Sensitive bispecific chimeric T cell receptors for cancer therapy.

The expression of a synthetic chimeric antigen receptor (CAR) to redirect antigen specificity of T cells is transforming the treatment of hematological malignancies and autoimmune diseases [1-7]. In cancer, durable efficacy is frequently limited by the escape of tumors that express low levels or lack the target antigen [8-12]. These clinical results emphasize the need for immune receptors that combine high sensitivity and multispecificity to improve outcomes. Current mono- and bispecific CARs do not faithfully recapitulate T cell receptor (TCR) function and require high antigen levels on tumor cells for recognition [13-17]. Here, we describe a novel synthetic chimeric TCR (ChTCR) that exhibits superior antigen sensitivity and is readily adapted for bispecific targeting. Bispecific ChTCRs mimic TCR structure, form classical immune synapses, and exhibit TCR-like proximal signaling. T cells expressing Bi-ChTCRs more effectively eliminated tumors with heterogeneous antigen expression in vivo compared to T cells expressing optimized bispecific CARs. The Bi-ChTCR architecture is resilient and can be designed to target multiple B cell lineage and multiple myeloma antigens. Our findings identify a broadly applicable approach for engineering T cells to target hematologic malignancies with heterogeneous antigen expression, thereby overcoming the most frequent mechanism of relapse after current CAR T therapies.

Interactions between marine megafauna and plastic pollution in Southeast Asia.

Southeast (SE) Asia is a highly biodiverse region, yet it is also estimated to cumulatively contribute a third of the total global marine plastic pollution. This threat is known to have adverse impacts on marine megafauna, however, understanding of its impacts has recently been highlighted as a priority for research in the region. To address this knowledge gap, a structured literature review was conducted for species of cartilaginous fishes, marine mammals, marine reptiles, and seabirds present in SE Asia, collating cases on a global scale to allow for comparison, coupled with a regional expert elicitation to gather additional published and grey literature cases which would have been omitted during the structured literature review. Of the 380 marine megafauna species present in SE Asia, but also studied elsewhere, we found that 9.1 % and 4.5 % of all publications documenting plastic entanglement (n = 55) and ingestion (n = 291) were conducted in SE Asian countries. At the species level, published cases of entanglement from SE Asian countries were available for 10 % or less of species within each taxonomic group. Additionally, published ingestion cases were available primarily for marine mammals and were lacking entirely for seabirds in the region. The regional expert elicitation led to entanglement and ingestion cases from SE Asian countries being documented in 10 and 15 additional species respectively, highlighting the utility of a broader approach to data synthesis. While the scale of the plastic pollution in SE Asia is of particular concern for marine ecosystems, knowledge of its interactions and impacts on marine megafauna lags behind other areas of the world, even after the inclusion of a regional expert elicitation. Additional funding to help collate baseline data are critically needed to inform policy and solutions towards limiting the interactions of marine megafauna and plastic pollution in SE Asia.

Insights into the distribution and ingestion of prey-like plastic fishing lures in Mediterranean rough-toothed dolphins.

Rough-toothed dolphins (Steno bredanensis) form an isolated subpopulation in the Mediterranean Sea that resides only in the eastern basin. Due to the paucity of records, the conservation threats these dolphins face and their ecology and distribution are poorly understood. While most observations indicate that individuals are found in two isolated clusters in the eastern basin, we hereby present five observations -three visual, one acoustic and one stranding- that possibly extend the range of this subpopulation to the entire offshore waters of the eastern basin. The stomach content remains of the stranded individual revealed a diet based on epipelagic squids and octopods. The stranded dolphin had also consumed seven plastic bags and nine squid-like plastic fishing lures, which had caused a complete gastric blockage and probably led to the stranding. High pollution loads from macroplastics in the Mediterranean Sea may evolve into a new potential threat for this subpopulation.

'Eye in the sky': Off-the-shelf unmanned aerial vehicle (UAV) highlights exposure of marine turtles to floating litter (FML) in nearshore waters of Mayo Bay, Philippines.

