Glucocorticoid Receptor (NR3C1) Gene Polymorphism Moderate Intervention Effects on the Developmental Trajectory of African-American Adolescent Alcohol Abuse.

Accumulative evidence from recent genotype × intervention studies suggests that individuals carrying susceptible genotypes benefit more from intervention and provides one avenue to identify subgroups that respond differentially to intervention. This study examined the moderation by glucocorticoid receptor (NR3C1) gene variants of intervention effects on the developmental trajectories of alcohol abuse through adolescence. Participants were randomized into Fast Track intervention and control groups self-reported past-year alcohol abuse annually from grade 7 through 2 years post-high school and provided genotype data at age 21 (69% males; European Americans [EAs] = 270, African-Americans [AAs] = 282). Latent growth curve models were fit to examine developmental trajectories of alcohol abuse. The interactions of 10 single nucleotide polymorphisms (SNPs) in NR3C1 with intervention were examined separately. Both EAs and AAs showed significant increases in past-year alcohol abuse with substantial inter-individual differences in rates of linear growth. AAs showed lower general levels and slower rates of linear growth than EAs. Adjusting for multiple tests, one NR3C1 SNP (rs12655166) significantly moderated intervention effects on the developmental trajectories of alcohol abuse among AAs. Intervention effects on the rates of linear growth were stronger among AAs carrying minor alleles than those not carrying minor alleles. The findings highlight the importance of taking a developmental perspective on adolescent alcohol use and have implications for future intervention design and evaluation by identifying subgroups that could disproportionally benefit from intervention.

Managing eosinophilic esophagitis: challenges and solutions.

Eosinophilic esophagitis (EoE) is a chronic and progressive immune-mediated condition defined by symptoms of esophageal dysfunction and dense eosinophilic infiltration of the esophageal mucosa. Therapies consist of anti-eosinophilic medications and specialized diets aimed to decrease the progression of EoE and alleviate its symptoms, namely, dysphagia and food impaction. Assessing response to therapy remains challenging, as treatment end points are not well defined and currently consist of clinical, histologic, and endoscopic features. Newer validated measures may help standardize treatment end points. Emerging data support the use of maintenance therapy, which may reduce disease progression. Optimal dosages, delivery techniques, and duration of treatment need to be determined. When features of fibrostenosis develop, esophageal dilation is a safe and effective adjunctive strategy for improving symptoms. In EoE cases refractory to conventional treatments, newer therapies targeting inflammatory mediators and cytokines are on the horizon.

Comparisons of Fluticasone to Budesonide in the Treatment of Eosinophilic Esophagitis.

BACKGROUND: Topical steroids are first-line treatment agents for eosinophilic esophagitis; however, some studies have demonstrated modest efficacy in inducing histologic remission. AIMS: The aim of this study was to determine response to two topical steroids (fluticasone and budesonide), compare their efficacy, and examine patient characteristics which could predict non-response to topical steroids. METHODS: We performed a retrospective review of an established EoE registry. Inclusion criteria were patients >1 year of age who were diagnosed with EoE as defined by the most recent consensus guidelines. All patients were treated with an 8-week course of either swallowed fluticasone or viscous budesonide. Responders were defined as achieving <15 eosinophils per high-power field (eos/hpf) in both proximal and distal esophageal biopsies. Demographic, clinical, endoscopic, and histologic features were examined. RESULTS: The study cohort included 75 EoE patients with a median age of 33 years (range 2-64 years), 71 % adults, 84 % male, and 76 % Caucasian. Overall histologic response rate to topical steroids was 51 %, while clinical response was 71 %. There was no significant differences in histologic response to treatment between children and adults (68 vs. 44 %, p = 0.111). There was no significant difference in response between males and females (47 vs. 73 %, p = 0.191) and between the two types of steroids (48 vs. 56 %, p = 0.632). Responders and non-responders were similar in clinical presentation and baseline endoscopic findings. Following treatment, responders had significantly less peak proximal (4.0 ± 4.4 vs. 46 ± 53, p < 0.001) and distal eosinophil counts (3.5 ± 3.8 vs. 60 ± 47, p < 0.001) compared to non-responders. There were no predictors of response to steroids identified. CONCLUSIONS: Histologic response to treatment was observed in approximately half the cohort, while more than two-thirds experienced clinical response to topical steroids. Response was similar between fluticasone and budesonide. Given the lack of differences in clinical presentation or endoscopic features, predictors of non-response were not seen.

