches targeted a broad sample; most adverts (79.1%; 586/741) were eligible to be shown to all genders, the remainder were restricted to men only. All were restricted to adults (minimum age 18 years) and most (95.6%; 708/741) had no upper age limit. Despite this, of pouch adverts eligible to be shown to all adults, adverts were more likely to reach men, particularly among younger men. Among 18-24-year-olds, pouch adverts reached around ten times as many men as women (RR 10.0, 95% CI 8.7-11.5), compared with a slight skew towards women for general adverts (RR 0.81, 95% CI 0.71-0.94), corresponding to an RRR of 12.3 (95% CI 10.0-15.1). Pouch adverts also showed a skew in reach towards younger age groups. Relative to those aged 35-44 years, reach was higher among 18-24-year-olds for nicotine pouch adverts (RR 1.33, 95% CI 1.17-1.51) but much lower for general adverts (RR 0.19, 95% CI 0.17-0.21), corresponding to an RRR of 7.0 (95% CI 6.0-8.2). Conclusions Nicotine pouch adverts on social media are often eligible to be shown broadly to all demographic groups but are disproportionately delivered to young men.

BackgroundThis study aimed to investigate whether retinal fractal dimension (Df), a measure of microvascular branching complexity from fundus images, together with plasma metabolites, can help identify pathways linking microvascular changes to cardiovascular disease (CVD) events. MethodsWe analyzed longitudinal data from a subset of 4,781 participants from the Comprehensive cohort of the Canadian Longitudinal Study on Aging (CLSA), free of CVD at baseline (mean age 58.74 {+/-} 8.39; 47% male), and with 811 plasma metabolites measured at baseline and retinal imaging. Total, arterial and venular Df were derived from fundus photographs using the Vessel Assessment and Measurement Platform for Images of the Retina. Incident CVD was defined as one or more of self-reported physician-diagnosed myocardial infarction, angina, coronary heart disease, stroke, transient ischemic attack, or peripheral vascular disease during follow-up. Regression models tested associations among Df, plasma metabolites and incident CVD. ResultsOver a median follow-up of 5.75 years (IQR 5.48-6.04), 546 participants (11.42%) developed CVD. Higher total, arterial and venular Df were associated with lower CVD risk in unadjusted analyses (Odds Ratio (OR)=0.62, 95% CI:0.53-0.72 for total Df; OR=0.78, 95% CI:0.70-0.86 for arterial Df; OR=0.74, 95% CI:0.67-0.82 for venular Df). Total Df demonstrated the strongest predictive value for incident CVD but not independently of established CVD risk factors. Nine plasma metabolites, including amino acids, lipids, and xenobiotics, were associated with both incident CVD and one Df measure (p < 0.05), with cotinine and hydroxycotinine satisfying a false discovery rate adjustment (q < 0.05). Consistent with these findings the Total Nicotine Equivalent (TNE-3) was also associated with both lower arterial Df and increased CVD risk. ConclusionsRetinal microvascular complexity is associated with incident CVD. Nicotine metabolism from tobacco smoking exposures emerged as the strongest association linking microvascular changes and CVD events. Clinical PerspectiveO_ST_ABSWhat is New?C_ST_ABSO_LILower retinal branching complexity, as measured through Df, is significantly associated with incident cardiovascular disease (CVD) in unadjusted analyses. C_LIO_LIIn a population-based sample, we found nine plasma metabolites associated with both retinal vascular complexity and incident CVD, but only nicotine metabolites were significant after multiple testing correction. C_LIO_LINicotine metabolites, particularly cotinine and hydroxycotinine, remained significantly associated with incident CVD even after adjustment for self-reported smoking status. C_LI What Are the Clinical Implications?O_LIRetinal Df measures could be used as a predictor of CVD event, although not independently of age and traditional cardiovascular risk factors. C_LIO_LIMicrovascular changes may lie on the pathway linking nicotine metabolites to CVD events. C_LIO_LIPlasma nicotine metabolites may provide additional cardiovascular risk information beyond self-reported smoking, reflecting individual exposure, metabolism and passive smoke exposure. C_LI

