2009 — 2013 |
Leventhal, Adam Matthew |
K08Activity Code Description: To provide the opportunity for promising medical scientists with demonstrated aptitude to develop into independent investigators, or for faculty members to pursue research aspects of categorical areas applicable to the awarding unit, and aid in filling the academic faculty gap in these shortage areas within health profession's institutions of the country. |
Affective and Genetic Correlates of Amphetamine Response @ University of Southern California
DESCRIPTION (provided by applicant): The goal of this award is to support the development of the candidate's skills to perform clinical research of affective and pharmacogenetic factors that influence stimulant abuse risk. Training will build upon the candidate's clinical psychology background in research on the association between affect and addiction. The career development plan consists of mentored training in stimulant psychopharmacology, the genetics of stimulant abuse, and affective mechanisms underlying addiction. The Brown University Center for Alcohol and Addiction Studies provides an intellectually stimulating environment with outstanding resources to ensure the candidate's successful achievement of his training plan. Dr. Christopher Kahler (primary mentor) and Drs. Harriet de Wit and Henry Kranzler (co-mentors) are each experts in affective mechanisms underlying addiction, stimulant psychopharmacology, and addiction genetics, respectively. The research plan will involve conducting an experimental pharmacogenetics laboratory study, which tests a putative model of stimulant abuse vulnerability that integrates affective and genetic sources of risk and is based on the notion that individual differences in the rewarding effects of drugs confer abuse liability. This model proposes that the influence of the dopamine transporter gene (a gene that regulates a key site of action for stimulants) on amphetamine's acute reinforcing effects is mediated by individual differences in hedonic capacity (a personality trait related to the ability to experience pleasure). Hypotheses derived from this model will be tested using a two-session double-blind within-subjects design laboratory experiment comparing response to placebo vs. 20mg oral d-amphetamine in 108 healthy drug-naive participants. Genotype and hedonic capacity will be assessed prior to testing as predictors of drug response. Results of this investigation are expected to support the submission of an R01 application that will expand this model to other genetic and affective sources of stimulant abuse vulnerability. In sum, this award will provide the candidate the necessary expertise to develop an independent innovative research program that will generate findings that elucidate mechanisms underlying stimulant abuse risk and inform more effective preventative interventions. PUBLIC HEALTH RELEVANCE: Stimulant abuse is a major public health epidemic with substantial societal costs. This project will elucidate how personality and genes concomitantly predispose individuals to stimulant abuse, which will have value for: (a) understanding which individuals are at greatest risk for stimulant abuse;and (b) developing more effective prevention treatments.
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2009 — 2012 |
Leventhal, Adam Matthew |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanisms Linking Anhedonia and Tobacco Addiction @ University of Southern California
DESCRIPTION (provided by applicant): Persistent smoking is a major cause of fatal disease. Despite this, many smokers relapse back to smoking shortly after making a quit attempt. These individuals may possess affective characteristics that leave them especially vulnerable to relapse. Anhedonia-an affective dimension indicative of inability to experience pleasure-may be such a characteristic. Evidence suggests that anhedonia is associated with relapse risk. However, research on the mechanisms linking anhedonia and smoking has been limited, leaving little data to guide the development of treatments that mitigate anhedonia's effect on relapse risk. Accordingly, a laboratory experiment is proposed to test hypotheses derived from an "appetitive- processing" model of anhedonia and smoking. This model purports that individuals with higher anhedonia have pre-existing deficits in reward processing, which heightens their sensitivity to the effects of acute tobacco deprivation on changes in appetitive motivational drives. Thus, when high-anhedonia individuals quit smoking, they may experience marked changes in appetitive motivation, which in turn distort the relative reward value of reinitiating smoking versus maintaining abstinence and pursuing alternate reinforcers. In this study, current smokers (N=128;>10 cig/day) will complete a baseline assessment followed by two counterbalanced experimental sessions, one in which they will have smoked ad lib and one in which they will have abstained from smoking for 12 hours. At both experimental sessions, participants will complete: (a) self-report measures of affect and cigarette craving;(b) computerized tasks that assess the motivational salience of reward-related, smoking-related, and aversive stimuli;and (c) a relapse analogue task that assesses the relative reward value of initiating smoking by measuring the extent to which participants choose to initiate smoking versus delay smoking for money. The primary aims are to test the hypotheses that smokers with higher baseline anhedonia will exhibit greater deprivation-induced: (1) deficits in the incentive properties of nonpharmacological rewards (exhibited by reductions in positive affect and the motivational salience of non-drug reinforcers);(2) increases in the incentive properties of smoking (exhibited by increases in cigarette craving and the motivational salience of smoking);(3) increases