Interaction Between State-Level Cigarette Prices and County-Level Tobacco 21 Coverage on Cigarette Smoking Outcomes Among US Adolescents.

PURPOSE: To examine whether Tobacco 21 (T21) law coverage moderated associations between cigarette prices and adolescent smoking and associated disparities. METHODS: We used nationally representative, repeated cross-sectional 2014-2020 Monitoring the Future study data (n = 20,547-96,083) to examine associations between state-level average cigarette price per pack and county-level T21 coverage (100% vs. < 100%) on past 30-day smoking participation, first and daily cigarette smoking initiation, and smoking intentions in US adolescents in eighth, 10th, and 12th grade. We implemented weighted, grade-stratified, modified Poisson regression models to test for interactions between price and T21 coverage for each outcome. We also tested for disparities by sex, race and ethnicity, parental education, and college educational expectations. RESULTS: Higher cigarette prices were associated with a lower probability of past 30-day smoking participation among eighth graders in counties with < 100% T21 coverage (average marginal effect = -0.003, 95% confidence interval = -0.006, 0.000) but not among eighth graders in counties with 100% T21 coverage (average marginal effect = 0.001, 95% confidence interval = -0.001, 0.004) (p for interaction = 0.005). There were no associations with other smoking outcomes or grades or evidence of differential associations by sociodemographic factors. DISCUSSION: Our findings suggested that higher cigarette prices were associated with lower adolescent smoking among eighth graders living in counties with < 100% T21 coverage. However, no such association was observed in other grades or smoking outcomes. Further investigation is necessary to determine the best combination of policies to reduce adolescent smoking, related sociodemographic disparities, and the use of other tobacco products in areas with fewer tobacco control policies.

Focused ultrasound ablation of melanoma with boiling histotripsy yields abscopal tumor control and antigen-dependent dendritic cell activation.

Background: Boiling histotripsy (BH), a mechanical focused ultrasound ablation strategy, can elicit intriguing signatures of anti-tumor immunity. However, the influence of BH on dendritic cell function is unknown, compromising our ability to optimally combine BH with immunotherapies to control metastatic disease. Methods: BH was applied using a sparse scan (1 mm spacing between sonications) protocol to B16F10-ZsGreen melanoma in bilateral and unilateral settings. Ipsilateral and contralateral tumor growth was measured. Flow cytometry was used to track ZsGreen antigen and assess how BH drives dendritic cell behavior. Results: BH monotherapy elicited ipsilateral and abscopal tumor control in this highly aggressive model. Tumor antigen presence in immune cells in the tumor-draining lymph nodes (TDLNs) was ~3-fold greater at 24h after BH, but this abated by 96h. B cells, macrophages, monocytes, granulocytes, and both conventional dendritic cell subsets (i.e. cDC1s and cDC2s) acquired markedly more antigen with BH. BH drove activation of both cDC subsets, with activation being dependent upon tumor antigen acquisition. Our data also suggest that BH-liberated tumor antigen is complexed with damage-associated molecular patterns (DAMPs) and that cDCs do not traffic to the TDLN with antigen. Rather, they acquire antigen as it flows through afferent lymph vessels into the TDLN. Conclusion: When applied with a sparse scan protocol, BH monotherapy elicits abscopal melanoma control and shapes dendritic cell function through several previously unappreciated mechanisms. These results offer new insight into how to best combine BH with immunotherapies for the treatment of metastatic melanoma.

Distress about social problems and tobacco and cannabis use outcomes among young adults in Los Angeles County.

OBJECTIVE: To examine associations of concern, worry, and stress about discrimination, shootings/violence, and police brutality and exclusive and dual tobacco and cannabis use among young adults. METHODS: A prospective, racially/ethnically diverse cohort of young adults (n = 1960) living in Los Angeles, California completed a baseline survey in 2020 (age range: 19-23) and a follow-up survey in 2021. Exploratory factor analysis (EFA) was employed on nine variables assessing levels of concern, worry, and stress about societal discrimination, societal shootings/violence, and community police brutality at baseline. Past 30-day tobacco and cannabis use at follow-up was categorized as current exclusive tobacco, exclusive cannabis, and dual tobacco and cannabis (vs never/former) use based on eleven use variables. Multinomial logistic regressions estimated adjusted associations between each factor score (translated to standard deviation units) with exclusive and dual tobacco and cannabis use. RESULTS: The EFA produced four factor scores representing concern/worry/stress (i.e., distress) about community police brutality (F1), distress about societal shootings/violence (F2), and distress about societal discrimination (F3), as well as generalized stress about police brutality, shootings/violence, and discrimination (F4). F1, F2, and F3 were associated with subsequent exclusive current cannabis use, with F1 having the strongest association (OR: 1.35, 95% CI: 1.18-1.55), while only F1 (OR: 1.51, 95% CI: 1.27-1.78) was associated with dual tobacco and cannabis use. None of the factors were associated with exclusive tobacco use. CONCLUSIONS: Young adult concern, worry, and/or stress about social problems may increase risk of cannabis use with or without concurrent tobacco use 6-12 months later.

