Discover hidden splicing variations by mapping personal transcriptomes to personal genomes.

RNA-seq has become a popular technology for studying genetic variation of pre-mRNA alternative splicing. Commonly used RNA-seq aligners rely on the consensus splice site dinucleotide motifs to map reads across splice junctions. Consequently, genomic variants that create novel splice site dinucleotides may produce splice junction RNA-seq reads that cannot be mapped to the reference genome. We developed and evaluated an approach to identify 'hidden' splicing variations in personal transcriptomes, by mapping personal RNA-seq data to personal genomes. Computational analysis and experimental validation indicate that this approach identifies personal specific splice junctions at a low false positive rate. Applying this approach to an RNA-seq data set of 75 individuals, we identified 506 personal specific splice junctions, among which 437 were novel splice junctions not documented in current human transcript annotations. 94 splice junctions had splice site SNPs associated with GWAS signals of human traits and diseases. These involve genes whose splicing variations have been implicated in diseases (such as OAS1), as well as novel associations between alternative splicing and diseases (such as ICA1). Collectively, our work demonstrates that the personal genome approach to RNA-seq read alignment enables the discovery of a large but previously unknown catalog of splicing variations in human populations

Evaluating Measures of Fidelity for Substance Abuse Group Treatment With Incarcerated Adolescents

The evaluation of treatment fidelity has become increasingly important as the demand for evidence-based practice grows. The purpose of the present study is to describe the psychometric properties of two measures of treatment fidelity that can be used by therapists and supervisors - one for group-based cognitive–behavioral therapy (CBT) and one for combined Substance Education and Twelve-Step Introduction (SET) for adolescent substance use. At the end of group sessions (CBT n = 307; SET n = 279), therapists and supervisors completed an evaluation measure assessing adherence to certain core components of the intervention. The supervisor version of the fidelity measure also included items for rating the level of competency the therapist demonstrated when providing each component of the intervention. Results from split-half cross-validation analyses provide strong support for an 11-item, three-factor CBT fidelity measure. Somewhat less consistent but adequate support for a nine-item, two-factor SET fidelity measure was found. Internal consistencies ranged from acceptable to good for both the CBT and SET adherence scales and from acceptable to good for the CBT and SET competency scales, with the exception of the CBT practices competency scale. Preliminary validation of the measures suggests that both measures have adequate to strong factor structure, reliability, and concurrent and discriminant validity. The results of this study have implications for research and clinical settings, including the supervision process

Ethnicity as a moderator of motivational interviewing for incarcerated adolescents after release

Motivational interviewing (MI) has been found to be an effective treatment for substance using populations, including incarcerated adolescents. Although some studies suggest MI is more successful with individuals from minority backgrounds, the research remains mixed. The current study investigated the impact of ethnicity on treatment in reducing alcohol and marijuana use among incarcerated adolescents. Adolescents (14–19 years of age) were recruited from a state juvenile correctional facility and randomly assigned to receive MI or relaxation therapy (RT) (N = 147; 48 White, 51 Hispanic, and 48 African American; 126 male; 21 female). Interviews were conducted at admission to the facility and 3 months after release. Results suggest that the effects of MI on treatment outcomes are moderated by ethnicity. Hispanic adolescents who received MI significantly decreased total number of drinks on heavy drinking days (NDHD) and percentage of heavy drinking days (PHDD) as compared to Hispanic adolescents who received RT. These findings suggest that MI is an efficacious treatment for an ethnic minority juvenile justice-involved population in need of evidence-based treatments

Cannabis Withdrawal Among Detained Adolscents: Exploring the Impact of Nicotine and Race

Rates of marijuana use among detained youths are exceptionally high. Research suggests a cannabis withdrawal syndrome is valid and clinically significant; however, these studies have mostly been conducted in highly controlled laboratory settings with treatment-seeking, White adults. The present study analyzed archival data to explore the magnitude of cannabis withdrawal symptoms within a diverse sample of detained adolescents while controlling for tobacco use and investigating the impact of race on symptom reports. Adolescents recruited from a juvenile correctional facility (N=93) completed a background questionnaire and the Marijuana Withdrawal Checklist. Analyses revealed a significant main effect for level of tobacco use on severity of irritability, and for level of marijuana use on severity of craving to smoke marijuana and strange/wild dreams. Furthermore, a significant main effect for race was found with Black adolescents reporting lower withdrawal discomfort scores and experiencing less severe depressed mood, difficulty sleeping, nervousness/anxiety, and strange/wild dreams. Although exploratory, these findings may have significant clinical implications for providers in juvenile detention facilities, allowing the execution of proper medical and/or behavioral interventions to assist adolescents presenting with problematic cannabis and/or tobacco withdrawal

Beliefs about causes of cancer in cancer patients

Beliefs about causes of cancer were studied in 120 patients with late-stage cancer and compared with beliefs of non-cancer patients matched for age, sex, and hospitalization. Cancer patients consistently had less strong beliefs about causes of cancer than did the other groups, even when causes such as smoking and having pulmonary cancer were probably associated with the development of their disease. Although some correlates of beliefs were found in cancer patients' personal and social background, these were generally of minimal levels of statistical significance. Those who had been diagnosed longer believed cancer was more often inherited. The non-cancer patients' beliefs were similar to those found in a large survey of the general population. It is likely that cancer patients need to defend themselves against self-blame as a means of coping with a terminal illness.

