Come for the Tobacco, Stay for the Flavor: Flavored Cigarillo-Use Trajectories Among Young Adult Sexual Gender Minority Women.

INTRODUCTION: The purpose of this research was to identify how young adult sexual gender minority (SGM) women who use cigarillos may respond to cigar flavor restrictions. AIMS AND METHODS: Young adults aged 21-28 years in the United States who currently use cigarillos were recruited between October 2020 and April 2021 to participate in an online survey. Due to high prevalence of cigarillo use among individuals who identify as sexual and/or gender minority (SGM) women, their (n = 192) flavored tobacco-use behaviors and anticipated responses to cigarillo flavor restrictions were compared to cisgender heterosexual (CisHet) women (n = 110). Logistic regression was used to model cigarillo cessation and product-switching behaviors (flavored and unflavored). RESULTS: SGM women were significantly less likely to report the use of flavor at the initiation of cigarillo use (61.7% vs. 86.1%) but were no different in current flavor use compared to CisHet women, with more than 80% of all women using any flavor. SGM women were 2.36 times as likely to say they would discontinue using cigarillos if flavors were unavailable. Among those who would continue using cigarillos, SGM women were 4.53 times as likely to endorse switching to an unflavored tobacco product but had the same likelihood of saying they would switch to flavored product compared to CisHet women. CONCLUSIONS: Flavor restriction policies may not reduce the initiation of cigarillos among SGM women and may elicit differential cigarillo use and tobacco product substitution by SGM identity. Flavor restriction policies should be coupled with targeted cessation resources to address potential remaining disparities. IMPLICATIONS: SGM US women have a unique cigarillo-use trajectory. These women are more likely to initiate cigarillos without flavor and then later integrate it into their behavior. National cigar flavor restrictions are expected to have a greater impact decreasing cigarillo initiation among CisHet women and decreasing current cigarillo use among SGM women. However, for those who would continue using unflavored cigarillos, SGM women may remain at risk for nicotine dependence due to increased product substitution. SGM women should be prioritized for cessation resources to reduce tobacco-use disparities leading up to and following the implementation of cigar flavor restrictions.

What is (Un)Flavored? A Scoping Review of the Conceptualization of Flavored Cigarillos.

PURPOSE: To identify how flavor is conceptualized with respect to cigarillos to illuminate areas of concordance and discordance and provide a pathway for the harmonization of tobacco flavor measurement. METHODS: Three methods were used to identify research measuring flavors respective to cigarillo products including: 1) querying research databases using key words 'cigarillo,' 'tobacco' and 'flavor'/'flavour,' 2) sub-sampling of the eligible literature with backwards and forwards reference searching, and 3) a bibliographic search of key experts. Two reviewers independently screened titles, abstracts, and full texts. Inclusion criteria required manuscripts to be available in English, published prior to 3/1/2022, be original and peer-reviewed, and include a measure of flavor pertaining to cigarillo products. A total of 163 manuscripts met these criteria and were subsequently evaluated. RESULTS: Cigarillo flavor determinations were made based on the presence of flavoring agents, sensory characteristics, marketing or package characteristics, pre-defined lists, the absence of any of these, and/or were undefined. Individual flavors and their related classifications were not altogether mutually exclusive due to differences in conceptualization which has evolved over time. CONCLUSION: Flavor measures continue to evolve, likely in response to both tobacco control policies and industry shifts. There is a lack of standardization in flavor conceptualization that can be ameliorated through intentional integration of multiple forms of research such as identifying patterns of flavoring agents and/or marketing strategies that elicit a specific flavor profile. By doing this, we may more comprehensively evaluate the impact of flavors, their constituents, and related marketing strategies on broader population health. IMPLICATIONS: There are discrepancies in the conceptualization of flavor in tobacco and nicotine products. The lack of standardized, definitive language limits our ability to comprehensively evaluate the population-level health impact of flavors in addition to our ability to effectively inform, implement and enforce policies restricting flavors in tobacco and nicotine products.

Time to Surgical Treatment and Facility Characteristics as Potential Drivers of Racial Disparities in Breast Cancer Mortality.