Discrimination and Tobacco Use Outcomes Among US Adults: Effect Modification by Race/Ethnicity.

INTRODUCTION: Racial/ethnic discrimination (hereafter, discrimination) is associated with tobacco use. However, little is known about the relationship between discrimination and dual/polytobacco use and tobacco use disorder (TUD), including how these relationships vary by race/ethnicity. METHODS: Data on adults 18 and older come from the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions-III (n = 35,881). Past-year discrimination was measured using the Experiences of Discrimination scale. Past 30-day exclusive, dual, and polytobacco use was measured as the mutually exclusive use of any combination of four types of tobacco products: cigarettes, electronic nicotine delivery systems, other combustibles (i.e., cigars and pipe), and smokeless tobacco. Past-year TUD was defined according to DSM-5 criteria. Associations between discrimination and exclusive, dual, and polytobacco use and discrimination and TUD were estimated using multinomial logistic regression and logistic regression, respectively. Models were stratified by race/ethnicity (i.e., Hispanic, non-Hispanic (NH) White, NH Black, another race/ethnicity) to assess effect modification. RESULTS: Adults who used tobacco and who had TUD was 24.2% and 19.2%, respectively. More discrimination was associated with higher odds of exclusive, dual, and polytobacco use as well as TUD. Models stratified by race/ethnicity suggest that discrimination was associated with dual/polytobacco use among NH Black adults (OR: 1.05, 95% CI: 1.002-1.11) and NH White adults (OR: 1.18, 95% CI: 1.13-1.22). While more discrimination was associated with TUD among all racial/ethnic groups, the relationship was the strongest for NH White adults. CONCLUSIONS: Discrimination was associated with more severe tobacco use outcomes among multiple racial/ethnic groups, but associations were the strongest for NH White adults.

Focused ultrasound ablation of melanoma with boiling histotripsy yields abscopal tumor control and antigen-dependent dendritic cell activation.

Background: Boiling histotripsy (BH), a mechanical focused ultrasound ablation strategy, can elicit intriguing signatures of anti-tumor immunity. However, the influence of BH on dendritic cell function is unknown, compromising our ability to optimally combine BH with immunotherapies to control metastatic disease. Methods: BH was applied using a sparse scan (1 mm spacing between sonications) protocol to B16F10-ZsGreen melanoma in bilateral and unilateral settings. Ipsilateral and contralateral tumor growth was measured. Flow cytometry was used to track ZsGreen antigen and assess how BH drives dendritic cell behavior. Results: BH monotherapy elicited ipsilateral and abscopal tumor control in this highly aggressive model. Tumor antigen presence in immune cells in the tumor-draining lymph nodes (TDLNs) was ~3-fold greater at 24h after BH, but this abated by 96h. B cells, macrophages, monocytes, granulocytes, and both conventional dendritic cell subsets (i.e. cDC1s and cDC2s) acquired markedly more antigen with BH. BH drove activation of both cDC subsets, with activation being dependent upon tumor antigen acquisition. Our data also suggest that BH-liberated tumor antigen is complexed with damage-associated molecular patterns (DAMPs) and that cDCs do not traffic to the TDLN with antigen. Rather, they acquire antigen as it flows through afferent lymph vessels into the TDLN. Conclusion: When applied with a sparse scan protocol, BH monotherapy elicits abscopal melanoma control and shapes dendritic cell function through several previously unappreciated mechanisms. These results offer new insight into how to best combine BH with immunotherapies for the treatment of metastatic melanoma.

Surrogacy validation for time-to-event outcomes with illness-death frailty models.