in the relative reward value of initiating smoking vs. delaying smoking for money. If successful, this study will generate essential information on the motivational mechanisms through which anhedonia increases relapse vulnerability. These data could be used to develop more effective treatments that mitigate anhedonia's influence on early relapse risk. Given the detrimental health effects of persistent smoking and the difficulty in quitting associated with anhedonia, such information could be of significant value to efforts to improve public health. PUBLIC HEALTH RELEVANCE: This study will help determine the reasons why people who have the psychological trait of anhedonia (i.e., the tendency to not enjoy pleasurable activities) are less successful when trying to quit smoking cigarettes. Uncovering these reasons could lead to the development of more effective smoking cessation treatments that prevent people from relapsing back to smoking after a quit attempt. Because of the enormous health costs associated with persistent smoking, such information could be of significant value to efforts to improve public health.
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2012 — 2016 |
Leventhal, Adam Matthew |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Anhedonia as a Risk Factor and Consequence of Substance Use @ University of Southern California
DESCRIPTION (provided by applicant): Substance use is a leading cause of preventable death and disability. Substance use typically onsets and progresses during adolescence. Thus, identifying novel risk factors for adolescent substance use initiation and progression may inform the development of innovative preventive interventions that reduce the public health burden of substance use. Anhedonia-an affective dimension indicative of diminished interest and pleasure in rewarding-has been recently identified as a correlate of substance use. However, critical gaps in the extant literature prevent research on anhedonia's relation with substance use from having a substantial impact on the field. For example, existing research has been entirely cross-sectional and has failed to parse out the role of common antecedents and contextual factors, leaving the casual features of this association unclear. Also, past work has primarily studied adults, with only three published studies of anhedonia-substance use relations in adolescents; each of these studies are subject to critical limitations. Furthermore, each prior study has used only a single measure anhedonia based on subjective report, which ignores multi-faceted nature of the anhedonia construct. Elucidating the relative roles of distinct facets of anhedonia in substance use is critical for designing novel prevention programs that raise hedonic response to an interest in healthy alternative non-drug reinforces. Additionally, this literature has been greatly disjointed and theoretical, with no previous effort to integrate findings into a unifying model within larger conceptualization of risk. Yet, it is important for models to identify theoretial mechanisms by which anhedonia increases substance use risk in a developmental pathway from use initiation to progression in order to advance basic theory and inform intervention development. Such research is critical in order to move forward with developing substance use preventive interventions that target anhedonia. Accordingly, we propose a longitudinal study to test hypotheses based on a novel integrative model, which predicts that anhedonia gives rise to a causal risk pathway that influences both substance use initiation and progression via positive reinforcement mechanisms. This model purports that individuals with higher anhedonia have expectations that substances will produce positive effects and are willing to use substances, which could promote substance use initiation. Once use is initiated, high-anhedonia individuals may be more sensitive to the acute subjective rewarding effects of drugs, which may further devalue the relative salience of non-drug rewards and result in declining engagement in alternative reinforces. These two factors may create a strong imbalance between the value of drug-related versus alternative reinforces, which may drive motivation to use again and increase likelihood of substance use progression. These pathways may be particularly prominent for those with concomitant characteristics that facilitate the expression of anhedonia's influence on motivation to initiation and progress substance use. Once consistent use is established, repeated drug exposure may cause psychobiological adaptations that further escalate anhedonia, recapitulate this cycle, and lead to more use. In this study, we will recruit a cohort f 2007 high school students to participate in a longitudinal study with 8 semiannual waves of self-report assessment (9th - 12th grades). Assessments will take place in the school setting, which will facilitate efficient and effective data collection, and will span both self-report measures an objective behavioral measures of anhedonia. The primary aims of the study are to test the hypotheses that: (1) anhedonia will prospectively predict substance use initiation among those with no prior history of use, (2) anhedonia will prospectively predict substance use progression, and (3) Greater frequency of use will prospectively predict increases in anhedonia over time. Secondary aims will positive reinforcement mechanisms that mediate and moderate the effects of anhedonia on substance use risk that are derived from the model. The information gained from this study could be of significant value to developing novel, more effective prevention strategies that enhance experiential pleasure and positive reinforcement to prevent substance use. Such efforts could ultimately allay the substantial public health burden caused by substance use disorders.