Cumulative stress in childhood is associated with blunted reward-related brain activity in adulthood.

Early life stress (ELS) is strongly associated with negative outcomes in adulthood, including reduced motivation and increased negative mood. The mechanisms mediating these relations, however, are poorly understood. We examined the relation between exposure to ELS and reward-related brain activity, which is known to predict motivation and mood, at age 26, in a sample followed since kindergarten with annual assessments. Using functional neuroimaging, we assayed individual differences in the activity of the ventral striatum (VS) during the processing of monetary rewards associated with a simple card-guessing task, in a sample of 72 male participants. We examined associations between a cumulative measure of ELS exposure and VS activity in adulthood. We found that greater levels of cumulative stress during childhood and adolescence predicted lower reward-related VS activity in adulthood. Extending this general developmental pattern, we found that exposure to stress early in development (between kindergarten and grade 3) was significantly associated with variability in adult VS activity. Our results provide an important demonstration that cumulative life stress, especially during this childhood period, is associated with blunted reward-related VS activity in adulthood. These differences suggest neurobiological pathways through which a history of ELS may contribute to reduced motivation and increased negative mood.

Can Genetics Predict Response to Complex Behavioral Interventions? Evidence from a Genetic Analysis of the Fast Track Randomized Control Trial.

Early interventions are a preferred method for addressing behavioral problems in high-risk children, but often have only modest effects. Identifying sources of variation in intervention effects can suggest means to improve efficiency. One potential source of such variation is the genome. We conducted a genetic analysis of the Fast Track randomized control trial, a 10-year-long intervention to prevent high-risk kindergarteners from developing adult externalizing problems including substance abuse and antisocial behavior. We tested whether variants of the glucocorticoid receptor gene NR3C1 were associated with differences in response to the Fast Track intervention. We found that in European-American children, a variant of NR3C1 identified by the single-nucleotide polymorphism rs10482672 was associated with increased risk for externalizing psychopathology in control group children and decreased risk for externalizing psychopathology in intervention group children. Variation in NR3C1 measured in this study was not associated with differential intervention response in African-American children. We discuss implications for efforts to prevent externalizing problems in high-risk children and for public policy in the genomic era.

Developmental mediation of genetic variation in response to the Fast Track prevention program.

We conducted a developmental analysis of genetic moderation of the effect of the Fast Track intervention on adult externalizing psychopathology. The Fast Track intervention enrolled 891 children at high risk to develop externalizing behavior problems when they were in kindergarten. Half of the enrolled children were randomly assigned to receive 10 years of treatment, with a range of services and resources provided to the children and their families, and the other half to usual care (controls). We previously showed that the effect of the Fast Track intervention on participants' risk of externalizing psychopathology at age 25 years was moderated by a variant in the glucocorticoid receptor gene. Children who carried copies of the A allele of the single nucleotide polymorphism rs10482672 had the highest risk of externalizing psychopathology if they were in the control arm of the trial and the lowest risk of externalizing psychopathology if they were in the treatment arm. In this study, we test a developmental hypothesis about the origins of this for better and for worse Gene × Intervention interaction (G × I): that the observed G × I effect on adult psychopathology is mediated by the proximal impact of intervention on childhood externalizing problems and adolescent substance use and delinquency. We analyzed longitudinal data tracking the 270 European American children in the Fast Track randomized control trial with available genetic information (129 intervention children, 141 control group peers, 69% male) from kindergarten through age 25 years. Results show that the same pattern of for better and for worse susceptibility to intervention observed at the age 25 follow-up was evident already during childhood. At the elementary school follow-ups and at the middle/high school follow-ups, rs10482672 predicted better adjustment among children receiving the Fast Track intervention and worse adjustment among children in the control condition. In turn, these proximal G × I effects early in development mediated the ultimate G × I effect on externalizing psychopathology at age 25 years. We discuss the contribution of these findings to the growing literature on genetic susceptibility to environmental intervention.

Categorization of patients with reflux symptoms referred for pH and impedance testing while off therapy.