Litter is a serious threat to the marine environment, with detrimental effects on wildlife and marine biodiversity. Limited data as a result of funding and logistical challenges in developing countries hamper our understanding of the problem. Here, we employed commercial unmanned aerial vehicle (UAV) as a cost-effective tool to study the exposure of marine turtles to floating marine litter (FML) in waters of Mayo Bay, Philippines. A quadcopter UAV was flown autonomously with on-board camera capturing videos during the flight. Still frames were extracted when either turtle or litter were detected in post-flight processing. The extracted frames were georeferenced and mapped using QGIS software. Results showed that turtles are highly exposed to FML in nearshore waters. Moreover, spatial dependence between FML and turtles was also observed. The study highlights the effectiveness of UAVs in marine litter research and underscores the threat of FML to turtles in nearshore waters.

Socio-temporal contextual and community factors associated with daily exclusive ENDS use and dual use with tobacco cigarettes among adolescent vapers: an ecological momentary assessment study.

BACKGROUND: Adolescents who dual use ENDS with tobacco cigarettes are more likely to have an increased risk of developing dependence. Yet, little is understood about the factors driving dual use among adolescents. The current study sought to reveal the day-to-day socio-temporal contextual and community factors associated with adolescents' use of electronic nicotine delivery systems (ENDS), and how these factors predict dual use with tobacco cigarettes. METHODS: We collected ecological momentary assessments (EMA) from a sample of 50 adolescent past two-week vapers (ages 14-17 years old) over 14 days. Daily EMA data were collected on ENDS and tobacco cigarette use, as well as a range of contextual (i.e., motivations to vape, location of vaping, who with when vaping) and community factors (i.e., exposure to peers vaping, to adults vaping, to ENDS advertising, to ENDS warning messages). Our primary analyses were multilevel regressions, accounting for daily observations nested within individuals (N = 700 observations). RESULTS: Participants used ENDS exclusively on 44% of days and dual used ENDS and tobacco cigarettes on 8% of the days. Dual use days (versus exclusive ENDS use days) were associated with "vaping because tobacco use was prohibited" (OR = 34.65, p < .05). Also, dual use days (versus no use days) were associated with greater exposure to adults vaping (OR = 5.59, p < .05), peers vaping (OR = 7.48, p < .05), and (c) ENDS advertisements or promotions (OR = 2.12, p < .01), whereas exclusive use days (versus no use days) were only associated with greater exposure to peers vaping (OR = 2.58, p < .01). CONCLUSIONS: Results showed that exposure to peers and adults vaping and exposure to ENDS marketing were associated with same day dual use behaviors. And, that adolescents who dual used were motivated to use ENDS because they were easy to conceal. Findings support stricter regulation of ENDS marketing and for smoke-free air laws that include ENDS. In addition, these findings support prioritizing family- and school-based prevention programming that effectively communicates risk associated with ENDS use, including heightened risk of dual use and dependence. Such efforts can reduce the number of adolescents who use ENDS as well as the number who transition to tobacco cigarette use.

"I don't know whose mouth has been on this": youth nicotine and cannabis vaping practices in the context of the COVID-19 pandemic.

Early COVID-19 safety protocols urged physical and social distancing, resulting in minimal contact with others. As social contexts are central to vaping among youth, we used semi-structured interviews to describe how youth who vape are making sense of their use practices and adaptations. The qualitative analyses revealed changes in vaping frequency and access, social isolation shaping substance- and product-specific use, and motivations and outcomes of dual use of nicotine and cannabis which were closely linked to the pandemic. The findings indicate variation of youth vaping experiences within the early stages of the pandemic that should be attended to in future studies.

Changes in the Patterns and Characteristics of Youth ENDS Use over Time.