A common practice in clinical trials is to evaluate a treatment effect on an intermediate outcome when the true outcome of interest would be difficult or costly to measure. We consider how to validate intermediate outcomes in a causally-valid way when the trial outcomes are time-to-event. Using counterfactual outcomes, those that would be observed if the counterfactual treatment had been given, the causal association paradigm assesses the relationship of the treatment effect on the surrogate outcome with the treatment effect on the true, primary outcome. In particular, we propose illness-death models to accommodate the censored and semicompeting risk structure of survival data. The proposed causal version of these models involves estimable and counterfactual frailty terms. Via these multistate models, we characterize what a valid surrogate would look like using a causal effect predictiveness plot. We evaluate the estimation properties of a Bayesian method using Markov chain Monte Carlo and assess the sensitivity of our model assumptions. Our motivating data source is a localized prostate cancer clinical trial where the two survival outcomes are time to distant metastasis and time to death.

Cigarette Prices and Disparities in Smoking Cessation in the United States.

INTRODUCTION: Achieving cessation in people with established smoking patterns remains a challenge. Increasing cigarette prices has been one of the most successful strategies for lowering smoking rates. The extent to which it has remained effective in encouraging cessation among adults in recent years and how the effectiveness has varied by sociodemographic characteristics is unclear. AIMS AND METHODS: Using repeated cross-sectional data collected by the Tobacco Use Supplement of the Current Population Survey, we investigate the relationship between cigarette prices and cessation from 2003 to 2019 in adults at least 25 years old. We examine the associations between price and cessation in the population overall and by sex, race and ethnicity, and socioeconomic status. RESULTS: We found mixed support for associations between greater local prices and cessation. Unadjusted models showed that greater local prices were associated with greater odds of cessation, but the associations did not persist after controlling for sociodemographic characteristics. The associations did not significantly differ by respondent characteristics. Sensitivity analysis using alternative specifications and retail state price as the main predictor showed similar results. Sensitivity analysis with controls for e-cigarette use in the 2014-2019 period showed that greater local price was associated with cessation among adults with less than a high school degree. When stratified by year of data collection, results show that greater local prices were associated with cessation after 2009. CONCLUSIONS: Overall, the study adds to the conflicting evidence on the effectiveness of increasing prices on smoking cessation among adults with established smoking patterns. IMPLICATIONS: Higher cigarette prices have been one of the most successful tools for lowering smoking prevalence. It remains unclear how effective they have been in recent years in encouraging adults with established smoking patterns to quit. The study's results show that greater local prices were associated with higher odds of cessation, but the association did not persist after sociodemographic adjustment. In a sensitivity analysis, greater local price was associated with cessation among people with less than a high school degree in models controlling for e-cigarette use. We also found evidence that greater local price was associated with cessation after 2009. More comprehensive smoke-free coverage was also associated with greater odds of cessation. The study's results highlight that encouraging cessation among adults with an established smoking pattern remains a challenging policy problem even when cigarette prices rise.

Racial and Ethnic Disparities in Mental Health Problems and Tobacco and Cannabis Use Among US Emerging Adults.

INTRODUCTION: Mental health problems in emerging adulthood are linked to tobacco and cannabis use, but whether race and ethnicity modifies these associations is unclear. METHODS: We used data from wave 4 of the Population Assessment of Tobacco and Health Study (youth n = 6898, young adult n = 10,304) to conduct latent class analysis (LCA) of six past 30-day tobacco and cannabis use indicators (i.e., cigarettes, electronic nicotine delivery systems (ENDS), cigars, blunts, cannabis vaping, other cannabis). We estimated associations between past 30-day internalizing and externalizing (i.e., low (referent), moderate, high) problems and latent classes of tobacco/cannabis use (vs. never/former use) using adjusted multinomial logistic regression. We explored whether associations varied by race and ethnicity through stratification. RESULTS: We identified four exclusive use latent classes and two dual/poly use latent classes for both youth and young adult samples. Race/ethnicity-stratified models identified associations between internalizing/externalizing problems and most use classes for Hispanic and non-Hispanic White youth/young adults, with mixed results for non-Hispanic Black youth/young adults. For example, Hispanic (OR: 2.50, 95% CI: 1.09-5.74) and non-Hispanic White (OR: 1.90, 95% CI: 1.18-3.06) youth with high internalizing problems had higher odds of ENDS + cannabis vaping. Externalizing problems were not associated with use among non-Hispanic Black youth while internalizing problems were not associated with use among non-Hispanic Black young adults. CONCLUSION: We observed racial/ethnic variation in mental health problems and tobacco and cannabis use. Understanding mental health problem and tobacco product and cannabis use comorbidity may better inform culturally relevant interventions aimed to prevent and reduce use.