BackgroundLung cancer remains a major public health burden, with poor survival largely driven by late-stage diagnosis. With declining and very low smoking prevalence in Singapore at 4.7% in 2024 among 18-29-year-olds, questions arise about future screening efficiency, eligibility criteria, and the impact of smoking cessation, including tobacco elimination. MethodsWe developed a large-scale microsimulation model calibrated to real-world data, generating individual life histories, smoking trajectories, and disease progression for Singapores 4.18 million residents to project smoking prevalence and lung cancer burden. We evaluated 271 low-dose computed tomography (LDCT) screening strategies (by age, gender, uptake, and frequency) under five tobacco control scenarios, from status quo to a complete smoking ban, between 2025 and 2050. FindingsUnder the status quo, all screening strategies were cost-effective relative to the 2024 GDP per capita threshold ([~]SGD 120,000). Among strategies with [&le;]10% overdiagnosis, annual screening of eligible ever-smokers aged 50- 80 years was most life-saving, yielding 51,312 (95% uncertainty interval: 36,821-72,830) QALYs at a total cost of SGD 12.2 (9.7-16.1) billion. Adding an immediate smoking ban increased QALY gains by 2.8 (2.2-3.5) times while reducing the total cost by 23.3% (17.0%-30.0%). Extending eligibility to individuals with lower smoking exposure or a first-degree family history remained cost-effective. InterpretationsTobacco elimination yields substantial health and economic benefits, while well-designed risk-based LDCT screening of residual high-risk populations remains cost-effective, supporting a continued role for screening even in settings with declining smoking prevalence.

RationaleThe progression of psychostimulant abuse is associated with a shift from recreational to habitual use (R2H-shift). Because this R2H-shift can be modeled using behavioral economics, we developed a novel Behavioral Economic model for the Analysis of Self-administration Time-curve (BEAST) to obtain R2H-shift variable(s). The relationship(s) between R2H-shift variables and drug intake (under normal and/or punishment conditions) is/are unknown. Our goal was to determine if the R2H-shift variable and intake variables obtained during the initial self-administration training phase were related to 1) drug intake at that time, and subsequent drug intake under 2) normal, 3) punishment, 4) post-punishment, and 5) price-constrained conditions. MethodLong Evans rats self-administered methamphetamine (METH, males n = 16, females n = 14), sucrose (males n = 22, females n = 22) and/or saline (males n = 3, females n = 10) under FR1 for 6 h per day for 20 days to obtain 1) followed by the assessment of subsequent drug intake under different conditions (2-5 above). We obtained all variables referenced above. We determined the relationships between all variables (multivariate analysis). ResultsThere were no sex differences detected in the METH and sucrose studies. For METH and sucrose, prior drug intake levels could predict drug intake under normal/punishment but not under price-constrained conditions. The R2H-shift variable could predict drug intake under a consumption-price curve but could not predict intake under normal/punishment conditions. ConclusionsWhile related to economic demand, the recreational-to-habitual shift rate was unrelated to drug intake levels (under normal and punishment conditions).

Background: Non-communicable diseases (NCDs) account for approximately 75% of global deaths, with 79% occurring in low- and middle-income countries. Tobacco use remains a major modifiable risk factor, contributing to more than 8 million deaths annually. In Zambia, evidence on tobacco use among individuals with hypertension, diabetes mellitus, and cardiovascular disease remains limited. This study assessed the prevalence and determinants of tobacco use among adults with NCDs in Zambia. Methods: We conducted a secondary analysis of the 2017 Zambia STEPS survey. The analytic sample included 716 adults aged 18-69 years with self-reported hypertension, diabetes, and/or cardiovascular disease. Tobacco use was defined as current smoking or smokeless tobacco use. Multivariable logistic regression was used to estimate adjusted odds ratios (AORs), accounting for the complex survey design. Results: Among 716 participants, 65.5% had hypertension, 7.7% diabetes, and 26.8% cardiovascular disease; 89.5% had multimorbidity. The overall prevalence of tobacco use was 12.2%. Prevalence was 12.2% among those with hypertension, 5.5% among those with diabetes, and 14.1% among those with cardiovascular disease. Tobacco use was significantly higher among males. Female sex was associated with lower odds of tobacco use (AOR = 0.16, 95% CI: 0.05-0.54, p = 0.004). Secondary education (AOR = 0.15, 95% CI: 0.03-0.66) and higher education (AOR = 0.04, 95% CI: 0.01-0.44) were protective. Alcohol consumption increased the odds of tobacco use (AOR = 5.23, 95% CI: 1.17-23.28). Conclusion: Tobacco use remains common among adults with NCDs in Zambia. Integration of tobacco cessation interventions into routine NCD care is urgently needed.

