"If You Just Tell Me You're 18, I'll Still Sell to You": A Qualitative Study of Underage Tobacco Product Purchasing Experiences in a Tobacco 21 Compliance Study.

BACKGROUND: Tens of thousands of underage tobacco buy attempts are conducted each year for research, compliance, and public health surveillance. However, little research has qualitatively examined the perceptions and experiences of underage buyers participating in these programs. We sought to understand underage buyers' experiences and gather recommendations for protocol improvements. METHODS: We conducted semi-structured interviews in the fall of 2022 to assess experiences with underage tobacco product purchasing. Participants (N = 19, 58% male, 42% White) were research assistants aged 18-20 in New Jersey, New York, or North Carolina. Interviews examined purchasing experiences in relation to store characteristics, clerk interactions, and buyer identities. We used deductive and inductive thematic coding to explore key themes related to buyer experiences. RESULTS: We identified four themes: (1) non-chain stores lacked consistency in verifying age; (2) female data collectors experienced uncomfortable situations more frequently than male data collectors; (3) not identifying with the store's typical demographics impacted purchase attempts; and (4) participants suggested improvements for inspections and research during training. DISCUSSION: Retailer education, widespread adoption of ID scanners, and enforcement could increase standardization of ID requests and verification. Male and female buyers can be trained on what they might expect based on their gender, as well as how to maneuver through unwanted situations. Consideration of shared identity is important for future waves of data collection and research. Efforts to improve training include more extensive mock purchase training with supervisors well-versed in this area. IMPLICATIONS: Electronic ID verification and promoting compliance at non-chain retailers could impact access to tobacco products for underage buyers. Training for underage buyers in research and compliance assessments should focus on ways to enhance data collectors' confidence when making a purchase attempt, which may improve the validity of the rate of sales to individuals under 21.

Evaluation of commercial devices for patient specific QA of stereotactic radiotherapy plans.

Stereotactic radiotherapy (SRT) methods have become common for the treatment of small tumors in various parts of the body. Small field dosimetry has a unique set of challenges when it comes to the pre-treatment validation of a radiotherapy plan that involves film dosimetry or high-resolution detectors. Comparison of commercial quality assurance (QA) devices to the film dosimetry method for pre-treatment evaluation of stereotactic radiosurgery (SRS), fractionated SRT, and stereotactic body radiation therapy treatment plans have been evaluated in this study. Forty stereotactic QA plans were measured using EBT-XD film, IBA Matrixx Resolution, SNC ArcCHECK, Varian aS1200 EPID, SNC SRS MapCHECK, and IBA myQA SRS. The results of the commercial devices are compared to the EBT-XD film dosimetry results for each gamma criteria. Treatment plan characteristics such as modulation factor and target volume were investigated for correlation with the passing rates. It was found that all detectors have greater than 95% passing rates at 3%/3 mm. Passing rates decrease rapidly for ArcCHECK and the Matrixx as criteria became more strict. In contrast, EBT-XD film, SNC SRS MapCHECK, and IBA myQA SRS passing rates do not decline as rapidly when compared to Matrix Resolution, ArcCHECK, and the EPID. EBT-XD film, SNC SRS MapCHECK, and IBA myQA SRS maintain greater than 90% passing rate at 2%/1 mm and greater than 80% at 1%/1 mm. Additionally, the ability of these devices to detect changes in dose distribution due to MLC positioning errors was investigated. Ten VMAT SBRT/SRS treatment plans were created with 6 MV FFF or 10 MV FFF beam energies using Eclipse 15.6. A MATLAB script was used to create two MLC positioning error scenarios from the original treatment plan. It was found that errors in MLC positioning were most reliably detected at 2%/1 mm for high-resolution detectors and that lower-resolution detectors did not consistently detect MLC positioning errors.

Switchable control over in vivo CAR T expansion, B cell depletion, and induction of memory.

Chimeric antigen receptor (CAR) T cells with a long-lived memory phenotype are correlated with durable, complete remissions in patients with leukemia. However, not all CAR T cell products form robust memory populations, and those that do can induce chronic B cell aplasia in patients. To address these challenges, we previously developed a switchable CAR (sCAR) T cell system that allows fully tunable, on/off control over engineered cellular activity. To further evaluate the platform, we generated and assessed different murine sCAR constructs to determine the factors that afford efficacy, persistence, and expansion of sCAR T cells in a competent immune system. We find that sCAR T cells undergo significant in vivo expansion, which is correlated with potent antitumor efficacy. Most importantly, we show that the switch dosing regimen not only allows control over B cell populations through iterative depletion and repopulation, but that the "rest" period between dosing cycles is the key for induction of memory and expansion of sCAR T cells. These findings introduce rest as a paradigm in enhancing memory and improving the efficacy and persistence of engineered T cell products.