Efferocytosis by bone marrow mesenchymal stromal cells disrupts osteoblastic differentiation via mitochondrial remodeling.

The efficient clearance of dead and dying cells, efferocytosis, is critical to maintain tissue homeostasis. In the bone marrow microenvironment (BMME), this role is primarily fulfilled by professional bone marrow macrophages, but recent work has shown that mesenchymal stromal cells (MSCs) act as a non-professional phagocyte within the BMME. However, little is known about the mechanism and impact of efferocytosis on MSCs and on their function. To investigate, we performed flow cytometric analysis of neutrophil uptake by ST2 cells, a murine bone marrow-derived stromal cell line, and in murine primary bone marrow-derived stromal cells. Transcriptional analysis showed that MSCs possess the necessary receptors and internal processing machinery to conduct efferocytosis, with Axl and Tyro3 serving as the main receptors, while MerTK was not expressed. Moreover, the expression of these receptors was modulated by efferocytic behavior, regardless of apoptotic target. MSCs derived from human bone marrow also demonstrated efferocytic behavior, showing that MSC efferocytosis is conserved. In all MSCs, efferocytosis impaired osteoblastic differentiation. Transcriptional analysis and functional assays identified downregulation in MSC mitochondrial function upon efferocytosis. Experimentally, efferocytosis induced mitochondrial fission in MSCs. Pharmacologic inhibition of mitochondrial fission in MSCs not only decreased efferocytic activity but also rescued osteoblastic differentiation, demonstrating that efferocytosis-mediated mitochondrial remodeling plays a critical role in regulating MSC differentiation. This work describes a novel function of MSCs as non-professional phagocytes within the BMME and demonstrates that efferocytosis by MSCs plays a key role in directing mitochondrial remodeling and MSC differentiation. Efferocytosis by MSCs may therefore be a novel mechanism of dysfunction and senescence. Since our data in human MSCs show that MSC efferocytosis is conserved, the consequences of MSC efferocytosis may impact the behavior of these cells in the human skeleton, including bone marrow remodeling and bone loss in the setting of aging, cancer and other diseases.

Latent Classes of Tobacco and Cannabis Use among Youth and Young Adults in the United States.

Background: Research characterizing patterns of tobacco and cannabis use by product type and route of administration among youth and young adults (YAs) is limited. Methods: We conducted latent class analysis of tobacco and cannabis use (i.e., cigarettes, electronic nicotine delivery systems (ENDS), cigars, blunts, cannabis vaping, and other cannabis use (without blunting/vaping)) among youth (ages 15-17) and YAs (ages 18-24) who used at least one product in the past 30 days, using data from the Population Assessment of Tobacco and Health Study (Wave 4, 2016-2017). We used multinomial logistic regression models to examine associations between sociodemographic characteristics and use classes. Results: The latent use classes for youth included cigarettes (2.5%), ENDS (2.6%), blunts (2.5%), other cannabis (6.3%), ENDS + cannabis vaping (2.7%), and cigarettes + cigars + other cannabis (1.5%), while the latent use classes for YAs included cigarettes (11.7%), ENDS (3.9%), blunts (5.3%), other cannabis (7.0%), cigarettes + cigars (8.2%), and cigarettes + ENDS + cannabis vaping (4.9%). We compared use classes to never/former use for youth (82.0%) and YAs (59.0%) and found that they differed by each sociodemographic characteristic. For example, non-Hispanic Black YAs had higher odds of cigarettes + cigar use compared to non-Hispanic White YAs, whereas racial/ethnic minority youth and YAs had lower odds of other dual/poly use groups compared to their non-Hispanic White counterparts. Conclusions: We observed differences in use classes by sociodemographic characteristics for youth and YAs. Health professionals must consider tobacco and cannabis use patterns when implementing prevention and cessation interventions.

Rituximab induced cytokine release with high serum IP-10 (CXCL10) concentrations is associated with infusion reactions.