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2013 — 2014 |
Leventhal, Adam Matthew |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Neuroendocrine Factors, Nicotine, and Behavioral Inhibition in Female Smokers @ University of Southern California
DESCRIPTION (provided by applicant): Gonadal neuroendocrine function is a key aspect of sex differences implicated in addiction. Focusing on the menstrual cycle and ovarian hormone modulation of nicotine's effects may elucidate etiologic mechanisms and neuroendocrine-based treatments for addiction among women and perhaps men also. Accordingly, this project tests a novel theoretical model which proposes that behavioral inhibition-a biobehavioral process that putatively influences addictive behavior, is modulated by nicotine, and is affected by ovarian hormones-is a mechanism linking neuroendocrine variation driven by the menstrual cycle and smoking in women. Behavioral inhibition refers to the ability to suppress habitual responses that are not required or appropriate in a given situation, which may be an important process that: (a) prevents compulsive drug use behavior among individuals not wishing to quit; and (b) promotes efforts to abstain during a cessation attempt. This model purports that poor behavioral inhibition during acute tobacco abstinence may be amplified during the menstrual cycle's late follicular phase (LF) when estrogen levels are high and unopposed by progesterone. By contrast, impaired behavioral inhibition during abstinence may be less pronounced during the mid-luteal phase (ML; when estrogen levels are moderate but are opposed by high progesterone levels) and the early follicular phase (EF; when both estrogen and progesterone are low; hormonal baseline). Nicotine may offset impaired behavioral inhibition caused by tobacco abstinence, particularly during the LF phase when behavioral inhibition deficits may be most pronounced. We will test this model in a placebo-controlled double-blind lab experiment with 80 non-treatment-seeking pre-menopausal female daily cigarette smokers. Females will complete three experimental visits (EF, LF, and ML) following 16-hr tobacco abstinence. During each visit, they will complete computer-based measures of behavioral inhibition at two time points during the session: (1) at the outset of the visit; and (2) following administration of transdermal patch. Thi study uses a mixed 2 (Between-Subject: Nicotine vs. Placebo) x3 (Within-Subject: Menstrual Cycle Phase) x2 (Within-Subject: Pre vs. Post Nicotine) factorial design. The primary aim of this study is to test the hypotheses that in the LF phase, as compared to the EF and ML phases, women will exhibit: (1) lower pre-nicotine behavioral inhibition and (2) higher nicotine-induced enhancement (Post - Pre nicotine) of behavioral inhibition. The secondary aim is to examine relations of phase-related changes in estrogen and progesterone levels to phase-related changes in behavioral inhibition to shed light on neuroendocrine pathways that underlie menstrual cycle and nicotine interactions. This project will pave the way for a program of research involving more intensive laboratory and clinical studies of neuroendocrine, pharmacological, and cognitive underpinnings of smoking and perhaps other addictions in women, with the ultimate aim of improving addiction treatment among women and across both sexes.