Research on youth use of electronic nicotine delivery systems (ENDS) has explored the correlates of initiation and use; however, little is known about the factors that predict continued youth use of ENDS. We used an ecological momentary assessment (EMA) burst design to explore both daily variability within adolescents over a two-week observation period and variability over time two years later (2018 and 2020). The contribution of device characteristics, motivations for use, contextual factors, and community factors to daily use occasions were explored. Youth participants (n = 35) at the start of the study were past two-week nicotine vapers, 14 to 17 years old, who resided within 100 miles of Louisville, KY, and reported past two-week ENDS use. Close to a quarter of participants ceased all tobacco use two years later, suggesting that some youth, despite prior regular vaping habits, may have only been experimenting with ENDS. The regular continued use of ENDS was predicted by trying to quit using cigarettes, appealing flavors, and being in locations where cigarette use was prohibited. Except for flavors, these factors did not affect ENDS use in year one. These findings suggest that tobacco policy might target ENDS use by prohibiting all tobacco use, including ENDS, in locations where smoking is already banned.

De novo design of protein homodimers containing tunable symmetric protein pockets.

Function follows form in biology, and the binding of small molecules requires proteins with pockets that match the shape of the ligand. For design of binding to symmetric ligands, protein homo-oligomers with matching symmetry are advantageous as each protein subunit can make identical interactions with the ligand. Here, we describe a general approach to designing hyperstable C2 symmetric proteins with pockets of diverse size and shape. We first designed repeat proteins that sample a continuum of curvatures but have low helical rise, then docked these into C2 symmetric homodimers to generate an extensive range of C2 symmetric cavities. We used this approach to design thousands of C2 symmetric homodimers, and characterized 101 of them experimentally. Of these, the geometry of 31 were confirmed by small angle X-ray scattering and 2 were shown by crystallographic analyses to be in close agreement with the computational design models. These scaffolds provide a rich set of starting points for binding a wide range of C2 symmetric compounds.

Daily variation in the patterns and characteristics of adolescent ENDS use.

OBJECTIVE: Adolescents are more likely than young adults to use electronic nicotine delivery systems (ENDS), yet most of what is known is concluded from young adult ENDS use as young adults are easier to survey. Additionally, while evidence about the prevalence and trends of adolescent ENDS use comes from cross-sectional studies, ecological momentary assessment (EMA) studies provide greater detail about the ways in which adolescents vape and the environments that are favorable to adolescent vaping, providing important guidance for policy, prevention, and intervention. METHOD: We conducted a 2-week EMA study with 50 adolescents to assess behaviors, contexts, and characteristics of ENDS use. Given longitudinal research showing strong associations between ENDS use and use of other substances, we also examined tobacco cigarettes use, and daily concurrent use with tobacco cigarettes and marijuana. RESULTS: There was little daily variability in motivations, willingness, and intentions, or in product characteristics. ENDS use varied by day and was more frequent on weekends, whereas cigarette use was less likely on weekends. We found daily variability in contexts and the characteristics of situations where adolescents used, which were largely social-normative, including whose device was used, which flavors were used, and where and with whom adolescents used ENDS. Unexpectedly, marijuana accompanied more than a quarter of ENDS use occasions. CONCLUSIONS: Socio-ecological context is important for explaining adolescent ENDS use and it is critical to developing adolescent ENDS prevention, intervention, and treatment resources. Prevention messaging may be most relevant and effective on weekends when youth exposure to advertising and peer influences are greatest. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Association of Travel Distance to Nearest Abortion Facility With Rates of Abortion.

