The single-cell opioid responses in the context of HIV (SCORCH) consortium.

Substance use disorders (SUD) and drug addiction are major threats to public health, impacting not only the millions of individuals struggling with SUD, but also surrounding families and communities. One of the seminal challenges in treating and studying addiction in human populations is the high prevalence of co-morbid conditions, including an increased risk of contracting a human immunodeficiency virus (HIV) infection. Of the ~15 million people who inject drugs globally, 17% are persons with HIV. Conversely, HIV is a risk factor for SUD because chronic pain syndromes, often encountered in persons with HIV, can lead to an increased use of opioid pain medications that in turn can increase the risk for opioid addiction. We hypothesize that SUD and HIV exert shared effects on brain cell types, including adaptations related to neuroplasticity, neurodegeneration, and neuroinflammation. Basic research is needed to refine our understanding of these affected cell types and adaptations. Studying the effects of SUD in the context of HIV at the single-cell level represents a compelling strategy to understand the reciprocal interactions among both conditions, made feasible by the availability of large, extensively-phenotyped human brain tissue collections that have been amassed by the Neuro-HIV research community. In addition, sophisticated animal models that have been developed for both conditions provide a means to precisely evaluate specific exposures and stages of disease. We propose that single-cell genomics is a uniquely powerful technology to characterize the effects of SUD and HIV in the brain, integrating data from human cohorts and animal models. We have formed the Single-Cell Opioid Responses in the Context of HIV (SCORCH) consortium to carry out this strategy.

Cancer-associated fibroblasts expressing fibroblast activation protein and podoplanin in non-small cell lung cancer predict poor clinical outcome.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are a dominant cell type in the stroma of non-small cell lung cancer (NSCLC). Fibroblast heterogeneity reflects subpopulations of CAFs, which can influence prognosis and treatment efficacy. We describe the subtypes of CAFs in NSCLC. METHODS: Primary human NSCLC resections were assessed by flow cytometry and multiplex immunofluorescence for markers of fibroblast activation which allowed identification of CAF subsets. Survival data were analysed for our NSCLC cohort consisting of 163 patients to understand prognostic significance of CAF subsets. RESULTS: We identified five CAF populations, termed CAF S1-S5. CAF-S5 represents a previously undescribed population, and express FAP and PDPN but lack the myofibroblast marker αSMA, whereas CAF-S1 populations express all three. CAF-S5 are spatially further from tumour regions then CAF-S1 and scRNA data demonstrate an inflammatory phenotype. The presence of CAF-S1 or CAF-S5 is correlated to worse survival outcome in NSCLC, despite curative resection, highlighting the prognostic importance of CAF subtypes in NSCLC. TCGA data suggest the predominance of CAF-S5 has a poor prognosis across several cancer types. CONCLUSION: This study describes the fibroblast heterogeneity in NSCLC and the prognostic importance of the novel CAF-S5 subset where its presence correlates to worse survival outcome.

Personal characteristics associated with switching from Cigarettes to Non-combustible tobacco and nicotine products among U.S. adults: Findings from PATH Study Wave 1 - Wave 5.