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2018 — 2020 |
Leventhal, Adam Matthew |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Project 4 @ University of Southern California
ABSTRACT: PROJECT 4 (P4) Background: E-cigarettes pose a regulatory challenge because they may adversely impact the health of some populations (e.g., young never-smokers), but reduce health risk in others (e.g., middle-aged/older smokers who switch to e-cigarettes). P4 aims to provide FDA with evidence to inform regulatory restrictions of dimensions of e-cigarette product diversity that put young adult never-smokers at risk of using e-cigarettes, yet does not deter middle/older adult smokers from adopting and potentially switching to e-cigarettes. P4 will test the hypotheses regarding how product diversity impacts the user experience?a key channel of exposure: a) Young never-smok- ers may prefer e-liquids with sweet flavorings due to age-related taste preferences and menthol flavors that mask the bitterness of nicotine; yet, middle-age/adult smokers may be more accustomed to tobacco flavorings, b) E- liquid labels with cartoon images and youth-oriented product names (e.g., ?Killer Kustard?) may appeal more to young (vs. middle-age/older) adults. c) Low propylene glycol (PG)/vegetable glycerin (VG) ratio in e-liquids pro- duces thick ?vapor clouds? and a weak throat hit, which may appeal to young adults, but middle-age/older adult smokers may prefer vapor that resembles cigarette smoke. Method: Drawing from the USC-TCORS cohort and Population Core resources, P4 will compare never-smoking young adult e-cigarette users to middle-age/older adult smokers with an interest in, but no significant experience with, e-cigarettes. In two studies, subjects will self-administer e-cigarette products systematically varied according to Flavor (sweet vs. menthol vs. tobacco) × PG/VG ratio (20:80 vs. 40:60 vs. 60:40 vs. 80:20) × Packaging (e-liquid characterizing flavor label [e.g., ?peach?] vs. youth-oriented non-characterizing flavor [e.g., ?gummy heaven?] vs. non-characterizing flavor + cartoon) de- sign. The Aim 1 study will test product exposure effects on subjective ratings of appeal (e.g., liking, desire to use again). The Aim 2 study will test product exposure effects on choice to use (vs. earn money): a) The previously- exposed e-cigarette product (an abuse liability test; never-smoking young adults only), or b) Own brand ciga- rettes (test of ability to resist smoking; middle-age/older adult smokers only). Aim 1. Determine which dimen- sions of e-cigarette product diversity differentially affect appeal across never-smoking young adult e-cigarette users (N=200) and middle-age/older smokers (N=200). Aim 2. Determine which dimensions of e-cigarette prod- uct diversity differentially affect abuse liability in never-smoking young adult e-cigarette users (N=360) and ability to resist smoking in middle-age/older adult smokers (N=360). Integration with ?Intersections of Products with Populations? theme: P4 will study dimensions of e-cigarette product diversity common to those studied in other USC-TCORS projects using a unique controlled experimental paradigm to inform causal mechanisms. P4 has a secondary aim (Aim 3) that will determine how population diversity in sex alters the appeal and abuse liability of e-cigarette products. FDA Scientific domains addressed: Addiction, Behavior, and Marketing.