BACKGROUND: Black women are more likely to die of breast cancer than White women. This study evaluated the contribution of time to primary surgical management and surgical facility characteristics to racial disparities in breast cancer mortality among both Black and White women. METHODS: The study identified 2224 Black and 3787 White women with a diagnosis with stages I to III breast cancer (2010-2014). Outcomes included time to surgical treatment (> 30 days from diagnosis) and breast cancer mortality. Odds ratios (ORs) and 95% confidence intervals (CIs) associating surgical facility characteristics with surgical delay were computed, and Cox proportional hazards regression was used to compute hazard ratios (HRs) and 95% CIs associating delay and facility characteristics with breast cancer mortality. RESULTS: Black women were two times more likely to have a surgical delay (OR, 2.15; 95% CI, 1.92-2.41) than White women. Racial disparity in surgical delay was least pronounced among women treated at a non-profit facility (OR, 1.95; 95% CI, 1.70-2.25). The estimated mortality rate for Black women was two times that for White women (HR, 2.00; 95% CI, 1.83-2.46). Racial disparities in breast cancer mortality were least pronounced among women who experienced no surgical delay (HR, 1.81; 95% CI, 1.28-2.56), received surgery at a government facility (HR, 1.31; 95% CI, 0.76-2.27), or underwent treatment at a Commission on Cancer-accredited facility (HR, 1.82; 95% CI, 1.38-2.40). CONCLUSIONS: Black women were more likely to experience a surgical delay and breast cancer death. Persistent racial disparities in breast cancer mortality were observed across facility characteristics except for government facilities.

Flavour loyalty may predict cessation or substitution following a cigarillo flavour ban among young adults in the USA.

SIGNIFICANCE: The purpose of this research was to measure flavour loyalty and identify how current cigarillo users may respond to a hypothetical flavour ban in the USA. METHODS: Cigarillo users aged 21-28 (n=531) were recruited between October 2020 and April 2021 to participate in an online survey. Respondents categorised their preferred, usual and current cigarillo flavours. Individuals who preferred tobacco flavours were compared with individuals who preferred any other flavours. Strength of preferences, or flavour loyalty, was defined when an individual's preferred flavour matched what they use both usually and currently creating a spectrum of individuals with a strong tobacco preference (n=34), weak tobacco preference (n=20), weak flavour preference (n=162) and strong flavour preference (n=315). Those preferring tobacco were aggregated into any tobacco preference (n=54). RESULTS: Individuals who preferred any flavour scored higher on a scale of nicotine dependence. There was a dose-response relationship in those who said they would discontinue cigarillos if flavoured options were not available: 11.4% of individuals with any tobacco flavour preference, 27.8% of those with a weak flavour preference and 38.1% of those with a strong flavour preference. A similar trend was noted among those who would switch to another product: 19.2% of those with tobacco flavour preference, 34.3% of those with a weak flavour preference and 43.2% of those with a strong flavour preference. CONCLUSION: Individuals who display strong flavour preferences were more likely to say they would discontinue use or seek out alternative flavoured products following a ban on flavoured cigarillos.

Cholesterol increases the open probability of cardiac KACh currents.

Cholesterol is one of the major lipid components of membranes in mammalian cells. In recent years, cholesterol has emerged as a major regulator of ion channel function. The most common effect of cholesterol on ion channels in general and on inwardly rectifying potassium (Kir) channels in particular is a decrease in activity. In contrast, we have recently shown that native G-protein gated Kir (GIRK or Kir3) channels that underlie atrial KACh currents are up-regulated by cholesterol. Here we unveil the biophysical basis of cholesterol-induced increase in KACh activity. Using planar lipid bilayers we show that cholesterol significantly enhances the channel open frequency of the Kir3.1/Kir3.4 channels, which underlie KACh currents. In contrast, our data indicate that cholesterol does not affect their unitary conductance. Furthermore, using fluorescent and TIRF microscopy as well as surface protein biotinylation, we also show that cholesterol enrichment in vitro has no effect on surface expression of GFP-tagged channels expressed in Xenopus oocytes or transfected into HEK293 cells. Together, these data demonstrate for the first time that cholesterol enhances Kir3-mediated current by increasing the channel open probability.

Distant cytosolic residues mediate a two-way molecular switch that controls the modulation of inwardly rectifying potassium (Kir) channels by cholesterol and phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)).

BACKGROUND: Cholesterol modulates inwardly rectifying potassium (Kir) channels. RESULTS: A two-way molecular cytosolic switch controls channel modulation by cholesterol and PI(4,5)P(2). CONCLUSION: Cholesterol and PI(4,5)P(2) induce a common gating pathway of Kir2.1 despite their opposite impact on channel function. SIGNIFICANCE: These findings provide insights into structure-function relationship of ion channels and contribute to understanding of the mechanisms underlying their regulation by lipids. Inwardly rectifying potassium (Kir) channels play an important role in setting the resting membrane potential and modulating membrane excitability. An emerging feature of several Kir channels is that they are regulated by cholesterol. However, the mechanism by which cholesterol affects channel function is unclear. Here we show that mutations of two distant Kir2.1 cytosolic residues, Leu-222 and Asn-251, form a two-way molecular switch that controls channel modulation by cholesterol and affects critical hydrogen bonding. Notably, these two residues are linked by a residue chain that continues from Asn-251 to connect adjacent subunits. Furthermore, our data indicate that the same switch also regulates the sensitivity of the channels to phosphatidylinositol 4,5-bisphosphate, a phosphoinositide that is required for activation of Kir channels. Thus, although cholesterol and phosphatidylinositol 4,5-bisphosphate do not interact with the same region of Kir2.1, these different modulators induce a common gating pathway of the channel.