INTRODUCTION: Reducing the disease burden from tobacco smoking may encompass switching to non-combustible (NCs), along with cessation. This study evaluates factors associated with switching to NCs (e-cigarettes, smokeless, snus) versus continued smoking, complete cessation, or dual use. METHODS: Population Assessment of Tobacco and Health adult data were analyzed in three two-year wave pairs across 2013-2019 to assess product transitions among people who exclusively smoked tobacco. Generalized estimating equations examined demographics, smoking characteristics, perceptions, and messaging exposure as predictors of transitions from cigarette smoking. RESULTS: Ages 18-44 years (ref=65+; aORs=3.79-5.92), males (aOR=1.18, 95%CI[1.01,1.37]), and perceiving NCs as less harmful than smoking (ref=not; aOR=1.47, 95%CI[1.28,1.69]) were positively associated with switching to NCs versus continued smoking, while being Black (ref=White; aOR=0.36, 95%CI[0.26,0.48]) or Hispanic (ref=Non-Hispanic; aOR=0.59, 95%CI[0.45,0.78]) were negatively associated. Ages 18-64 years (aORs=2.49-5.89), noticing promotional ads (ref=not; aOR=1.34, 95%CI[1.14,1.58]), daily light or heavy smoking (ref=nondaily; aORs=2.33-3.72), and smoking within 30 mins of waking (ref=>30min; aOR=1.47, 95%CI[1.18,1.85]) were positively associated with switching to NCs versus cessation, while being Black (aOR=0.55, 95%CI[0.38,0.74]) or Hispanic (aOR=0.52, 95%CI[0.38,0.71]) were negatively associated.. Incomes of $10,000->$100,000 (ref=<$10,000; aORs=2.08-3.13) and daily heavy smoking (aOR=1.96, 95%CI[1.11,3.48]) were positively associated with switching to NCs versus dual use, while being male (aOR=0.44, 95%CI[0.29,0.65]) was negatively associated. CONCLUSION: Transitioning to NCs was unequally distributed among sociodemographic groups and smoking characteristics. The mere availability of NCs may not promote health equity. Continued market and regulatory efforts that promote both smoking cessation and transitioning to NCs among various populations may promote public health gains. IMPLICATIONS: This study examines factors associated with transitioning from smoking to non-combustible tobacco product use. We examined three different product use scenarios that may be associated with varied levels of exposure to harm. We observed that younger ages and perceiving NCs as less harmful than cigarettes were more likely to transition to NCs as compared to continued smoking and cessation, while Black or Hispanic individuals were less likely to transition to NCs. This highlights the need for more focused harm reduction efforts for racial and ethnic minority populations as a complementary strategy to cessation to reduce health disparities from smoking.

Awareness and perceived behaviour changes following the New York state vaping flavour ban, 2021-2022.

SIGNIFICANCE: Despite an electronic cigarette (e-cigarette) flavour ban in New York (NY) since May 2020, most youth who vape continue to report vaping restricted flavours. This study aims to examine youth awareness and perceived behaviour change associated with the NY vaping flavour ban. METHODS: NY cross-sectional data from 2021 and 2022 ITC Youth Survey were combined and analysed (N=1014). Weighted analyses were used to describe awareness and understanding of the e-cigarette flavour ban, as well as changes in tobacco use behaviour. RESULTS: Only 0.9% (n=8) of NY youth understood the flavour ban, in that they were both aware of the flavour ban in all stores and accurately reported that all non-tobacco flavours were banned. Awareness and understanding of the flavour ban differed by vaping status (p<0.01): respondents who had vaped in the past 12 months or 30 days were more likely (adjusted OR (aOR)=2.15, 95% CI 1.34, 3.45; aOR=2.07, 95% CI 1.17, 3.64, respectively) to be aware of the flavour ban but misunderstand the stores or flavours included. Of the majority of youth who reported awareness of a flavour ban and vaped (n=122) or smoked (n=78) in the past 12 months reported no changes in behaviour (64.0% and 69.7%, respectively). CONCLUSIONS: Less than one-third of NY youth, regardless of vaping status, reported that an e-cigarette flavour ban was present where they live. Further, most youth who were aware of the ban misunderstood which flavours were restricted and/or that the ban applied to all stores that sold e-cigarettes. Increased enforcement and educational efforts could improve awareness and understanding of the NY e-cigarette flavour ban.

Evaluation of modified risk claim advertising formats for Camel Snus.