Monoclonal antibody induced infusion reactions (IRs) can be serious and even fatal. We used clinical data and blood samples from 37 treatment naïve patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) initiating therapy for progressive disease with a single 50 mg dose of intravenous (IV) rituximab at 25 mg/h. Twenty-four (65 %) patients had IRs at a median of 78 min (range 35-128) and rituximab dose of 32 mg (range 15-50). IR risk did not correlate with patient or CLL characteristics, CLL counts or CD20 levels, or serum rituximab or complement concentrations. Thirty-five (95 %) patients had cytokine release response with a ≥ 4-fold increase in serum concentration of ≥ 1 inflammatory cytokine. IRs were associated with significantly higher post-infusion serum concentrations of gamma interferon induced cytokines IP-10, IL-6 and IL-8. IP-10 concentrations increased ≥ 4-fold in all patients with an IR and were above the upper limit of detection (40,000 pg/ml) in 17 (71 %). In contrast, to only three (23 %) patients without an IR had an ≥ 4-fold increase in serum concentrations of IP-10 (highest 22,013 pg/ml). Our data suggest that cytokine release could be initiated by activation of effector cells responsible for clearance of circulating CLL cells with IRs occurring in those with higher levels of gamma interferon induced cytokines. These novel insights could inform future research to better understand and manage IRs and understand the role of cytokines in the control of cytotoxic immune responses to mAb.

Racial/ethnic discrimination and tobacco and cannabis use outcomes among US adults.

INTRODUCTION: Racial/ethnic discrimination (hereafter, discrimination) is associated with use of individual tobacco and cannabis products. However, we know little about how discrimination affects dual/polytobacco and cannabis use and associated use disorders. METHODS: We used cross-sectional data on adults (18+) from the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions-III (n = 35,744). We defined past-year discrimination as a summary scale (range: 0-24) based on six scenarios. We created a mutually exclusive six-category use variable: noncurrent, individual tobacco and noncannabis, individual tobacco and cannabis, individual cannabis and nontobacco, dual/polytobacco and noncannabis, and dual/polytobacco and cannabis based on past 30-day tobacco use of four products (i.e., cigarettes, electronic nicotine delivery systems, other combustibles (cigars, pipe), smokeless tobacco) and cannabis use. We also examined past-year tobacco use disorder (TUD) and cannabis use disorder (CUD) as a four-level variable: no disorders, TUD only, CUD only, and TUD and CUD. We estimated associations between discrimination and each outcome using adjusted multinomial logistic regression and assessed effect modification by stratifying adjusted models by race/ethnicity (i.e., Hispanic, non-Hispanic (NH) White, NH Black, and another race/ethnicity). RESULTS: Experiencing more discrimination was associated with each outcome but was most strongly associated with dual/polytobacco and cannabis use (OR: 1.13, 95 % CI: 1.07-1.19) and joint TUD and CUD (OR: 1.16, 95 % CI: 1.12-1.20). Models stratified by race/ethnicity showed that discrimination was associated with dual/polytobacco and cannabis only among NH White adults, and with joint TUD and CUD only among NH Black and NH White adults. CONCLUSIONS: Discrimination was associated with tobacco and cannabis use outcomes among multiple adult racial/ethnic populations, but associations were more profound for NH White and NH Black adults than adults from other racial/ethnic populations.

Differential impact of the Canadian point-of-sale tobacco display bans on quit attempts and smoking cessation outcomes by sex, income and education: longitudinal findings from the ITC Canada Survey.

SIGNIFICANCE: This study examines the differential effects of Canadian point-of-sale (POS) tobacco display bans across provinces on quit attempts and smoking cessation, by sex, education and income. METHODS: We analysed survey data from five waves (waves 4-8) of the International Tobacco Control Canada Survey, a population-based, longitudinal survey, where provinces implemented display bans between 2004 and 2010. Primary outcomes were quit attempts and successful cessation. We used generalised estimating equation Poisson regression models to estimate associations between living in a province with or without a POS ban (with a 24-month threshold) and smoking outcomes. We tested whether these associations varied by sex, education and income by including interaction terms. RESULTS: Across survey waves, the percentage of participants in provinces with POS bans established for more than 24 months increased from 5.0% to 95.8%. There was no association between POS bans and quit attempts for provinces with bans in place for 0-24 months or more than 24 months, respectively (adjusted relative risk (aRR)=0.99, 95% CI: 0.89 to 1.10; 1.03, 95% CI: 0.88 to 1.20). However, we found a differential impact of POS bans on quit attempts by sex, whereby bans were more effective for women than men for bans of 0-24 months. Participants living in a province with a POS ban for at least 24 months had a higher chance of successful cessation (aRR=1.49; 95% CI: 1.08 to 2.05) compared with those in a province without a ban. We found no differences in the association between POS bans and quit attempts or cessation by education or income, and no differences by sex for cessation. CONCLUSION: POS bans are associated with increased smoking cessation overall and more quit attempts among women than men.