Efficacy of Targeted Mast Cell Inhibition Therapy in Chronic Prostatitis/Chronic Pelvic Pain Syndrome.

OBJECTIVE: To identify a subgroup of patients with mast cell dysfunction in chronic prostatitis/chronic pelvic pain syndrome and evaluate efficacy of mast cell-directed therapy. MATERIALS AND METHODS: Men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) were recruited and evaluated in an open-label, interventional uncontrolled trial after therapy with cromolyn sodium and cetirizine hydrochloride. The primary endpoint was a change in mast cell tryptase concentrations after treatment while secondary endpoints were changes in the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) and AUA-SI. Isolated cells from postprostatic massage urine were evaluated for immune changes using mRNA expression analysis. RESULTS: 31 patients with a diagnoses of Category III CP/CPPS were consented, 25 patients qualified and 20 completed the study after meeting a prespecified threshold for active tryptase in expressed prostatic secretions. After treatment with cromolyn sodium and cetirizine dihydrochloride for 3-week, active tryptase concentrations were significantly reduced from 49.03±14.05 ug/mL to 25.49±5.48 ug/mL (P<.05). The NIH-CPSI total score was reduced with a mean difference of 5.2±1 along with reduction in the pain, urinary and quality of life subscores (P<.001). A reduction in the AUA-SI was observed following treatment (P<.05). NanoString mRNA analysis of isolated cells revealed downregulation of immune-related pathways including Th1 and Th17 T cell differentiation and TLR signaling. Marked reduction in CD45+ cells and specifically macrophages and neutrophil abundance was observed. CONCLUSION: Identification of CP/CPPS patients with mast cell dysfunction may be achieved using tryptase as a discriminating biomarker. Mast cell-directed therapy in this targeted subgroup may be effective in reducing symptoms and modulating the immune inflammatory environment.

Evaluation of Restrictions on Tobacco Sales to Youth Younger Than 21 Years in Cleveland, Ohio, Area.

Importance: Tobacco 21 (T21) policies raise the minimum legal age to purchase tobacco from 18 to 21 years to curb youth access to tobacco products. While some studies have found that T21 is associated with reducing prevalence of youth tobacco use, little is known about the impact it may have on youth of different racial and ethnic identities. Objective: To evaluate the association of T21 policy with the prevalence of high school youth tobacco use across sex, race, and ethnicity. Design, Setting, and Participants: This survey study used representative survey data collected from the local biennial Youth Risk Behavior Survey from 2013 to 2017 comparing Cleveland, Ohio (which has a T21 policy), to proximal jurisdictions in the first-ring suburbs in Cuyahoga County (which do not have T21 policies). Within-Cleveland demographic information was also collected for 2013 to 2019. Overall high school youth tobacco use rates were compared between Cleveland and the first-ring suburbs and then examined within Cleveland among Hispanic, non-Hispanic Black, and non-Hispanic White high school students. Percentage data were adjusted to more closely align with local population demographics. Data were analyzed from January to June 2022. Exposures: T21 was implemented in Cleveland in 2016 and not adopted in proximal jurisdictions or at the state and federal level until at least 1 year later. Main Outcomes and Measures: The main outcomes were prevalence of past 30-day cigarette, cigar product, or e-cigarette use, measured using geographically representative high school youth survey data from 2013 to 2015 (prelegislation) and 2017 to 2019 (postlegislation) and compared using a difference-in-differences analysis. Results: The unweighted sample included 12 616 high school students (27.0% [95% CI, 26.9%-28.0%] in 10th grade; 50.9% [95% CI, 50.3%-51.6%] females) participating in 1 or more Youth Risk Behavior Surveys from 2013 to 2019, including 7064 students in Cleveland and 5552 students in the first-ring suburbs. Compared with the first-ring suburbs, Cleveland had a greater proportion of younger students (1623 [28.5%] ninth grade students vs 2179 [34.0%] ninth grade students) and Hispanic students (436 students [1.1%] vs 1433 students [12.6%]) and non-Hispanic Black students (2000 students [53.1%] vs 3971 students [75.1%]). Cigars were the most commonly used tobacco product in Cleveland, with use reported by 6201 students (19.8%) in 2013, 5877 students (21.3%) in 2015, and 5784 students (16.8%) in 2019. Compared with the first-ring suburbs, there was a greater decline in prevalence of use of cigars in Cleveland (ß = 0.18 [SE, 0.05]; P < .001). The disparity across race, ethnicity, and sex decreased for all current tobacco product use. For example, the maximum difference between demographic subpopulations in current cigarette use was 11.6 (95% CI, 9.5-13.7) percentage points in 2013 between White females (16.1% [95% CI, 11.3%-20.8%]) and Black males (4.5% [95% CI, 3.5%-5.4%]). This maximum difference in current cigarette use decreased significantly to 5.1 (95% CI, 3.5-6.7) percentage points in 2019 between White females (6.9% [95% CI, 3.4%-10.3%]) and Black females (1.8% [95% CI, 0.7%-2.8%]). Conclusions and Relevance: This survey study found that there was a decline in youth-reported tobacco use across every tobacco product category from 2013 to 2019. This decline changed the trajectory of use among several demographic groups and brought the youth populations with the highest tobacco product use to similar rates of others.