Manufacturers are adopting propellants for use in pressurized metered-dose inhalers (pMDIs) that have lower global warming potentials (GWPs) than the propellants traditionally used in pMDIs. Hydrofluoroalkane (HFA)-134a has been used as the propellant in the pMDI used to deliver the fixed-dose triple combination of budesonide, glycopyrrolate and formoterol fumarate (BGF); following successful clinical evaluation, the BGF pMDI is now being transitioned to the next generation propellant hydrofluoroolefin (HFO)-1234ze(E), which has near-zero GWP. We describe formulation development efforts that led to selection of HFO-1234ze(E) over another propellant, HFA-152a, for reformulation. Propellant-specific studies evaluated active pharmaceutical ingredient (API) stability and aerodynamic particle size distribution (aPSD). Those analyses have been complemented by in silico regional lung deposition modeling conducted after the clinical evaluation of the reformulated BGF pMDI. HFO-1234ze(E) supported favorable stability and aPSD characteristics for BGF pMDI reformulation, compared with HFA-152a, and modeling predicted regional deposition consistent with therapeutic intent. Given that each pMDI is a unique combination of APIs, device, propellant, and excipients, propellant substitution requires product-specific evidence and regulatory approval, and typically takes several years. Targeted analyses, such as those described here, helped to identify the most suitable candidate propellant for successful substitution in the BGF pMDI. HighlightsO_LIFormulation development efforts that led to evaluation of a budesonide-glycopyrrolate-formoterol fumarate pressurized metered-dose inhaler (BGF pMDI) reformulated with the next generation propellant HFO-1234ze(E) in a clinical trial program are described; the suitability of another propellant, HFA-152a, was also assessed C_LIO_LIOver 6 months under accelerated storage conditions (40{degrees}C/75% relative humidity [RH]), the HFA-152a formulation approached and, in one replicate, fell below the 90% of formulation label claim threshold of evaluation, whereas the original HFA-134a product and the HFO-1234ze(E) formulation remained above that threshold C_LIO_LIOver 6 months under accelerated storage conditions (40{degrees}C/75% RH) and 18 months under long-term stability storage conditions (25{degrees}C/60% RH), the fine particle mass and fine particle fraction for all active pharmaceutical ingredients (APIs) showed that the HFO-1234ze(E) formulation tracked more closely than the HFA-152a formulation to the original HFA-134a product C_LIO_LILater in silico modeling, conducted after clinical testing, predicted a trend for greater deposition of APIs in early airway generations with HFA-152a, whereas HFO-1234ze(E) was predicted to more closely match HFA-134a, indicating a greater likelihood of achieving equivalence to the original HFA-134a product with HFO-1234ze(E) than with HFA-152a C_LIO_LIBased on these analyses and other formulation development efforts, HFO-1234ze(E) was identified as the most suitable propellant for reformulation of the BGF pMDI; for HFA-152a, analyses raised concerns about storage stability, and differences in aerosol characteristics that can impact API deposition in the lungs and, in turn, efficacy C_LI