Televised Anti-Tobacco Media and Smoking Outcomes Among Heterosexual and Sexual Minority Adults in the United States.

BACKGROUND: The prevalence of smoking is higher among sexual minority (SM) individuals compared with heterosexuals. The impact of televised anti-tobacco mass media campaigns on smoking outcomes among SMs is not known. AIMS: We examined whether televised anti-tobacco advertising was differentially associated with current smoking and smoking intensity for SM and heterosexual adults. METHOD: We combined county-level anti-tobacco advertising data (gross rating points) with restricted, geocoded individual-level National Health Interview Survey data on smoking (2013-2015). We estimated associations between advertising and smoking outcomes, including potential effect modification by SM status. RESULTS: Greater anti-tobacco advertising exposure was associated with lower smoking prevalence (prevalence ratio [PR] = 0.97; 95% confidence interval [CI] = [0.94, 1.00]). Although the direction of the association differed for heterosexual and SM adults, differences were not statistically significant. No significant associations were observed with regard to smoking intensity. CONCLUSION: Associations between anti-tobacco advertising and smoking were not significantly different for heterosexual and SM adults.

Exploring the Potential for Smoke-Free Laws to Reduce Smoking Disparities by Sexual Orientation in the USA.

BACKGROUND: We examined associations between smoke-free laws and smoking outcomes in a nationally representative sample of US adults, including exploring whether these associations differed for heterosexual and sexual minority (SM) adults. METHODS: We constructed county-level variables representing the percent of the population covered by state-, county-, or city-level smoke-free laws in workplaces and hospitality venues. We combined this information with restricted individual-level adult data with masked county identifiers from the National Health Interview Survey (NHIS), 2013-2018. We used modified Poisson regression to explore associations between each type of smoke-free law and the prevalence ratio (PR) of current smoking, and we used linear regression to explore associations with smoking intensity (mean cigarettes per day). We assessed interactions between smoke-free laws and SM status on the additive scale to determine whether associations were different for SM and heterosexual adults. RESULTS: In adjusted models without interaction terms, smoke-free laws in hospitality venues were associated with lower prevalence of current smoking (PR = 0.93, 95% confidence interval (CI) = 0.89, 0.98). Both types of smoke-free laws were associated with lower mean cigarettes per day (workplace law change in mean = - 0.50, 95% CI = - 0.89, - 0.12; hospitality law change in mean = - 0.72, 95% CI = - 1.14,-0.30). We did not observe any statistically significant interactions by SM status, though statistical power was limited. CONCLUSIONS: We did not find evidence that smoke-free laws were differentially associated with smoking outcomes for heterosexual and SM adults. Additional studies are needed to further explore the potential for tobacco control policies to address the elevated risk of smoking in SM communities.

Impact of the Tips From Former Smokers Anti-Smoking Media Campaign on Youth Smoking Behaviors and Anti-Tobacco Attitudes.