Objectives: The US Food and Drug Administration (FDA) has regulatory authority for modified risk tobacco product advertising claims. To guide future regulatory efforts, we investigated how variations in modified risk claim advertisements influence consumer perceptions of product risk claims for Camel Snus. Methods: Young people and adults (15-65), including current, never, and former smokers, were randomised to view one of five Camel Snus print advertisements as part of a web-based survey. Four of the advertisements presented information related to nitrosamine content of snus using four formats: (1) text, (2) a bar chart, (3) a text/testimonial and (4) a bar chart/testimonial. The fifth format, used as a control, was a current advertisement for Camel Snus without the explicit claims made about nitrosamine content. After viewing advertisements for all products, participants were asked which product they would be most interested in trying. Results: Participants exposed to advertisements that contained an explicit reduced risk message agreed the advertising claim for that product posed fewer health risks than cigarettes. However, advertisements containing the reduced risk messages were also viewed as containing less truthful information and respondents were more sceptical of the information presented. Advertisement claim format was not associated with selecting snus over the other tobacco products, nor was it associated with purchase intentions. Conclusion: The results of this research indicate that consumers respond to reduced risk messages, though perhaps not in the direct way anticipated. We found no significant differences by advertisement format (numerical, graphical, testimonial).

Social intuition: behavioral and neurobiological considerations.

Social intuition is instrumental in bringing about successful human interactions, yet its behavioral and neural underpinnings are still poorly understood. We focus in this article on the automatic, involuntary, nature of social intuition, rather than on higher-level cognitive and explicit Theory-of-Mind processes (which contribute to rendering social intuition meaningful in real-life situations). We argue that social-affective implicit learning plays a crucial role in establishing automatic social intuition. These implicit learning processes involve associations between the perception of other's bodily articulations, concurrent events, and the consequences or outcomes in terms of subsequent actions, affective valences and visceral states. The traditional non-social implicit learning paradigms do not allow one to draw conclusions about the role of implicit learning processes in social intuition, as they lack these vital characteristics typically associated with human actions. We introduce a new implicit learning paradigm, which aims to fill these gaps. It targets agile, rapid, social-affective learning processes, involving cue contingencies with a relatively simple structure, unlike the very complex structures that underpin the traditional tasks. The paradigm features matching social and non-social versions, allowing direct comparison. Preliminary data suggest equal performance of TD (typically-developed) and ASC (autism spectrum conditions) groups on the non-social version, but impaired implicit learning in ASC on the social version. We hypothesize that this reflects an anomalous use of implicitly learned affective information in ASC when judging other people. We further argue that the mirror neuron mechanism (MNM), which is part of the Action Observation Network, forms an integral part of the neural substrate for social intuition. In particular as there are indications that the MNM supports action anticipation, and that implicitly learned information can trigger MNM activation, which both seem vital to a social intuition ability. The insights that can be derived from comparing the performances of TD and ASC individuals on (non)social implicit learning tasks, and the implications for the role of MNM activation, are discussed.

The Cannabis Gray Market: A Case for Cannabis Regulatory Science Research.

The cannabis gray market poses significant public health concerns and remains a major threat to consumer and/or potential consumer uptake of regulated cannabis markets in jurisdictions with legal state-sponsored cannabis programs. In this perspective, we provide an overview of the cannabis gray market, and describe an integrated epidemiological and regulatory science framework to study the gray market. Using tobacco regulatory science as a guide, we introduce example cannabis regulatory science research activities as a means to improve the field's understanding of the cannabis gray market. Cannabis regulatory science is a developing field that can improve our understanding of the cannabis regulatory ecosystem and provide regulatory officials and policymakers alike with much needed data to inform regulatory decision-making and improve the success and uptake of state-sponsored cannabis programs.

FABEL: Forecasting Animal Behavioral Events with Deep Learning-Based Computer Vision.