Background and Aims: Synthetic opioids cause tens of thousands of deaths each year in North America, and there are indications that synthetic opioids are also becoming increasingly prevalent in the European drug market. This study aimed to examine high-risk substance use in the German drug-using community with a particular focus on the synthetic opioids fentanyl and nitazenes and related awareness, concerns, overdose experiences, and harm-reduction behavior. Design: Cross-sectional, observational online survey. Setting: Open drug-use scenes, addiction clinics, and substitution practices at numerous geographic locations throughout Germany, August to September 2025. Participants: 235 individuals aged 14+ from the drug using community (mean age 43.4 years; 57.9% male), 79.6% recruited by peers in open drug-use scenes. Measurements: The primary outcome was substances used within the past 12 months. In addition, sources, forms, routes of administration, and perceived changes in availability and price of (synthetic) opioids were assessed as well as risk perceptions, fears, harm-reduction behavior, and overdose-related experiences. Findings: 227 respondents reported substance use with an average of 6.2 substances, and 73.1% (95% confidence interval [CI] = 67.0-78.5%) had used at least one opioid in the past year. Synthetic opioids were consumed in many parts of Germany and across all age and gender groups. Among participants who experienced a shortage of their primary opioid in the past year, 25% (95% CI = 15.8-37.2%) reported having used fentanyl instead. 56.5% (95% CI = 36.8-74.3%) of individuals using synthetic opioids reported having experienced an overdose in the past twelve months. Most of the respondents perceived synthetic opioids as posing a high risk, and a substantial proportion expressed fear that they could be mixed into their own substances. However, only 9.9% (95% CI = 6.6-14.7%) use drug checking, although the vast majority stated they would use it if it were available to them. Conclusions: Synthetic opioids, including fentanyl and nitazenes, have entered the German drug scene, with users reporting high rates of overdose and limited access to harm reduction measures. Germany may be in an early phase of a synthetic opioid transition, warranting urgent expansion of surveillance, naloxone distribution, and drug checking services.

BackgroundEvidence suggests steeper accelerating opioid-related overdose, and non-medical use rates, in middle aged men in recent years compared with younger cohorts. Little is known about whether this is driven by age-related differences in the effects of opioids compared with socio-cultural factors driving non-medical consumption. Rodent models can be useful for dissociating biological from psychosocial factors, however, only minimal evidence exists on the effects of opioids in middle-age rats. ObjectiveTo determine if the anti-nociceptive and rewarding effects of opioids differ between adult and middle-age rats. MethodsFemale and male Wistar rats were obtained in early adulthood and examined across 4 to 11 months of age for nociceptive responses to heroin (0-1.56 mg/kg, s.c.) using a warm-water tail withdrawal assay. Subgroups (N=8 per group) were initiated on intravenous self-administration (IVSA) of heroin at either 5 months or 12 months of age. ResultsAnti-nociceptive effects of heroin did not differ across age. Female rats that initiated IVSA in early adulthood or middle-age obtained significantly more infusions of heroin than male rats of the same age during acquisition, and in dose-substitution under a FR1 schedule. Male, but not female, rats that initiated IVSA in middle age self-administered less heroin then rats that initiated in early adulthood; this was observed in acquisition and in dose-substitution. DiscussionThis study shows that opioid reward is diminished in middle aged male rats. It also found that middle age rats can be used effectively to model opioid-related outcomes, including drug seeking using the IVSA procedure.

Background/Objectives: Influenza infection is a major trigger of pneumonia and acute exacerbations among patients with chronic obstructive pulmonary disease (COPD). However, national laboratory-confirmed evidence on influenza vaccine effectiveness (VE) in this high-risk population remains limited. This study aimed to estimate the effectiveness of seasonal influenza vaccination against influenza-associated pneumonia and COPD exacerbations among patients with COPD in Thailand.Methods: We conducted a nationwide retrospective test-negative design study using administrative healthcare data from the National Health Security Office linked with laboratory-confirmed influenza surveillance data between June 1, 2013, and May 31, 2025, covering twelve influenza seasons (2013-2024). COPD-related clinical episodes among patients aged [&ge;]40 years who presented with pneumonia or acute exacerbation of COPD and underwent RT-PCR testing for influenza were included. Multilevel Poisson regression models were used to estimate adjusted risk ratios (RRs), and VE was calculated as (1 - adjusted RR) x 100.Results: A total of 606,072 COPD-related clinical episodes were included, of which 192,224 (31.7%) were influenza-positive. The overall adjusted VE against influenza-associated pneumonia was 63.2% (95% CI: 62.5-64.0), while VE against influenza-associated COPD exacerbations was 67.0% (95% CI: 48.8-78.8). VE estimates were broadly similar across age groups and remained substantial across COPD severity strata. Although point estimates were numerically higher in severe and very severe COPD, subgroup differences should be interpreted cautiously.Conclusions: Seasonal influenza vaccination was associated with substantial protection against influenza-associated pneumonia and COPD exacerbations among patients with COPD in Thailand.