'Being politically active does not have to be difficult.' A content analysis of tobacco industry-sponsored advocacy websites.

OBJECTIVE: To characterise the thematic content of tobacco industry-sponsored advocacy websites in the USA and to compare these sites to identify differences in products, target audience, policies or themes. METHODS: In 2017, US-based Google and purposive searches identified six US tobacco industry-sponsored advocacy websites. A coding guide based on existing literature, tobacco policy issues and iterative review of the websites was developed and, descriptive analyses of themes on individual websites and overall were conducted. RESULTS: We identified 18 themes; the most common of these were: tobacco taxes (13.9%), providing advocacy resources (10.6%) and pleas for action (10.3%). Related themes were aggregated into four broad categories: advocacy (36.7%), taxes (31.4%), legislation is excessive or unnecessary (21%), and support for weaker tobacco control policies (10.9%). Websites targeting consumers provided more resources to facilitate advocacy than websites targeting retailers. CONCLUSIONS: Websites promoting protobacco advocacy are an important and evolving strategy for the tobacco industry. Websites are particularly well suited to leverage marketing activities (eg, building relationships with retailers and consumers) to achieve policy objectives. Monitoring these tactics may allow advocates to counter and anticipate industry opposition to tobacco policy.

Evaluation of cystatin C as an early biomarker of cadmium nephrotoxicity in the rat.

Cadmium (Cd) is a nephrotoxic environmental pollutant that causes insidious injury to the proximal tubule that results in severe polyuria and proteinuria. Cystatin C is a low molecular weight protein that is being evaluated as a serum and urinary biomarker for various types of ischemic and nephrotoxic renal injury. The objective of the present study was to determine if cystatin C might be a useful early biomarker of Cd nephrotoxicity. Male Sprague-Dawley rats were given daily injections of Cd for up to 12 weeks. At 3, 6, 9 and 12 weeks, urine samples were analyzed for cystatin C, protein, creatinine, ß2 microglobulin and kidney injury molecule-1. The results showed that Cd caused a significant increase in the urinary excretion of cystatin C that occurred 3-4 weeks before the onset of polyuria and proteinuria. Serum levels of cystatin C were not altered by Cd. Immunolabeling studies showed that Cd caused the relocalization of cystatin C from the cytoplasm to the apical surface of the epithelial cells of the proximal tubule. The Cd-induced changes in cystatin C labelling paralleled those of the brush border transport protein, megalin, which has been implicated as a mediator of cystatin C uptake in the proximal tubule. These results indicate that Cd increases the urinary excretion of cystatin C, and they suggest that this effect may involve disruption of megalin-mediated uptake of cystatin C by epithelial cells of the proximal tubule.

Assessing the Effectiveness of Tobacco 21 Laws to Reduce Underage Access to Tobacco: Protocol for a Repeated Multi-Site Study.

Prior to the federal law passed in December 2019, many states passed an increased age of sale law prohibiting youth under age 21 (or Tobacco 21) from purchasing tobacco products, including e-cigarettes. Although previous research has documented tobacco retail sale violations, fewer studies have examined age verification and illegal tobacco sales in the context of Tobacco 21 or repeated purchase attempts in various settings. In this study conducted between 2019 and 2022, buyers aged 18 to 20 years made repeated unsupervised purchase attempts of cigarettes, cigars, e-cigarettes, tobacco-free nicotine pouches, and smokeless tobacco at over 180 tobacco or e-cigarette retailers in New Jersey, New York City, and Pitt County (North Carolina). Buyers documented whether they were asked for identification and whether they were able to successfully purchase a tobacco or nicotine product at each visit. The primary outcome will be the percent of retailers that checked the buyers' identification at store visits and the percent of visits that resulted in a successful underage tobacco product purchase. We will compare the results across time periods, study sites, products, and buyer characteristics (i.e., gender, minoritized racial/ethnic identity) while controlling for repeated visits. These results will inform improvements to current compliance check inspection programs as well as interventions that reduce youth access to tobacco.