BACKGROUND & AIMS: Patients with suspected gastroesophageal reflux disease (GERD) often are treated empirically with proton pump inhibitors (PPIs). Patients whose symptoms are not reduced during the PPI trial are referred for further tests. We investigated whether patients referred for the evaluation of reflux symptoms had GERD. We also aimed to categorize patients with a poor response to PPIs into groups with hypersensitive esophagus or functional heartburn. METHODS: We performed a retrospective study, searching a clinical database of patients referred for GERD testing from 2006 through 2011. We collected data on all patients who underwent upper endoscopy, esophageal manometry, and 24-hour pH-impedance monitoring, and were off PPIs for at least 1 week. Evidence of GERD was determined by an abnormal upper endoscopy or 24-hour pH-impedance monitoring. Further categorization was determined by impedance results and the symptom association probability index. RESULTS: We identified 221 patients (mean age, 47.6 ± 13.3 y; 56% male; 61% Caucasians); 97% previously had been prescribed PPIs, before they were tested. The patients had erosive esophagitis (n = 21; 10%), nonerosive reflux disease with increased pH (n = 61; 27%), nonerosive reflux disease with abnormal impedance (n = 18; 8%), hypersensitive esophagus (n = 30; 14%), functional heartburn (n = 18; 8%), functional disorders other than heartburn (n = 30; 14%), and undetermined disorders (n = 43; 19%). CONCLUSIONS: In a retrospective analysis of 221 patients, roughly half of the patients referred for testing did not have evidence of GERD. Further categorization of patients can help guide diagnosis and management.

Effects of anonymous peer observation on adolescents' preference for immediate rewards.

Research suggests that the presence of peers influences adolescent risk-taking by increasing the perceived reward value of risky decisions. While prior work has involved observation of participants by their friends, the current study examined whether observation by an anonymous peer could elicit similarly increased reward sensitivity. Late adolescent participants completed a delay discounting task either alone or under the belief that performance was being observed from a neighboring room by an unknown viewer of the same gender and age. Even in this limited social context, participants demonstrated a significantly increased preference for smaller, immediate rewards when they believed that they were being watched. This outcome challenges several intuitive accounts of the peer effect on adolescent risk-taking, and indicates that the peer influence on reward sensitivity during late adolescence is not dependent on familiarity with the observer. The findings have both theoretical and practical implications for our understanding of social influences on adolescents' risky behavior.

Peer Influences on Adolescent Decision Making.

Research efforts to account for elevated risk behavior among adolescents have arrived at an exciting new stage. Moving beyond laboratory studies of age differences in "cool" cognitive processes related to risk perception and reasoning, new approaches have shifted focus to the influence of social and emotional factors on adolescent neurocognition. We review recent research suggesting that adolescent risk-taking propensity derives in part from a maturational gap between early adolescent remodeling of the brain's socio-emotional reward system and a gradual, prolonged strengthening of the cognitive control system. At a time when adolescents spend an increasing amount of time with their peers, research suggests that peer-related stimuli may sensitize the reward system to respond to the reward value of risky behavior. As the cognitive control system gradually matures over the course of the teenage years, adolescents grow in their capacity to coordinate affect and cognition, and to exercise self-regulation even in emotionally arousing situations. These capacities are reflected in gradual growth in the capacity to resist peer influence.

Factors associated with adolescents' propensity to drive with multiple passengers and to engage in risky driving behaviors.

PURPOSE: Research shows that parenting factors and individual difference variables, such as sensation seeking (SS) and risk perceptions (RPs), are associated with increased motor vehicle crash risk for young drivers. The presence of peer passengers is also known to be associated with increased crash risk. However, as previous studies did not study these factors concurrently, less is known about the factors that are associated with driving with peer passengers and if peer passengers may mediate the effect of parenting and individual difference variables on adolescents' engagement in risky driving behavior. METHODS: We examined predictors of driving with multiple passengers (DWMPs) and explored it as a potential mediator of pathways from three factors: (1) SS, (2) RPs, and (3) Parental monitoring and rule-setting to risky driving behaviors in a convenience sample of 198 adolescent drivers using a cross-sectional Web-based survey. RESULTS: Findings indicate that both stronger RPs and perceiving parents as strong monitors and rule setters were associated with less engagement in risky driving, whereas greater SS was associated with more engagement in risky driving; RPs, monitoring, and SS were also significantly associated with DWMPs in these same directions. DWMPs partially mediated the effect of these risk factors on risky driving behavior. CONCLUSIONS: Results inform theory and policy by examining factors associated with risk taking in the context of adolescent driving. Interventions can be developed to complement graduated driver licensing laws by targeting individual difference variables and decreasing opportunities for peer passenger carriage.

Evolving science in adolescence: comment on Ellis et al. (2012).