Background: Genome-wide association studies (GWAS) have identified numerous lung cancer susceptibility loci based on single nucleotide polymorphisms (SNPs), yet a substantial proportion of heritability remains unexplained. We therefore evaluated germline copy number variants (CNVs) as an underexplored source of genetic susceptibility and potential contributors to genomic instability in lung cancer. Methods: We conducted a genome-wide analysis of germline CNVs using 19,342 cases and 15,917 controls from the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium, with replication in two independent cohorts. High-confidence CNVs were identified by integrating two CNV callers including PennCNV and modSaRa2. Association analyses were performed using both gene-based and CNV region-based approaches. Polygenic risk scores (PRS) were constructed from top loci, and functional validation was conducted using siRNA-mediated knockdown in lung fibroblast cells. Results: We identified CNVs in four genomic regions (1p36.22, 2q31.2, 6p21.32, and 19q13.32) significantly associated with lung cancer risk. Two loci (1p36.22 and 2q31.2) were consistently supported across both analytical strategies. A CNV-based PRS constructed from key genes (CLCN6, NFE2L2, OPA3, and PSMB8) was significantly associated with lung cancer risk and replicated across independent datasets. Functional assays demonstrated that knockdown of NFE2L2 and OPA3 increased endogenous DNA damage, supporting a role in genomic stability. Conclusions: Germline CNVs contribute to lung cancer susceptibility and may influence carcinogenesis through mechanisms related to genomic instability. Impact: These findings expand the genetic architecture of lung cancer and highlight CNVs as potential biomarkers for improving risk stratification and informing precision prevention strategies.

Background: Despite the significant risks associated with online substance procurement (SP), few researchers have examined this practice in U.S. youth. The studies that do exist are cross-sectional and cannot temporally connect specific digital behaviors to online SP. This longitudinal cohort study examined youth SP and digital media habits to determine whether use of certain smartphone applications correlated with increased odds of online SP or being contacted online about procuring drugs or alcohol. Methods: A cohort of U.S. youth (aged 15-20) with a history of non-daily substance use in the 3 months prior to enrollment was recruited to use the digital phenotyping smartphone application EARS for 90 days. On a nightly basis, participants were asked to complete surveys about online experiences related to SP and instances of substance use. Smartphone-generated screen use data were also collected passively each day. Results: Out of 112 enrolled participants, 106 were able to be included in analyses. Over approximately 3 months, 28.3% of participants (n=30) reported a collective 91 instances where they used social media to acquire drugs or alcohol. Screen use data demonstrated temporal relationships between social media SP and applications previously connected to the social media drug-purchasing process (e.g., TikTok, encrypted apps), as well as other school-specific social media. Discussion: Our results provide critically needed research evidence to support a body of literature composed predominantly of anecdotal reports. Despite measures taken by social media companies to prevent use of their platforms for drug procurement, underage youth continue to engage in this practice.