The Applications and Pitfalls of Cone-Beam Computed Tomography-Based Synthetic Computed Tomography for Adaptive Evaluation in Pencil-Beam Scanning Proton Therapy.

PURPOSE: The study evaluates the efficacy of cone-beam computed tomography (CBCT)-based synthetic CTs (sCT) as a potential alternative to verification CT (vCT) for enhanced treatment monitoring and early adaptation in proton therapy. METHODS: Seven common treatment sites were studied. Two sets of sCT per case were generated: direct-deformed (DD) sCT and image-correction (IC) sCT. The image qualities and dosimetric impact of the sCT were compared to the same-day vCT. RESULTS: The sCT agreed with vCT in regions of homogeneous tissues such as the brain and breast; however, notable discrepancies were observed in the thorax and abdomen. The sCT outliers existed for DD sCT when there was an anatomy change and for IC sCT in low-density regions. The target coverage exhibited less than a 5% variance in most DD and IC sCT cases when compared to vCT. The Dmax of serial organ-at-risk (OAR) in sCT plans shows greater deviation from vCT than small-volume dose metrics (D0.1cc). The parallel OAR volumetric and mean doses remained consistent, with average deviations below 1.5%. CONCLUSION: The use of sCT enables precise treatment and prompt early adaptation for proton therapy. The quality assurance of sCT is mandatory in the early stage of clinical implementation.

Spatial relations and spatial locations are dissociated within prefrontal and parietal cortex.

Item-specific spatial information is essential for interacting with objects and for binding multiple features of an object together. Spatial relational information is necessary for implicit tasks such as recognizing objects or scenes from different views but also for explicit reasoning about space such as planning a route with a map and for other distinctively human traits such as tool construction. To better understand how the brain supports these two different kinds of information, we used functional MRI to directly contrast the neural encoding and maintenance of spatial relations with that for item locations in equivalent visual scenes. We found a double dissociation between the two: whereas item-specific processing implicates a frontoparietal attention network, including the superior frontal sulcus and intraparietal sulcus, relational processing preferentially recruits a cognitive control network, particularly lateral prefrontal cortex (PFC) and inferior parietal lobule. Moreover, pattern classification revealed that the actual meaning of the relation can be decoded within these same regions, most clearly in rostrolateral PFC, supporting a hierarchical, representational account of prefrontal organization.

A Pilot Study to Examine Retailer Compliance Before and After Tobacco 21 in New Jersey.

Despite rapid diffusion of Tobacco 21 (T21) laws in the last several years, research examining T21 compliance remains limited. This pilot study examined retailer compliance with carding before and after T21 as well as sales violations after T21 in New Jersey. A 19-year-old buyer made alternating cigar and cigarette purchase attempts in 15 licensed tobacco retailers weekly for five weeks before and 10 weeks following the T21 effective date for a total of 222 visits. We analyzed carding pre and post T21 and sales violations post T21, by store and product type. Failure to card declined post T21 (81.3% to 69.4%), particularly for cigarettes, but not cigars. Overall, 63.3% of retailers sold tobacco to the underage buyer post T21. Following New Jersey's T21 law, compliance with carding improved, but underage sales persisted. Future research examining T21 compliance should consider using a familiarity protocol to mimic real word conditions.

Neighborhood distribution of availability of newer tobacco products: A US four-site study, 2021.

Audits of tobacco retailers can identify marketing patterns as newer tobacco products are introduced in the US. Our study examined store and neighborhood correlates of availability of nicotine pouches and disposable e-cigarettes in four US sites. We conducted standardized store audits of n = 242 tobacco retailers in 2021 in different states: New Jersey, Kentucky, North Carolina, and New York. We geocoded stores linking them with census tract demographics. We conducted unadjusted and adjusted Poisson regression of availability of each product with correlates of the proportion of Non-Hispanic White residents, households under poverty, proximity to schools, site, and store type. Nicotine pouches and disposable e-cigarettes were each available in around half the stores overall, but availability differed across sites (range: 76 %-32 %). In adjusted analyses, nicotine pouches were less likely to be available in each store type vs chain convenience (IRR range 0.2-0.6) and more likely in stores in census tracts with a greater percentage of non-Hispanic White residents (IRR range 1.8-2.3). In contrast, disposable e-cigarettes were more likely to be available in tobacco/vape shops (IRR 1.9 (1.4-2.5) than convenience stores and less likely in non-specialty store types like groceries (IRR 0.2 (0.1-0.4). Newer tobacco products like nicotine pouches and disposable e-cigarettes were widely available in stores across sites, but retail marketing patterns appear to differ. As these product types become subject to increased regulation as they go through the FDA pre-market authorization process, understanding patterns and changes in the retail environment is critical to inform potential policies regulating their sale and marketing.