Ellis et al. (2012) bring an evolutionary perspective to bear on adolescent risky behavioral development, clinical practice, and public policy. The authors offer important insights that (a) some risky behaviors may be adaptive for the individual and the species by being hard-wired due to fitness benefits and (b) interventions might be more successful if they move with, rather than against, the natural tendencies of an adolescent. Ellis and colleagues criticize the field of developmental psychopathology, but we see the 2 fields as complementary. Their position would be enhanced by integrating it with contemporary perspectives on dynamic cascades through which normative behavior turns into genuinely maladaptive outcomes, dual processes in adolescent neural development, and adolescent decision making. Finally, they rightly note that innovation is needed in interventions and policies toward adolescent problem behavior.

Pathways to treatment retention for individuals legally coerced to substance use treatment: the interaction of hope and treatment motivation.

BACKGROUND: Although several states have adopted policies diverting individuals convicted of non-violent drug offenses to substance use treatment, in lieu of incarceration or as a condition of probation, previous research has produced inconsistent findings on the effectiveness of such programs when comparing outcomes for legally coerced individuals to more voluntary entrants. Less studied in these populations is within group variation in treatment expectations and motivation influences, which have been shown to affect retention as well. METHODS: As motivation has traditionally been viewed as contributing to treatment retention and higher levels of hope (the perception that goals can be met) are viewed as an asset in treatment, the role of these factors in predicting better retention between legally coerced and more voluntary clients were examined in a sample of 289 treatment admissions in California. RESULTS: Results found that motivation mediates the relationship between hope and retention for participants in general. Although the differences in mediation between the legally coerced and the non-legally coerced were not significant, when examining the groups separately, there was a significant mediation of the relationship between hope and retention by motivation only for those individuals who were not legally coerced into treatment (p<.05). CONCLUSION: The findings imply that while being legally coerced may lead to different pathways to treatment retention, for individuals who were not legally coerced, higher levels of hope may play an important role in determining treatment retention.

Age differences in strategic planning as indexed by the tower of London.

The present study examined age differences in performance on the Tower of London, a measure of strategic planning, in a diverse sample of 890 individuals between the ages of 10 and 30. Although mature performance was attained by age 17 on relatively easy problems, performance on the hardest problems showed improvements into the early 20s. Furthermore, whereas age-related performance gains by children and adolescents (ages 10-17) on the hardest problems were partially mediated by maturational improvements in both working memory and impulse control, improved performance in adulthood (ages 18+) was fully mediated by late gains in impulse control. Findings support an emerging picture of late adolescence as a time of continuing improvement in planned, goal-directed behavior.

Peers increase adolescent risk taking by enhancing activity in the brain's reward circuitry.

The presence of peers increases risk taking among adolescents but not adults. We posited that the presence of peers may promote adolescent risk taking by sensitizing brain regions associated with the anticipation of potential rewards. Using fMRI, we measured brain activity in adolescents, young adults, and adults as they made decisions in a simulated driving task. Participants completed one task block while alone, and one block while their performance was observed by peers in an adjacent room. During peer observation blocks, adolescents selectively demonstrated greater activation in reward-related brain regions, including the ventral striatum and orbitofrontal cortex, and activity in these regions predicted subsequent risk taking. Brain areas associated with cognitive control were less strongly recruited by adolescents than adults, but activity in the cognitive control system did not vary with social context. Results suggest that the presence of peers increases adolescent risk taking by heightening sensitivity to the potential reward value of risky decisions.

Age differences in sensation seeking and impulsivity as indexed by behavior and self-report: evidence for a dual systems model.

It has been hypothesized that sensation seeking and impulsivity, which are often conflated, in fact develop along different timetables and have different neural underpinnings, and that the difference in their timetables helps account for heightened risk taking during adolescence. In order to test these propositions, the authors examined age differences in sensation seeking and impulsivity in a socioeconomically and ethnically diverse sample of 935 individuals between the ages of 10 and 30, using self-report and behavioral measures of each construct. Consistent with the authors' predictions, age differences in sensation seeking, which are linked to pubertal maturation, follow a curvilinear pattern, with sensation seeking increasing between 10 and 15 and declining or remaining stable thereafter. In contrast, age differences in impulsivity, which are unrelated to puberty, follow a linear pattern, with impulsivity declining steadily from age 10 on. Heightened vulnerability to risk taking in middle adolescence may be due to the combination of relatively higher inclinations to seek excitement and relatively immature capacities for self-control that are typical of this period of development.