Importance: Travel distance to abortion services varies widely in the US. Some evidence shows travel distance affects use of abortion care, but there is no national analysis of how abortion rate changes with travel distance. Objective: To examine the association between travel distance to the nearest abortion care facility and the abortion rate and to model the effect of reduced travel distance. Design, Setting, and Participants: This cross-sectional geographic analysis used 2015 data on abortions by county of residence from 1948 counties in 27 states. Abortion rates were modeled using a spatial Poisson model adjusted for age, race/ethnicity, marital status, educational attainment, household poverty, nativity, and state abortion policies. Abortion rates for 3107 counties in the 48 contiguous states that were home to 62.5 million female residents of reproductive age (15-44 years) and changes under travel distance scenarios, including integration into primary care (<30 miles) and availability of telemedicine care (<5 miles), were estimated. Data were collected from April 2018 to October 2019 and analyzed from December 2019 to July 2020. Exposures: Median travel distance by car to the nearest abortion facility. Main Outcomes and Measures: US county abortion rate per 1000 female residents of reproductive age. Results: Among the 1948 counties included in the analysis, greater travel distances were associated with lower abortion rates in a dose-response manner. Compared with a median travel distance of less than 5 miles (median rate, 21.1 [range, 1.2-63.6] per 1000 female residents of reproductive age), distances of 5 to 15 miles (median rate, 12.2 [range, 0.5-23.4] per 1000 female residents of reproductive age; adjusted coefficient, -0.05 [95% CI, -0.07 to -0.03]) and 120 miles or more (median rate, 3.9 [range, 0-12.9] per 1000 female residents of reproductive age; coefficient, -0.73 [95% CI, -0.80 to -0.65]) were associated with lower rates. In a model of 3107 counties with 62.5 million female residents of reproductive age, 696 760 abortions were estimated (mean rate, 11.1 [range, 1.0-45.5] per 1000 female residents of reproductive age). If abortion were integrated into primary care, an additional 18 190 abortions (mean rate, 11.4 [range, 1.1-45.5] per 1000 female residents of reproductive age) were estimated. If telemedicine were widely available, an additional 70 920 abortions were estimated (mean rate, 12.3 [range, 1.4-45.5] per 1000 female residents of reproductive age). Conclusions and Relevance: These findings suggest that greater travel distances to abortion services are associated with lower abortion rates. The results indicate which geographic areas have insufficient access to abortion care. Modeling suggests that integrating abortion into primary care or making medication abortion care available by telemedicine may decrease unmet need.

The impact of flavored ENDS use among adolescents on daily use occasions and number of puffs, and next day intentions and willingness to vape.

BACKGROUND: The FDA's policies restricting sale of sweet flavored cartridge-based and disposable electronic nicotine delivery systems (ENDS) comprise important steps toward curbing adolescent ENDS use. However, additional evidence is needed about the contribution of specific flavors to adolescents' ENDS use. This study investigated the effects of flavor use on same day vaping behaviors, and next day intentions and willingness. METHODS: We collected ecological momentary assessments (EMA) from 50 adolescent past two-week vapers (ages 14-17) over 14 days. Daily EMA data were collected on vaping occasions, total puffs, vaping intentions, vaping willingness, and flavor used. RESULTS: On average, data were obtained on 13.4 days per participant (670 observations). Participants vaped flavors on 87% of days (fruit = 55%; mint = 30%; tobacco = 6%; menthol = 5%, and candy, sweets, or chocolate = 5%). On days when participants vaped fruit flavors, they took more puffs (r = 0.13, p = .030). On days when they vaped tobacco flavor, they reported more vaping occasions (r = 0.20, p = .005) and more puffs (r = 0.15, p = .033). On days when they vaped because of flavor appeal, they reported more vaping occasions (r = 0.19, p = .001) and more puffs (r = 0.24, p < .001). On days when they vaped menthol flavor, they were less likely to report willingness to vape the next day (r = -0.14, p = .042). Adolescents who reported vaping due to flavor appeal were more likely to report intentions (OR = 5.63, p = .035) and willingness to vape the next day (r = 0.23, p < .001) CONCLUSION: These findings provide additional support for policies restricting the sale of flavored ENDS products to adolescents.

Differential patterns of e-cigarette and tobacco marketing exposures among youth: Associations with substance use and tobacco prevention strategies.