Chemical Inhibition of ENL/AF9 YEATS Domains in Acute Leukemia.

Transcriptional coregulators, which mediate chromatin-dependent transcriptional signaling, represent tractable targets to modulate tumorigenic gene expression programs with small molecules. Genetic loss-of-function studies have recently implicated the transcriptional coactivator, ENL, as a selective requirement for the survival of acute leukemia and highlighted an essential role for its chromatin reader YEATS domain. Motivated by these discoveries, we executed a screen of nearly 300,000 small molecules and identified an amido-imidazopyridine inhibitor of the ENL YEATS domain (IC50 = 7 µM). Improvements to the initial screening hit were enabled by adopting and expanding upon a SuFEx-based approach to high-throughput medicinal chemistry, ultimately demonstrating that it is compatible with cell-based drug discovery. Through these efforts, we discovered SR-0813, a potent and selective ENL/AF9 YEATS domain inhibitor (IC50 = 25 nM). Armed with this tool and a first-in-class ENL PROTAC, SR-1114, we detailed the biological response of AML cells to pharmacological ENL disruption for the first time. Most notably, we discovered that ENL YEATS inhibition is sufficient to selectively suppress ENL target genes, including HOXA9/10, MYB, MYC, and a number of other leukemia proto-oncogenes. Cumulatively, our study establishes YEATS domain inhibition as a viable approach to disrupt the pathogenic function of ENL in acute leukemia and provides the first thoroughly characterized chemical probe for the ENL YEATS domain.

Changes in Tobacco Product Advertising at Point of Sale: 2015-2018.

OBJECTIVES: Tobacco point-of-sale advertising, particularly in retailers surrounding schools, is associated with youth tobacco use and must be monitored. This study examines how the point-of-sale environment surrounding youth changed over time with regard to diverse tobacco products. METHODS: Each spring from 2015 to 2018, research staff visited the same tobacco retailers (n = 141) within a half-mile of New Jersey high schools. For cigarettes, cigars, electronic cigarettes, and smokeless tobacco, advertisement presence, volume, and share of advertising voice (SAV) were measured for both the exterior and interior of the store. Analyses examined changes over time by product, controlling for store type and poverty. RESULTS: Over time, exterior cigarette advertisements declined in presence (61% to 49%) and SAV (50% to 40%), whereas interior advertisements maintained stable presence, volume, and SAV. In contrast, cigar advertisements increased in presence (exterior 11% to 23%; interior 19% to 30%) and volume (exterior mean 0.2 to 0.5; interior 0.3 to 0.8). For electronic cigarettes, exterior and interior advertising presence, volume, and SAV decreased from 2015 to 2017 but increased in 2018. Smokeless tobacco advertising was infrequent and stayed consistent except in volume in the interior of stores (mean 0.2 to 0.3). When there were any differences by store type, chain convenience stores had the most exterior and interior advertising for all products. CONCLUSIONS: The longitudinal changes observed for each product's advertising reflect national youth use rates of the corresponding products. The point-of-sale environment around schools may be influencing youth tobacco use and must be monitored and regulated.

Availability of menthol cigarettes in Oakland, California after a partial flavor ban.

This study measures the availability of menthol cigarettes in Oakland, California where such products were banned from the majority of tobacco retailers, except for those who sold a significant amount of tobacco (e.g., 60% gross income). Out of a total of 385 retailers in Oakland, only forty-eight retailers were exempt from this ban at the time of data collection. In February 2019, seven months after the ban went into effect, we selected a stratified random sample of 15 census tracts, based on race/ethnicity. In pairs, data collectors walked on opposite sides of the street and collected all discarded cigarette packs (n = 641) from the streets and sidewalks on weekdays. Overall, we found almost half (46.0%; 95% CI = 32.6%-59.3%) of the packs collected were menthol, with Newport as the dominant brand. We found at least one pack of menthol cigarettes in 14 of the 15 sampled census tracts. In predominantly black/African American census tracts, the proportion of menthol cigarettes collected was significantly higher (70.1%; 95% CI = 62.6%-77.7%) when compared to mixed race/ethnicity (55.9%; 95% CI = 41.0-70.9%) and white tracts (35.1%; 95% CI = 13.2%-57.1%). Finally, there was a moderate and negative correlation between distance to exempt tobacco retailer and menthol availability (r = -0.66, p < .05). The proportion of menthol cigarette packs decreased the further away census tracts were from exempt tobacco retailers. Results from this study lend support that partial bans provide disproportionate availability of menthol cigarettes in black/African American census tracts. Complete bans may help eliminate disparities associated with menthol cigarette use across communities.