Objectives In Quebec, Canada, vaccination against human papillomavirus (HPV) has been publicly-funded since January 2016 for gay, bisexual, and other men who have sex with men (GBM) aged [&le;]26 years. The study aimed to analyze data collected in Greater Montreal (Engage study) to evaluate the HPV vaccination program for GBM in Quebec. Study Design Engage is a cohort of sexually active GBM aged [&ge;]16 recruited via respondent-driven-sampling (RDS) in Canada. Participants completed a questionnaire and tested for sexually transmitted infections. Methods RDS-II weights were applied to adjust for recruitment. Subgroups were compared using standardized mean differences. Odds ratios of HPV vaccination and prevalence ratios of anal HPV infection adjusted for potential confounders were estimated using robust regression models. Results Of 1179 participants, 309 were eligible for free HPV vaccination. Vaccine coverage among eligible GBM was 42%. Among those who disclosed same-sex sexual activity and discussed HPV vaccination with their healthcare provider, coverage reached 82%. Anal HPV prevalence among eligible GBM was 26.5% for [&ge;]1 HPV-6/11/16/18 genotypes without significant difference between vaccinated and unvaccinated individuals. Among unvaccinated GBM aged [&le;]26 who were aware of the vaccine, 60% intended to get vaccinated within the next year. Conclusions One to two years after GBM aged [&le;]26 were included in the Quebec HPV vaccination program, 42% of eligible GBM in Greater Montreal had been vaccinated. Anal HPV prevalence was high among GBM. Vaccinees were more likely to self-report a prior STI diagnosis. Offering vaccination to all preadolescents in schools appears essential to maximize vaccination benefits.

RationalePrenatal alcohol exposure (PAE) can result in Fetal Alcohol Spectrum Disorder (FASD), which consists of a group of diagnosable medical conditions that can include an increased risk for anxiety disorders and/or alcohol misuse, and sensory issues, such as increased mechanical sensitivity. ObjectiveThis study investigated how a single moderate PAE on gestational day 12 (G12) alters anxiety-like behavior, ethanol (EtOH) intake, and mechanical sensitivity across the lifespan of Sprague Dawley rats. MethodsPregnant dams were exposed to vaporized EtOH or room air (control) for 6 hours (BECs [~]108 mg/dL). Testing in male and female offspring began at three different ages: juveniles ([~]postnatal day (P) 25), adolescents ([~]P45) and adults ([~]P80). ResultsThe greatest PAE effects were observed in adolescent animals, with alterations in anxiety-like behaviors demonstrated in the light-dark box and elevated plus maze. Additionally, adolescent female animals consumed more sweetened EtOH compared to males. However, PAE adolescent animals consuming less sweetened EtOH compared to their counterparts, which was also observed in adult PAE females. Interestingly, this effect is reversed in juvenile and adolescent males when tested with unsweetened EtOH, with juvenile females consuming more EtOH also. Finally, PAE and air animals exhibited increased mechanical sensitivity following post-natal EtOH consumption across all ages. ConclusionThese data demonstrate that there are age- and sex-specific effects of PAE on anxiety-like behaviors, EtOH intake, and mechanical sensitivity that are more distinct in adolescent animals.

Background and Aims: The North American overdose crisis is increasingly characterized by complex polysubstance use alongside a transition from injecting to smoking unregulated opioids. However, transitions involving multiple substances remain understudied. We characterized longitudinal transitions in the route of administration and frequency of heroin, fentanyl, and methamphetamine use and examined whether these transitions differed by multilevel factors hypothesized to influence patterns of polysubstance use and routes of administration over time. Design: People who inject drugs (PWID) enrolled in a cohort study completed baseline surveys (October 2020-2021) and three biannual follow-up visits (through April 2023). Setting: San Diego, California, and Tijuana, Baja California. Participants: Among 612 PWID, median age was 43 years; most were male (74%), Hispanic, Latino, or Mexican (72%), and San Diego residents (67%). Measurements: Based on past six-month substance use behaviors reported at each visit, we categorized participants according to six indicators over time: low- (< weekly) and high-frequency ([&ge;] weekly) smoking and injecting of heroin, fentanyl, and methamphetamine. We then used latent transition analysis (LTA) to identify distinct subgroups of participants with respect to these indicators at baseline and examine transitions between them over 18 months. We fit models with 2-5 subgroups, selecting the final model based on fit and interpretability and used multiple-groups LTA to examine differences in subgroup transitions by multilevel factors. Findings: We identified four subgroups: Subgroup 1 (Heroin-Methamphetamine Polyroute), characterized by high-frequency heroin and methamphetamine smoking and injection, included 22% of participants at baseline but 0% at 18 months. Subgroup 2 (Methamphetamine-dominant Smoking), characterized by high-frequency methamphetamine smoking, accounted for 14% of participants at baseline and 18 months. Subgroup 3 (Fentanyl-Methamphetamine Smoking), characterized by high-frequency fentanyl and methamphetamine smoking, included 4% of participants at baseline and 21% at 18 months. Subgroup 4 (Heroin-dominant Injecting), characterized by high-frequency heroin injection, included 61% of participants at baseline and 65% at 18 months. Participants in Subgroup 1 primarily transitioned to Subgroups 3 and 4 over time. Larger increases in Subgroup 3 prevalence occurred for participants who, at baseline, experienced homelessness, resided in San Diego (vs. Tijuana), received syringes from a syringe services program, and overdosed in the past six months. Conclusions: PWID in this region increasingly transitioned from high-frequency heroin and methamphetamine injection toward fentanyl and methamphetamine smoking, likely reflecting shifts in drug availability. Results highlight the need for multilevel interventions that address health harms resulting from polysubstance smoking alongside continued injection.