BACKGROUND: This study identified patterns of tobacco marketing exposures among youth and examined their associations with substance use and tobacco prevention strategies. METHODS: In Fall 2018, 2,058 middle and high school students (ages 11-18) in an Appalachian county completed a substance use and behavioral health surveillance survey. We conducted latent class analysis (LCA) to identify exposure classes based on responses to 14 tobacco marketing exposures. Multinomial logistic regression was then performed to determine associations between the latent classes with past 30-day substance use and tobacco prevention strategies (e.g., school policies, parental rules, prevention messages). RESULTS: Four latent classes of marketing exposure were identified among middle school students: low exposure, television, social media, and high exposure. Multinomial logistic regression found significant associations between e-cigarette use with the social media and high exposure classes, while prescription drug use was associated with the social media class and alcohol use with the high exposure class. For high school students, five classes were identified: low exposure, social media, environmental, cigarettes, and high exposure. E-cigarette and prescription drug use were associated with the social media and high exposure classes. Cigarette use was associated with the social media class. School rules prohibiting e-cigarettes were associated with the television class for middle school students. Self-reported exposure to prevention messages about the harms of tobacco were associated with multiple exposure classes for both middle (television and social media) and high school (social media and cigarettes) students, suggesting that both pro- and anti-tobacco communications have become ubiquitous and may be saturating youth. CONCLUSION: This study demonstrates the need for stricter tobacco marketing regulations and multi-level interventions beginning in early adolescence that focus on increasing media-based literacy for youth to better discern tobacco prevention messages from pro-tobacco communications.

Peer-Led Training to Reduce Alcohol Misuse and Related Harm among Greek-Affiliated Students.

BACKGROUND: High-risk alcohol use on college campuses is a significant public health concern, especially among students in fraternities and sororities. Alcohol harm-reduction programs that include protective behavioral strategies (PBSs) provide a promising approach to curb drinking among students, yet results have been inconsistent among high-risk drinkers. Purpose: To evaluate the impact of a harm-reduction, peer-led training program called "Voice of Reason" (VOR) on alcohol knowledge and behaviors among students in Greek chapters. Methods: We conducted two studies with students directly trained in VOR (Study 1: N = 118; Study 2: N = 53) and with students in affiliated Greek chapters (Study 1: N = 1363; Study 2: N = 1446). Study 1 included 13 chapters and Study 2 included 15 chapters. Results: Results of analyses across both studies showed that among those directly trained in VOR, there were pre-post increases in alcohol knowledge, medical amnesty law awareness, talking with friends about PBS, use of PBS, and intentions to use PBS, as well as pre-post decreases in drinking and driving and riding with drinking drivers. In addition, VOR had an impact on students in affiliated chapters, indicating an increase in medical amnesty law awareness and a decrease in the number of drinks consumed on a typical day. Conclusions: Overall, results provide some early evidence of VOR impact, while also demonstrating the challenge of changing normative drinking behaviors among high-risk college students. Ongoing research is needed to assess the effectiveness of VOR, especially after successive implementations with the same chapters.

Rapid uptake of early medical abortions in the Northern Territory: A family planning-based model.

BACKGROUND: Abortion law reform does not necessarily translate into services, especially for those in regional areas. Although abortion has been legal in the Northern Territory (NT) since 1974, prior to 2017 legislation change, early medical abortions (EMAs) were effectively prohibited in primary care. In July 2017, Family Planning Welfare Association of the Northern Territory (FPNT) was awarded funding to provide EMAs free of charge for Medicare eligible clients. AIMS: To describe the demographics and clinical outcomes of clients accessing the EMA service in the first 12 months after legislation change. MATERIALS AND METHODS: Retrospective audit of FPNT's Unplanned Pregnancy Database from 1 July 2017 to 30 June 2018 and analysis of the NT Government's Termination of Pregnancy 12 Month Data Report. RESULTS: Of 742 abortions in the NT in the first 12 months after legislation change, 426 were EMAs prescribed at FPNT. Eleven percent of these (47/426) were for Aboriginal or Torres Strait Islander women and 15% (64/426) were for women from Remote or Very Remote Australia. Outcomes were definitively documented for 326 (77%); 5% of these required further misoprostol and 99% had a complete abortion without surgical intervention. Eighty-six percent (281/326) commenced effective hormonal contraception following their EMA. CONCLUSIONS: Providing funding to a Family Planning service was effective in devolving the majority of abortions from tertiary to primary healthcare and increasing the use of effective contraception. Some women remain under-represented, particularly women from more remote areas of the NT. Further work is required to ensure equity of access to services for these women.