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2018 — 2020 |
Leventhal, Adam Matthew Pentz, Mary Ann [⬀] |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Tobacco Regulatory Science Investigating the Intersections of Products With Diverse Populations @ University of Southern California
ABSTRACT: Overall Tobacco products are increasingly diverse. Non-cigarette products now garner a large market share; their use and health impact varies across populations. Youth and young adult non-users of tobacco products are vulner- able to initiation of e-cigarettes?a product posing risks both of nicotine dependence and of combustible tobacco uptake. Yet, middle-aged/older adults may switch from combustible to e-cigarette products with potential health benefits. The FDA is required to consider how regulatory policy has differing impact across subgroups to ensure protection of the ?population as a whole.? Research addressing population diversity is scant. Through its theme, the Intersections of Products with Populations, the University of Southern California Tobacco Center of Regula- tory Science (USC-TCORS) will conduct research on the use and health effects of specific e-cigarette products across populations. We will study e-cigarette product characteristics and marketing approaches hypothesized to increase tobacco product attraction, use, and addiction in youth and young adult non-smokers and have little impact on tobacco product use in older smokers. These e-cigarette products include: (a) non-tobacco flavorings; (b) constituents and devices that produce large vapor clouds; (c) modifiable devices; (d) device designs not resembling cigarettes; (e) cartoons in packaging and advertising; (f) candy flavors or other youth-oriented mar- keting themes. Product standards and marketing requirements limiting non-combustible products with these features to protect young people, while minimizing collateral effects on switching in adult smokers, would satisfy FDA?s mission to protect the overall population. We will provide evidence to forecast whether such requirements would have equitable impact across vulnerable groups defined by ethnicity, socioeconomic status, and sex that are affected by widening tobacco disparities. Four complementary research projects employing differing meth- odologies will test shared hypotheses on variation of the impact of e-cigarette product diversity on tobacco prod- uct use by age, combustible tobacco use, and sociodemographic diversity: (1) characterization of publicly avail- able social media postings of e-cigarette product characteristics and marketing themes that will be linked pro- spectively with tobacco product use behavior in youth and young adults, (2) intercept interviews with customers at vape shops to assess the impact of scenarios of e-cigarette regulation on tobacco product use, (3) cohort studies of associations of e-cigarette product characteristics and marketing exposures with tobacco product use and dependence across 10 years of early life, (4) laboratory tests of the impact of e-cigarette product character- istics and marketing exposure manipulations on product appeal, abuse liability, and other outcomes. Supported by a Center-wide scientific and career development infrastructure, USC-TCORS will provide the FDA with a robust body of evidence to assess how various regulatory approaches to e-cigarettes are likely to affect the health of vulnerable groups and the whole population. Scientific Domains: Addiction, Behavior, and Marketing.
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2019 — 2020 |
Leventhal, Adam Matthew |
K24Activity Code Description: To provide support for the clinicians to allow them protected time to devote to patient-oriented research and to act as mentors for beginning clinical investigators. |
Tobacco Use Treatment Research For Vulnerable Populations @ University of Southern California
PROJECT SUMMARY/ABSTRACT This application for a Mid-Career Investigator Award (K24) will advance the capacity of the candidate, Dr. Adam Leventhal, to operate a productive program of mentoring and science dedicated to tobacco use treatment patient oriented research (POR) with vulnerable populations, including individuals with behavioral health comorbidities and other disadvantaged groups. Dr. Leventhal will engage in his own training and career development activities that will improve his scientific skills and ability to mentor by completing coursework, attending workshops, and interacting with an outstanding group of expert clinical scientist collaborators. Planned activities will optimize success in his training goals of increasing knowledge and skills in the areas of tobacco use treatment-outcome: (1) clinical trial protocol design and implementation (i.e., recruiting, retaining, following, treating, and assessing treatment-seeking patients) with an emphasis on vulnerable populations, (2) advanced data analysis, (3) clinical trial design methodologies, and (4) mentoring. The proposed research projects will position Dr. Leventhal and his trainees to leverage existing strengths in patient-oriented research on the mechanisms underlying tobacco use and translate this research program to clinical treatment outcome trials in the form of: (Aim 1) A new pilot clinical trial testing high-dose bupropion for smokers with anhedonia-related psychopathology, (Aim 2) A new analysis of existing data from an ongoing smoking cessation trial testing varenicline + naltrexone combination therapy in heavy drinking smokers, and (Aim 3) Completion and submission of other funded POR grants. The plan to advance Dr. Leventhal?s mentoring capacity will involve dedicated time and resources for recruiting and training junior faculty, post-docs, medical residents, graduate students, and undergraduate students in health behavior studies, clinical psychology, psychiatry, medicine, social work, and other fields who wish to conduct patient-oriented tobacco use research. He will provide training in the areas of clinical translational research methods, data analysis, data interpretation, manuscript preparation, grantsmanship, research ethics, and pro- fessional development. Mentoring will occur through Dr. Leventhal?s active research laboratory, which includes 4 junior faculty who each have their own external research funding, and hosts weekly individual and group meet- ings with mentees, a journal club, and an external speaker series. A new university-wide multi-school initiative to develop a collaborative Institute for Addiction Science at USC led by Dr. Leventhal will provide him additional opportunities to interact with trainees form a wide variety of clinical science disciplines across numerous depart- ments and programs. By executing the proposed activities in this Mid-Career (K24) award, Dr. Leventhal will be optimally-positioned to develop a new talented generation of patient-oriented researchers engaged in a high- impact translational treatment research program that reduces the tobacco burden in vulnerable populations.