Dissonance in Young Adult Cigarillo Users' Categorization of Concept Flavored and Unflavored Products.

This study asks young adult cigarillo users to categorize their preferred flavor in order to examine user consensus and potential methodological and regulatory implications of flavor name-based categorization systems. Young adult (21-28 years) cigarillo users (n = 426) named and categorized their favorite cigarillo flavor into one of seven categories: Fruit, Sweet and Candy, Mint, Alcohol, Menthol, Tobacco, and Other. Flavor responses were coded as characterizing (ex: Grape, Wine) or concept (ex: Jazz, Diamond) flavors. Variation within and between categories was assessed, including the presence of concept flavors and the placement of flavors in multiple categories. Of the 66 unique flavor names provided, participants placed 20 (30.1%) in more than one flavor category. Most of the Tobacco (76.9%) and Other (69.2%) flavor names appeared in multiple categories. The majority of flavor names in the Tobacco (69.2%) and Other (61.5%) categories were concept flavors. Concept flavors were placed in multiple categories (45.0%) twice as often as characterizing flavors (23.9%). This study has identified dissonance among cigarillo users' flavor categorizations, particularly for concept flavored and unflavored products. Flavor names may obscure how and whether a product is flavored. Research on and regulation of flavored tobacco products should classify products by flavor additives rather than by name alone.

Substitution of flavored cigarillos with menthol cigarettes among young adults in the U.S.

BACKGROUND: Young adult cigarillo users often cite flavor as a primary reason for initiating and sustaining product use and are more likely to concurrently use other tobacco products such as menthol cigarettes. This study examines substitution with menthol cigarettes among cigarillo users facing a hypothetical ban on flavored cigarillos. METHODS: Current young adult (21-28 years) cigarillo users were recruited from October 2020 to April 2021 for an online survey about cigarillo and other tobacco use behaviors. Participants (n = 500) self-reported past or current menthol cigarette experience, and if they would switch to menthol cigarettes if they could not get flavored cigarillos. Logistic regression was used to test differences in switching behaviors by level of experience with menthol cigarettes. RESULTS: Most young adult cigarillo users (76.8 %) had ever used a menthol cigarette and 46.6 % reported current use of menthol cigarettes. No participant who had never used menthol cigarettes reported they would switch to menthol cigarettes. Current users were 4.2 times as likely to say they would switch after controlling for demographic characteristics and nicotine dependence. CONCLUSION: Most young adult cigarillo users reported they would not switch to menthol cigarettes if flavored cigarillos became unavailable. However, participants who currently use or have used menthol cigarettes were more likely to report their intention to switch products than those who had never used menthol cigarettes. There may be a subsequent increase in menthol cigarette use among past menthol cigarette users if policies restricting flavored tobacco products exclude menthol cigarettes, diluting these policies' intended population health impact.

Hypercholesterolemia-Induced Loss of Flow-Induced Vasodilation and Lesion Formation in Apolipoprotein E-Deficient Mice Critically Depend on Inwardly Rectifying K+ Channels.