Joy of gardening: a hospital-based cooking and gardening program.

BACKGROUND: Nutrition interventions aid in implementing healthy eating. Garden-enhanced nutrition intervention programs have been conducted in schools. We sought to assess feasibility of a hospital-based cooking and gardening program. METHODS: The cohort study implemented a 3-week integrated cooking and gardening program in the United States (Seattle, WA). We recruited participants with ages 8-15 years from ambulatory clinics. We conducted three 3-week series hospital-based cooking and gardening program. Children and parents were given pre- and post-program (1 year) surveys. The surveys assessed child participation in food preparation and gardening, strengths and weaknesses of the program, and identified parents' opinions towards sustaining healthy behaviors. RESULTS: Eighteen children participated in the hospital-based cooking and gardening program. At 1-year follow-up, 78% of participants were gardening at home and 100% of participants were cooking at home. CONCLUSIONS: Novel approaches to combat obesity are needed. A hospital-based cooking and gardening program is a novel intervention to consider for nutrition education.

Autumn shifts in cold tolerance metabolites in overwintering adult mountain pine beetles.

The mountain pine beetle, Dendroctonus ponderosae (Coleoptera: Curculionidae) is a major forest pest of pines in western North America. Beetles typically undergo a one-year life cycle with larval cold hardening in preparation for overwintering. Two-year life cycle beetles have been observed but not closely studied. This study tracks cold-hardening and preparation for overwintering by adult mountain pine beetles in their natal galleries. Adults were collected in situ between September and December 2016 for a total of nine time points during 91 days. Concentrations of 41 metabolites in these pooled samples were assessed using quantitative nuclear magnetic resonance (NMR). Levels of glycerol and proline increased significantly with lowering temperature during the autumn. Newly eclosed mountain pine beetles appear to prepare for winter by generating the same cold-tolerance compounds found in other insect larvae including mountain pine beetle, but high on-site mortality suggested that two-year life cycle adults have a less efficacious acclimation process. This is the first documentation of cold acclimation metabolite production in overwintering new adult beetles and is evidence of physiological plasticity that would allow evolution by natural selection of alternate life cycles (shortened or lengthened) under a changing climate or during expansion into new geoclimatic areas.

If momma ain't happy with the mentoring relationship, ain't nobody happy with the mentoring relationship: Parental satisfaction as a predictor of mentoring match strength and length.

Much evidence exists on whether an individual's perception of a match relationship impacts match strength and length, but relatively less is known about whether parental perceptions of the match (i.e., whether the match is meeting their goals) impacts the length and strength of mentoring relationships. These relationships were examined in a sample of 350 newly formed youth-mentor matches who completed multiple measures of match strength and satisfaction with the match. Parents/guardians were also surveyed about their level of satisfaction with the match. The primary finding of this paper was that parent/guardian dissatisfaction with the match relationships meeting goals was the only significant predictor of a higher likelihood of match closure. Although youth and mentor self-reports of satisfaction with how match time was spent were the strongest predictors of volunteer and youth match strength ratings, parent/guardian satisfaction with the match relationship also remained a strong predictor of match strength. The implications of these findings are discussed.

Social media as a novel source of data on the impact of marine litter on megafauna: The Philippines as a case study.

Marine litter is a global threat to marine biodiversity. However, there is a key knowledge gap on the impacts of marine litter in the Philippines - a country of high marine biodiversity and large exclusive economic zone. This gap is addressed here by using information shared on the internet by citizen scientists and conservation groups to assess the impacts of marine litter on megafauna. Facebook, presently the largest social media platform, was scanned for posts concerning the interaction between litter and marine species in the Philippines. Results showed thirty-two individuals from 17 species were affected by marine litter in the country. Furthermore, ingestion (61%) was the most frequent interaction reported. Mindanao was also identified as a hotspot for marine litter interactions. The study highlights the utility of social media in providing data to create an inventory of marine species adversely affected by litter and the spatial distribution of these interactions.