Behavioral neuroscience aims to provide a connection between neural phenomena and emergent organism-level behaviors. This requires perturbing the nervous system and observing behavioral outcomes, and comparing observed post-perturbation behavior with predicted counterfactual behavior and therefore accurate behavioral forecasts. In this study we present FABEL, a deep learning method for forecasting future animal behaviors and locomotion trajectories from historical locomotion alone. We train an offline pose estimation network to predict animal body-part locations in behavioral video; then sequences of pose vectors are input to deep learning time-series forecasting models. Specifically, we train an LSTM network that predicts a future food interaction event in a specified time window, and a Temporal Fusion Transformer that predicts future trajectories of animal body-parts, which are then converted into probabilistic label forecasts. Importantly, accurate prediction of food interaction provides a basis for neurobehavioral intervention in the context of compulsive eating. We show promising results on forecasting tasks between 100 milliseconds and 5 seconds timescales. Because the model takes only behavioral video as input, it can be adapted to any behavioral task and does not require specific physiological readouts. Simultaneously, these deep learning models may serve as extensible modules that can accommodate diverse signals, such as in-vivo fluorescence imaging and electrophysiology, which may improve behavior forecasts and elucidate invervention targets for desired behavioral change.

Acute effects of charcoal filters and package color on cigarette perceptions and use behaviors: Results from a randomized pilot study examining Natural American Spirit "Sky".

INTRODUCTION: Charcoal-filtered cigarettes have been available for decades but have never held a major share of the U.S. cigarette market. This pilot study gathered initial behavioral data characterizing how "Sky"-a recently introduced charcoal-filtered cigarette variety that uses potentially misleading marketing features-is used and what impact its packaging color has on consumer perceptions. METHODS: Forty adult daily non-menthol cigarettes users (52.5% male, 75.0% White, mean age = 46.1, 14.3 mean cigarettes/day) completed a single-session deception study utilizing a 2 ×2 mixed factorial design to manipulate cigarette filter condition (charcoal vs. non-charcoal) and pack color (light vs. dark). Participants smoked two cigarettes identical in appearance and packaging but differing in filter type (blinded and order counterbalanced) and completed pre- and post-cigarette CO samples and post-cigarette questionnaires. RESULTS: Participants endorsed more favorable subjective ratings, puffed less of, held more correct beliefs about risks, and expressed greater intentions to use the charcoal (vs. non-charcoal)-filtered cigarette (p's <0.05). Pack color had few effects on outcomes; however, cigarettes in light vs. dark colored packs were rated as cleaner tasting (p <0.01). Neither filter condition nor pack color affected CO boost. There were no interaction effects on any outcomes. CONCLUSIONS: Under blinded conditions, Sky charcoal-filtered cigarettes are initially appealing independent of their packaging color. Findings warrant further study of these effects on perceptions, behavior, and harm exposure after longer, open-label use periods. Findings may inform regulatory decisions regarding cigarette packaging and filter composition.

Nicotine, Humectants, and Tobacco-Specific Nitrosamines (TSNAs) in IQOS Heated Tobacco Products (HTPs): A Cross-Country Study.

Heated Tobacco Products (HTPs) purport to reduce exposure to tobacco-related toxicants compared to combustible cigarettes. This cross-sectional study examined the content of nicotine, two humectants (propylene glycol (PG) and vegetable glycerin (VG)), and four tobacco-specific nitrosamines (TSNAs: NNN, NNK, NAT, and NAB) in the tobacco filler of a popular HTP brand (IQOS). Non-menthol and menthol IQOS sticks were purchased from nine countries between 2017 and 2020 and were classified into two versions ("Bold" and "Light") using Philip Morris's flavor descriptors. The average nicotine concentration was 4.7 ± 0.5 mg/stick, and the highest nicotine concentration was found in products from Japan (5.1 ± 0.2 mg/stick). VG was the dominant humectant found in all sticks, with an average concentration of (31.5 ± 2.3 mg/stick). NNN, NNK, and NAT were substantially higher in the "Bold" sticks than the "Light" sticks. Significant differences between countries for TSNAs were also observed: the NAT and NAB contents were the highest in the "Light" products from Canada (192.5 ± 24.1 and 22.9 ± 1.0 ng/stick, respectively); the NNK concentration was the highest in the "Bold" products from Poland (64.8 ± 7.9 ng/stick); and the highest NNN concentrations were observed in the "Bold" products from South Africa (488.9 ± 26.7 ng/stick). As NNN and NNK are known human carcinogens, and as humectants like PG and VG can degrade into toxic carbonyl compounds upon heating, monitoring the concentration of these chemicals in HTPs is important for protecting users' health and ensuring compliance with regulations.