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2019 — 2021 |
Barrington-Trimis, Jessica Louise Leventhal, Adam Matthew |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Vaping Nicotine and Cannabis Across Adolescence and Young Adulthood @ University of Southern California
! PROJECT SUMMARY In 2015, evidence that e-cigarette use (?vaping?) in adolescents and young adults (AYAs) had increased and was associated with increased risk of cigarette smoking initiation generated concern in the public health community. Subsequent research has left the field with several critical questions, including: (1) whether vaping truly has a causal effect on smoking or merely reflects a common liability toward deviancy among ?high-risk? AYAs with emotional or behavioral problems, (2) whether an emerging wave of new vaping products, including new nicotine products such as JUUL, and an increasingly diverse class of products dedicated to vaping cannabis plant, oils, and waxes, may increase the appeal and addictive potential of vaping, and (3) whether there exist particular characteristics of vaping products and biopsychosocial mechanisms that underlie the risk of AYA vaping initiation, progression, and transition to other forms of drug use that could be targeted in prevention efforts. The uncertainties regarding the impact of AYA vaping have left policy officials with little evidence to determine if AYA vaping should be prioritized in public health programs, and if so, the most effective strategies for prevention. To address the evidence needs and provide a flexible framework for future study of the impact of various vaping products on the AYA tobacco product and cannabis use burden, we will test a novel ?catalyst model? of AYA vaping. The catalyst model proposes two steps, which we will evaluate in Aims 1 and 2 of this proposal. Step 1 (AIM 1). To determine whether (a) AYAs with fewer emotional-behavioral risk factors who have been previously deterred from drug use in traditional (non-vaporized) forms are at risk of vaping initiation, (b) the unique qualities and product features of vaping (e.g., concealability, flavors, appealing technology, social acceptability, low perceived harm) increase risk of AYA vaping, and (c) features of vaping products disproportionately increase the risk of vaping initiation for low-risk AYAs. Step 2 (AIM 2). To determine whether (a) vaping increases the risk of cross-product transitions involving initiation of other vaping products, or combustible nicotine or cannabis, as well as increases risk of progression to problematic drug use outcomes, including dependence, poly-drug use, and chronic drug use through early adulthood, (b) rewarding effects from exposure to nicotine, cannabinoids, and other product components (e.g. flavorings) increases risk of cross-product transitions and problematic drug use outcomes, and (c) product characteristics modify this association. To test the model, we will leverage data collected from participants from age 14-19 (2013-2018) from our existing cohort and follow participants into early adulthood (20-23, from 2019-2023; N~2000). We will also recruit a new cohort of 9th grade students at age 14 (N=2500) at the same schools as part of a cohort-sequential design that will apply causal inference analytic approaches to determine whether observed associations are likely causal. Collectively, this project will provide critical information regarding the priority and potential targets of public health efforts aimed at reducing the potential adverse public health effects resulting from AYA vaping, including tobacco-related cancer.
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