RationaleCholinergic signalling is critical for attentional control and signal detection, yet the contribution of specific acetylcholine receptor (AChR) subtypes remains poorly understood. Although the 7 nicotinic AChR (nAChR) holds promise as a target for cognition-enhancing therapy, clinical findings to date have been inconsistent. ObjectiveTo investigate the effects of putative cognitive enhancing drugs, including those targeting cholinergic transmission and 7 nAChRs on a visual signal detection task (SDT). MethodsMale and female Sprague Dawley rats were trained on an SDT. Cholinergic transmission was probed systemically with nicotinic and muscarinic receptor antagonists (mecamylamine and scopolamine), a cholinesterase inhibitor (galantamine), an M4-AChR positive allosteric modulator (PAM; VU0467154), an 7 nAChR antagonist (MLA), an 7 nAChR PAM (CCMI), and an 7 nAChR partial agonist (SSR-180,711). Dopaminergic transmission was probed using the catechol-O-methyltransferase (COMT) inhibitor, tolcapone. A novel, trial-level signal detection theory-based generalised linear mixed-effects model (SDT-GLMM) was used to index response bias and perceptual sensitivity (d'), the latter reflecting subjects ability to discriminate signal from noise. ResultsMecamylamine profoundly impaired SDT performance across all measures. Galantamine significantly improved d' at moderate doses but not when a distractor was present. MLA uniquely produced dose-dependent improvements in d' that were preserved under distraction. In contrast, positive allosteric modulation and agonism of 7 nAChRs impaired task performance. Scopolamine, VU0467154, and tolcapone had no consistent or interpretable effects on signal detection. ConclusionsThis work demonstrates that 7 nAChR modulation bidirectionally and dose-dependently regulates perceptual sensitivity, irrespective of attentional distraction. These findings have implications for targeted cognitive enhancement in disorders of attention.

Objectives: To examine COVID19 vaccine uptake among people diagnosed with sexually transmitted and bloodborne infections (STBBI) and reported methamphetamine users in Manitoba, Canada, during the acute phase of the COVID19 pandemic. Methods: We conducted a retrospective matched cohort study using linked population based administrative healthcare, laboratory, and vaccination databases in Manitoba. Individuals aged 16+ years with laboratory confirmed chlamydia/gonorrhea (CT/NG), syphilis, HIV, and/or documented methamphetamine use during the four years prior to March 1, 2020 were included in eight exposed cohorts. Each cohort was matched to unexposed comparators on age, sex, geographic region, and income quintile. The primary outcome was receipt of 2+ COVID19 vaccine doses between December 1, 2020 and March 31, 2022. Poisson regression models estimated adjusted rate ratios (aRRs) and 95% confidence intervals (95% CIs) for vaccine uptake. Results: Compared with matched comparators, most exposed cohorts were less likely to complete the COVID19 primary vaccine series. Individuals in the Syphilis Only (aRR: 0.87, 95% CI: 0.85 0.90), Syphilis Plus (aRR: 0.84, 95% CI: 0.81 0.86), CT/NG Only (aRR: 0.95, 95% CI: 0.94 0.96), CT/NG Plus (aRR: 0.82, 95% CI: 0.80 0.85), Methamphetamine Only (aRR: 0.78, 95% CI: 0.76 0.80), and Methamphetamine + STBBI cohorts (aRR: 0.74, 95% CI: 0.72 0.77) had significantly lower vaccine uptake. The HIV Only cohort did not differ significantly from matched comparators (aRR: 0.98, 95% CI: 0.95 1.01). Lower uptake was concentrated among individuals living in lower-income areas. Conclusions: People diagnosed with STBBI and methamphetamine users in Manitoba experienced significant inequities in COVID19 vaccine uptake, particularly those with STBBI coinfections and concurrent substance use. Integrated vaccination approaches linked with HIV, harm reduction, and addiction services may improve vaccine equity during future public health emergencies.