How to Identify e-Cigarette Brands Available in the United States During 2020-2022: Development and Usability Study.

BACKGROUND: Prior studies have demonstrated that the e-cigarette market contains a large number of brands. Identifying these existing e-cigarette brands is a key element of market surveillance, which will further assist in policy making and compliance checks. OBJECTIVE: To facilitate the surveillance of the diverse product landscape in the e-cigarette market, we constructed a semantic database of e-cigarette brands that have appeared in the US market as of 2020-2022. METHODS: In order to build the brand database, we searched and compiled e-cigarette brands from a comprehensive list of retail channels and sources, including (1) e-liquid and disposable brands sold in web-based stores, (2) e-cigarette brands sold in brick-and-mortar stores and collected by the Nielsen Retail Scanner Data, (3) e-cigarette brands compiled by Wikipedia, (4) self-reported e-cigarette brands from the 2020 International Tobacco Control Four-Country Smoking and Vaping (ITC 4CV) US survey, and (5) e-cigarette brands on Twitter. We also estimated the top 5 e-cigarette brands by sales volume in brick-and-mortar stores, by the frequency and variety of offerings in web-based shops, and by the frequency of self-reported brands from the 2020 ITC 4CV US survey. RESULTS: As of 2020-2022, a total of 912 e-cigarette brands have been sold by various retail channels. During 2020-2022, the top 5 brands are JUUL, vuse, njoy, blu, and logic in brick-and-mortar stores; blu, king, monster, twist, and air factory for e-liquids in web-based stores; hyde, pod mesh, suorin, vaporlax, and xtra for disposables sold in web-based stores; and smok, aspire, vaporesso, innokin, and eleaf based on self-reported survey data. CONCLUSIONS: As the US Food and Drug Administration enforces the premarket tobacco market authorization, many e-cigarette brands may become illegal in the US market. In this context, how e-cigarette brands evolve and consolidate in different retail channels will be critical for understanding the regulatory impacts on product availability. Our semantic database of e-cigarette brands can serve as a useful tool to monitor product and marketplace development, conduct compliance checks, assess manufacturers' marketing behaviors, and identify regulatory impacts.

Amygdala-liver signaling orchestrates rapid glycemic responses to stress and drives stress-induced metabolic dysfunction.

Behavioral adaptations to environmental threats are crucial for survival and necessitate rapid deployment of energy reserves. The amygdala coordinates behavioral adaptations to threats, but little is known about its involvement in underpinning metabolic adaptations. Here, we show that acute stress activates medial amygdala (MeA) neurons that innervate the ventromedial hypothalamus (MeAVMH neurons), which precipitates hyperglycemia and hypophagia. The glycemic actions of MeAVMH neurons occur independent of adrenal or pancreatic glucoregulatory hormones. Instead, using whole-body virus tracing, we identify a polysynaptic connection from MeA to the liver, which promotes the rapid synthesis of glucose by hepatic gluconeogenesis. Repeated stress exposure disrupts MeA control of blood glucose and appetite, resulting in diabetes-like dysregulation of glucose homeostasis and weight gain. Our findings reveal a novel amygdala-liver axis that regulates rapid glycemic adaptations to stress and links recurrent stress to metabolic dysfunction.

A master regulator of opioid reward in the ventral prefrontal cortex.