BACKGROUND: Hypercholesterolemia-induced decreased availability of nitric oxide (NO) is a major factor in cardiovascular disease. We previously established that cholesterol suppresses endothelial inwardly rectifying K+ (Kir) channels and that Kir2.1 is an upstream mediator of flow-induced NO production. Therefore, we tested the hypothesis that suppression of Kir2.1 is responsible for hypercholesterolemia-induced inhibition of flow-induced NO production and flow-induced vasodilation (FIV). We also tested the role of Kir2.1 in the development of atherosclerotic lesions. METHODS AND RESULTS: Kir2.1 currents are significantly suppressed in microvascular endothelial cells exposed to acetylated-low-density lipoprotein or isolated from apolipoprotein E-deficient (Apoe-/- ) mice and rescued by cholesterol depletion. Genetic deficiency of Kir2.1 on the background of hypercholesterolemic Apoe-/- mice, Kir2.1+/-/Apoe-/- exhibit the same blunted FIV and flow-induced NO response as Apoe-/- or Kir2.1+/- alone, but while FIV in Apoe-/- mice can be rescued by cholesterol depletion, in Kir2.1+/-/Apoe-/- mice cholesterol depletion has no effect on FIV. Endothelial-specific overexpression of Kir2.1 in arteries from Apoe-/- and Kir2.1+/-/Apoe-/- mice results in full rescue of FIV and NO production in Apoe-/- mice with and without the addition of a high-fat diet. Conversely, endothelial-specific expression of dominant-negative Kir2.1 results in the opposite effect. Kir2.1+/-/Apoe-/- mice also show increased lesion formation, particularly in the atheroresistant area of descending aorta. CONCLUSIONS: We conclude that hypercholesterolemia-induced reduction in FIV is largely attributable to cholesterol suppression of Kir2.1 function via the loss of flow-induced NO production, whereas the stages downstream of flow-induced Kir2.1 activation appear to be mostly intact. Kir2.1 channels also have an atheroprotective role.

The atypical dopamine D1 receptor agonist SKF 83959 induces striatal Fos expression in rats.

The effects of dopamine D1 receptor agonists are often presumed to result from an activation of adenylyl cyclase, but dopamine D1 receptors may also be linked to other signal transduction cascades and the relative importance of these various pathways is currently unclear. SKF 83959 is an agonist at dopamine D1 receptors linked to phospholipase C, but has been reported to be an antagonist at receptors linked to adenylyl cyclase. The current report demonstrates that SKF 83959 induces pronounced, nonpatchy, expression of the immediate-early gene product Fos in the striatum of intact rats which can be converted to a patchy pattern by pretreatment with the dopamine D2-like receptor agonist quinpirole. In rats with unilateral 6-hydroxydopamine lesions SKF 83959 induces strong behavioral rotation and a greatly potentiated Fos response. All of the responses to SKF 83959, in both intact and dopamine-depleted animals, can be blocked by pretreatment with the dopamine D1 receptor antagonist SCH-23390. In intact subjects, SKF 83959 induced Fos expression less potently than the standard dopamine D1 receptor agonist SKF 82958, but the two drugs were approximately equipotent in deinnervated animals. These results demonstrate for the first time that possession of full efficacy at dopamine D1 receptors linked to adenylyl cyclase is not a necessary requirement for the induction of striatal Fos expression in intact animals and suggest that alternative signal transduction pathways may play a role in dopamine agonist induced Fos expression, especially in dopamine-depleted subjects.

The distribution of m4 muscarinic acetylcholine receptors in the islands of Calleja and striatum of rats and cynomolgus monkeys.

The distribution of m4 muscarinic acetylcholine receptors, and their relation to a number other markers, was examined using immunocytochemical techniques. Staining in the dorsal striatum tended to be more pronounced in the striosomal than the matrix compartment of both rats and cynomolgus monkeys. Within the ventral striatum, immunoreactivity was more pronounced within the olfactory tubercle and the shell region of the nucleus accumbens than in the nucleus accumbens core and was especially marked within the lateral striatal stripe. Modest staining was also seen in the external plexiform layer of the olfactory bulb. By far, the most intense staining in the forebrain of both rats and cynomolgus monkeys was found in islands of Calleja, where it appeared to be a selective marker for the core or hilus regions of the islands, or an analogous region found adjacent to them. The core regions of different islands appear to be continuous with each other so as to form a complex three-dimensional structure, which is largely encased by layers of granule cells. The neuronal elements in the islands of Calleja, which express m4 receptors, remain to be identified, but it is unlikely that cholinergic neurons are a major locus of these receptors. Although there are certain similarities between the islands of Calleja and other components of the striatal complex, the current studies emphasize the extent to which the islands are unique in terms of their architecture and chemical anatomy.