Opioid withdrawal is associated with heightened pain sensitivity, including allodynia. Although opioid-induced allodynia is well-documented in humans and animal models, the relationship between the severity of opioid withdrawal-induced allodynia and individual addiction-like behaviors remains poorly understood. To address this gap, Heterogeneous Stock rats underwent long access (12 hours/day) intravenous oxycodone self-administration, followed by measurement of mechanical sensitivity at six timepoints across three weeks of abstinence. Rats were stratified by an Addiction Index derived from individual differences in the escalation of oxycodone intake, motivation to consume oxycodone, tolerance to oxycodones analgesic effects, and acute withdrawal-induced mechanical pain sensitivity. Here, we show that oxycodone withdrawal induces significant and prolonged allodynia for up to three weeks, with High Addiction Index rats exhibiting greater intensity and longer duration of pain sensitivity than Low Addiction Index rats. Results remained consistent even when excluding allodynia from the Addiction Index, highlighting the robustness of the association between addiction-like severity and protracted allodynia. Linear regression associations revealed that self-administration behaviors, particularly oxycodone intake escalation and motivation to seek oxycodone, predicted subsequent withdrawal-induced allodynia severity. These findings demonstrate that greater addiction-like severity is associated with more intense and prolonged withdrawal-induced pain, supporting mechanical allodynia as a marker of addiction severity. These results motivate future work to define the mechanisms linking addiction severity to protracted opioid withdrawal-induced pain, with the goal of informing targeted clinical interventions for individuals most susceptible to severe abstinence-related allodynia.

Current treatments for opioid use disorder (OUD) have major barriers to access. As such, researching new potential therapies for OUD is important to public health. Previous research has implicated glucagon-like peptide-1 (GLP-1) receptor agonists in decreasing the use of addictive substances by animals. In this study, female Wistar rats (N=32) were surgically implanted with jugular catheters and trained to self-administer fentanyl at a fixed-ratio 1 (FR1) schedule of reinforcement for 21 sessions under short- (ShA; 1 hour) or long-access (LgA; 8 hours) conditions. Next, the animals received injections of semaglutide (0.1 mg/kg, s.c.) or saline (0.9% NaCl, s.c.) prior to another FR1 session. The animals underwent a progressive ratio (PR) schedule of reinforcement while receiving saline (i.v.) or fentanyl (0.625-10 {micro}g/kg/inf, i.v.) and semaglutide (0.1 mg/kg, s.c.) or saline (s.c.). Next, the animals underwent a semaglutide (0-0.1 mg/kg, s.c.) dose response procedure at FR1 and a single dose of fentanyl (2.5 {micro}g/kg/inf, i.v.). Following drug discontinuation, spontaneous locomotor activity and withdrawal-like symptoms were measured. Semaglutide dose-dependently decreased fentanyl rewards under ShA and LgA conditions (p<0.05). Under a PR, semaglutide significantly decreased breakpoint (p<0.05), suggesting semaglutide decreases motivation to self-administer fentanyl. Semaglutide-treated ShA animals displayed significantly less withdrawal-like behavior (p<0.05) but not LgA animals. Overall, these findings suggest semaglutide may modulate motivation to seek opioid reward and could be useful in the development of pharmacotherapies to address OUD.