In addition to their intrinsic rewarding properties, opioids can also evoke aversive reactions that protect against misuse. Cellular mechanisms that govern the interplay between opioid reward and aversion are poorly understood. We used whole-brain activity mapping in mice to show that neurons in the dorsal peduncular nucleus (DPn) are highly responsive to the opioid oxycodone. Connectomic profiling revealed that DPn neurons innervate the parabrachial nucleus (PBn). Spatial and single-nuclei transcriptomics resolved a population of PBn-projecting pyramidal neurons in the DPn that express µ-opioid receptors (µORs). Disrupting µOR signaling in the DPn switched oxycodone from rewarding to aversive and exacerbated the severity of opioid withdrawal. These findings identify the DPn as a key substrate for the abuse liability of opioids.

Exposure to IQOS ads and reduced exposure claims, and association with perceived risk from COVID-19 on IQOS purchase and use intentions: results from a web-based survey.

Introduction: IQOS was authorized to be marketed as a reduced exposure product by the Food and Drug Administration in October 2020 during the global COVID-19 pandemic. Those who smoke may be more sensitive to reduced exposure marketing claims and may have an increased inclination toward IQOS use. We evaluated the likelihood of trying and purchasing IQOS as a function of exposure to ads, product appeal, and COVID-19 risk perceptions using the original IQOS ads with reduced exposure marketing. Method: An online cross-sectional survey recruited 604 US adults (18-45 years), both who smoke and do not smoke. Participants saw one of the six randomly assigned IQOS ads with or without reduced exposure claims, and they answered questions about product appeal and likelihood to try and purchase IQOS. Generalized linear models were used to examine associations. Results: A per unit increase in product appeal was associated with a greater likelihood of purchasing (B = 0.17, 95% CI: 0.15-0.18) and trying IQOS (B = 0.16, 95% CI = 0.14-0.18). Current smokers and former e-cigarette users reported greater intentions to try IQOS than never-smokers and never e-cigarette users, respectively. Likelihood to purchase IQOS was associated with greater confidence in not contracting COVID-19 (B = 0.11, 95% CI: 0.01-0.21). No significant differences were observed between different ad conditions. Current (B = -0.34, 95% CI = -0.50-(-0.19)) and former (B = -0.92, 95% CI = -0.15-(-0.68)) cigarette smokers who were someday e-cigarette users reported less intentions to purchase IQOS than never e-cigarette users. However, never smokers who were someday (B = 0.58, 95% CI = 0.27-0.89; B = 0.68, 95% CI = 0.39-0.98) and former e-cigarette (B = 0.38, 95% CI = 0.15-0.61) users reported greater intentions to purchase and try IQOS, respectively. Discussion: IQOS may have a higher product appeal, especially for those who currently smoke and those who have lower risk perceptions from COVID-19. Among never smokers, those who currently use or have used e-cigarettes in the past may be more receptive to IQOS marketing. The data are informative for potential trends in the use of IQOS in the future and may have implications for marketing regulations of heated tobacco products (HTPs).

Smokers Awareness and Risk Perceptions of Filter Ventilation.

Objectives: The addition of tiny rows of holes in the tipping paper (filter ventilation) of cigarettes allows air to mix with the smoke, which can change risk perceptions. In this study, we examine smokers' knowledge and beliefs about filter ventilation. Methods: Web-based panel surveys conducted in 2016 and 2017 of current adult cigarette smokers (N = 2355) provided data on awareness and understanding of filter vents in their cigarettes, whether they believed blocking the holes would change the taste of their cigarettes, and their perceptions about their future risk of being diagnosed with lung cancer. The most commonly used cigarette brands reported by participants also were characterized on the presence and level of ventilation holes. Results: Approximately 40% of participants (mostly younger and male) reported awareness of the filter ventilation in their cigarettes. Only 30% of the participants were both aware of and understood the function of filter ventilation; they also were significantly more likely to worry about developing lung cancer. Conclusion: Although misleading descriptors associated with filter ventilation are prohibited, most smokers still smoked cigarettes with filter vents, and many are unaware and misunderstand the potential risks of filter ventilation.