Cell-Based Ligand Discovery for the ENL YEATS Domain.

ENL is a transcriptional coactivator that recruits elongation machinery to active cis-regulatory elements upon binding of its YEATS domain-a chromatin reader module-to acylated lysine side chains. Discovery chemistry for the ENL YEATS domain is highly motivated by its significance in acute leukemia pathophysiology, but cell-based assays able to support large-scale screening or hit validation efforts do not presently exist. Here, we report on the discovery of a target engagement assay that allows for high-throughput ligand discovery in living cells. This assay is based on the cellular thermal shift assay (CETSA) but does not require exposing cells to elevated temperatures, as small-molecule ligands are able to stabilize the ENL YEATS domain at 37 °C. By eliminating temperature shifts, we developed a simplified target engagement assay that requires just two steps: drug treatment and luminescence detection. To demonstrate its value for higher throughput applications, we miniaturized the assay to a 1536-well format and screened 37 120 small molecules, ultimately identifying an acyl-lysine-competitive ENL/AF9 YEATS domain inhibitor.

Retailer Compliance With Tobacco 21 in New Jersey, 2019-2020.

This cross-sectional study assesses retailer compliance with the Tobacco 21 law in New Jersey during 2019 and 2020.

A Review of Diabetes Mellitus and Exposure to the Environmental Toxicant Cadmium with an Emphasis on Likely Mechanisms of Action.

There is increasing interest in how exposure to environmental substances can contribute to the onset of Type II diabetes mellitus (T2DM). Impaired insulin release is a hallmark of type I diabetes mellitus and is involved in the progression of T2DM. Both epidemiological and experimental studies show that exposure to the environmental pollutant cadmium (Cd), is associated with hyperglycemia, T2DM and reduced serum insulin. The goal of this review is to examine likely mechanisms of action of Cd-induced dysglycemia based on experimental studies in the literature and from the most recent findings in the Edwards lab. The primary focus of this review will examine how Cd may cause islet dysfunction and subsequent impaired insulin release. Recent findings in the Edwards lab indicate that Cd causes timedependent and statistically significant changes in fasting leptin, Glucose-dependent Insulinotropic Polypeptide (GIP) and pancreas polypeptide hormone levels in a subchronic animal model of Cd-induced hyperglycemia. This review summarizes the most likely cellular mechanisms by which the ubiquitous environmental contaminant Cd disrupts glucose homeostasis. While individual cellular effects of Cd are reviewed it is likely that no one single mechanism is involved, rather multiple mechanisms exist and work synergistically resulting in islet dysfunction and ultimately dysglycemia.

Resolving complex research data management issues in biomedical laboratories: Qualitative study of an industry-academia collaboration.

This paper describes a distributed collaborative effort between industry and academia to systematize data management in an academic biomedical laboratory. Heterogeneous and voluminous nature of research data created in biomedical laboratories make information management difficult and research unproductive. One such collaborative effort was evaluated over a period of four years using data collection methods including ethnographic observations, semi-structured interviews, web-based surveys, progress reports, conference call summaries, and face-to-face group discussions. Data were analyzed using qualitative methods of data analysis to (1) characterize specific problems faced by biomedical researchers with traditional information management practices, (2) identify intervention areas to introduce a new research information management system called Labmatrix, and finally to (3) evaluate and delineate important general collaboration (intervention) characteristics that can optimize outcomes of an implementation process in biomedical laboratories. Results emphasize the importance of end user perseverance, human-centric interoperability evaluation, and demonstration of return on investment of effort and time of laboratory members and industry personnel for success of implementation process. In addition, there is an intrinsic learning component associated with the implementation process of an information management system. Technology transfer experience in a complex environment such as the biomedical laboratory can be eased with use of information systems that support human and cognitive interoperability. Such informatics features can also contribute to successful collaboration and hopefully to scientific productivity.