INTRODUCTION: Anti-tobacco media campaigns can prevent youth smoking, but there is little research on how adult-targeted campaigns affect youth. We investigated the association between the Tips From Former Smokers (Tips) campaign and youth smoking behaviors and anti-tobacco attitudes, and variation by sex, race and/or ethnicity, or socioeconomic status. AIMS AND METHODS: We used data from the monitoring of the future study, a nationally representative survey on 8th, 10th, and 12th graders, from 2013-2015. Quartiles of Tips gross rating points (GRPs) were used to estimate exposure. Youth smoking behavior outcomes included smoking prevalence, initiation, and susceptibility. The anti-tobacco attitude outcomes included the extent that anti-tobacco ads made participants (1) less favorable towards smoking or (2) less likely to smoke cigarettes. Modified Poisson regression models estimated average marginal effects; separate additive interactions between Tips GRP exposure and sex, race and/or ethnicity, parents' highest education, and college plans (12th graders only) were used to test for effect modification. RESULTS: Tips GRPs were not associated with smoking behaviors within any grade. However, 12th graders in the highest quartile of Tips had a 7.0 percentage point higher probability (95% CI = 0.023-0.116) of responding that anti-tobacco ads made them less likely to smoke. Tips GRPs were associated with a lower probability of past 30-day smoking prevalence among 10th grade females, but not males (joint P-value = .002). No additional statistically significant interactions were found for any other outcomes for any grade. CONCLUSIONS: This study revealed the potential for adult-targeted campaigns to increase youth's anti-smoking attitudes, but campaign exposure was not associated with smoking behaviors. IMPLICATIONS: Few studies have examined the potential for anti-smoking media campaigns to influence audiences outside their targeted audience. In this study, we show the potential for adult-targeted campaigns to impact youth and suggest that Tips exposure may promote anti-smoking attitudes among youth.

Tobacco 21 laws may reduce smoking and tobacco-related health disparities among youth in the U.S.

The goal of our study is to understand the impact of Tobacco 21 (T21) laws on youth smoking and health equity. We conducted modified Poisson regression models using 2014-2019 Monitoring the Future data to measure the impact of attending school in a county 100% covered by a T21 law versus counties with <100% T21 coverage on past 30-day smoking participation (n = 262,632), first cigarette smoking initiation (n = 189,698), and daily smoking initiation among 8th, 10th, and 12th graders (n = 214,496), separately. Additive interactions were tested between T21 coverage and sex, race/ethnicity, parental education, and college plans. T21 coverage was associated with a lower likelihood of smoking participation among 12th graders. T21 coverage was most strongly associated with a lower likelihood of smoking participation among: Hispanic and NH (Non-Hispanic) Other/Multiracial individuals; respondents with parents who had less than a college education; and respondents who were not definitely planning on attending college. T21 laws were associated with a lower likelihood of smoking participation among 12th graders. T21 policies were most impactful for individuals disproportionately impacted by tobacco, indicating T21 laws might help reduce tobacco-related health disparities.

Gas6 induces inflammation and reduces plaque burden but worsens behavior in a sex-dependent manner in the APP/PS1 model of Alzheimer's disease.

BACKGROUND: Alzheimer's disease is the leading cause of dementia worldwide. TAM receptor tyrosine kinases (Tyro3, Axl, MerTK) are known for their role in engagement of phagocytosis and modulation of inflammation, and recent evidence suggests a complex relationship between Axl, Mer, and microglial phagocytosis of amyloid plaques in AD. Gas6, the primary CNS TAM ligand, reduces neuroinflammation and improves outcomes in murine models of CNS disease. Therefore, we hypothesized that AAV-mediated overexpression of Gas6 would alleviate plaque pathology, reduce neuroinflammation, and improve behavior in the APP/PS1 model of Alzheimer's disease. METHODS: Adeno-associated viral vectors were used to overexpress Gas6 in the APP/PS1 model of Alzheimer's disease. Nine-month-old male and female APP/PS1 and nontransgenic littermates received bilateral stereotactic hippocampal injections of AAV-Gas6 or AAV-control, which expresses a non-functional Gas6 protein. One month after injections, mice underwent a battery of behavioral tasks to assess cognitive function and brains were processed for immunohistochemical and transcriptional analyses. RESULTS: Gas6 overexpression reduced plaque burden in male APP/PS1 mice. However, contrary to our hypothesis, Gas6 increased pro-inflammatory microglial gene expression and worsened contextual fear conditioning compared to control-treated mice. Gas6 overexpression appeared to have no effect on phagocytic mechanisms in vitro or in vivo as measured by CD68 immunohistochemistry, microglial methoxy-04 uptake, and primary microglial uptake of fluorescent fibrillar amyloid beta. CONCLUSION: Our data describes a triad of worsened behavior, reduced plaque number, and an increase in proinflammatory signaling in a sex-specific manner. While Gas6 has historically induced anti-inflammatory signatures in the peripheral nervous system, our data suggest an alternative, proinflammatory role in the context of Alzheimer's disease pathology.