A Brief Screen to Detect Cannabis Use Disorder Among Incarcerated Youth

Chronic cannabis use among adolescents is associated with many adverse health effects. One group of adolescents at the highest risk for chronic use are those involved in the juvenile justice system. While cannabis use disorder (CUD) screening tools have recently become briefer, ideally a single-item measure could be used to efficiently identify those who likely meet the criteria for CUD. These analyses aimed to determine whether a cut score, based on the frequency of cannabis use in the past year, could predict whether participants met the criteria for CUD among a sample of juvenile detainees (n = 189). DSM-IV diagnostic criteria for CUD were mapped onto current DSM-V criteria to determine a diagnosis. Two CUD severity cut scores were explored: (1) a cut score that distinguished those with no CUD or mild CUD from those who have a moderate or severe CUD, and (2) a cut score that distinguishes those with no, mild, or moderate CUD from those who have severe CUD. t-Tests revealed significant differences in the number of cannabis use days in the past year by both sets of CUD comparison categories. When predicting none/mild vs. moderate/severe CUD, the optimal cut score was found to be ≥24 cannabis use days; for no/mild/moderate vs. severe CUD, the optimal cut score was ≥57 days. Hierarchical regression demonstrated the addition of cannabis use days provided significant incremental validity beyond the proportion of friends who use substances when predicting diagnostic symptom count. This 1-item cannabis screener is an effective tool to quickly determine the need for further assessment of CUD

Discover hidden splicing variations by mapping personal transcriptomes to personal genomes.

RNA-seq has become a popular technology for studying genetic variation of pre-mRNA alternative splicing. Commonly used RNA-seq aligners rely on the consensus splice site dinucleotide motifs to map reads across splice junctions. Consequently, genomic variants that create novel splice site dinucleotides may produce splice junction RNA-seq reads that cannot be mapped to the reference genome. We developed and evaluated an approach to identify 'hidden' splicing variations in personal transcriptomes, by mapping personal RNA-seq data to personal genomes. Computational analysis and experimental validation indicate that this approach identifies personal specific splice junctions at a low false positive rate. Applying this approach to an RNA-seq data set of 75 individuals, we identified 506 personal specific splice junctions, among which 437 were novel splice junctions not documented in current human transcript annotations. 94 splice junctions had splice site SNPs associated with GWAS signals of human traits and diseases. These involve genes whose splicing variations have been implicated in diseases (such as OAS1), as well as novel associations between alternative splicing and diseases (such as ICA1). Collectively, our work demonstrates that the personal genome approach to RNA-seq read alignment enables the discovery of a large but previously unknown catalog of splicing variations in human populations

Studying process and proximal outcomes of supervision for motivational interviewing

This report applies competency-based supervision using a psychotherapy-based approach for training and supervision in motivational interviewing (MI). Procedures and measures are presented for assessing training outcomes and quality of ongoing supervision processes (N = 36). Simple pre-post test design is utilized followed by a series of t-tests and correlations to illustrate applicability of the psychotherapybased approach to training and supervision. Although some analyses were underpowered, results support this psychotherapy-based approach to training and supervision. Supervision processes and outcomes are an understudied area in general, and in particular the literature has yet to articulate a competency-based approach to training and supervising in MI. Procedures presented here can be used to assess and maintain training and supervision quality

The Impact of Motivational Interviewing on Delinquent Behaviors in Incarcerated Adolescents

The impact of Motivational Interviewing (MI) on risky behaviors of incarcerated adolescents and adults has been investigated with promising results. Findings suggest that MI reduces substance use, improves motivation and confidence to reduce use, and decreases risky behaviors. The current study investigated the impact of MI on general, alcohol-related, and marijuana-related delinquent behaviors in incarcerated adolescents. Participants in the study were incarcerated adolescents in a state correctional facility in the Northeast region and were assessed as part of a larger randomized clinical trial. Adolescents were randomly assigned to receive MI or relaxation therapy (RT) (N = 189) treatment. Delinquent behaviors and depressive symptomatology were measured using the Delinquent Activities Scale (DAS; Reavy, Stein, Paiva, Quina, & Rossi, 2012) and the Center for Epidemiological Studies-Depression scale (CES-D; Radloff, 1991) respectively. Findings indicate that depression moderated treatment effects. Compared to RT, MI was better at reducing predatory aggression and alcohol-related predatory aggression 3 months post-release when depressive symptoms were low. Identifying an efficacious treatment for these adolescents may benefit society in that it may decrease crimes against persons (i.e., predatory aggression) post release

Mathematical modeling identifies optimum lapatinib dosing schedules for the treatment of glioblastoma patients

<div><p>Human primary glioblastomas (GBM) often harbor mutations within the epidermal growth factor receptor (EGFR). Treatment of EGFR-mutant GBM cell lines with the EGFR/HER2 tyrosine kinase inhibitor lapatinib can effectively induce cell death in these models. However, EGFR inhibitors have shown little efficacy in the clinic, partly because of inappropriate dosing. Here, we developed a computational approach to model the <i>in vitro</i> cellular dynamics of the EGFR-mutant cell line SF268 in response to different lapatinib concentrations and dosing schedules. We then used this approach to identify an effective treatment strategy within the clinical toxicity limits of lapatinib, and developed a partial differential equation modeling approach to study the <i>in vivo</i> GBM treatment response by taking into account the heterogeneous and diffusive nature of the disease. Despite the inability of lapatinib to induce tumor regressions with a continuous daily schedule, our modeling approach consistently predicts that continuous dosing remains the best clinically feasible strategy for slowing down tumor growth and lowering overall tumor burden, compared to pulsatile schedules currently known to be tolerated, even when considering drug resistance, reduced lapatinib tumor concentrations due to the blood brain barrier, and the phenotypic switch from proliferative to migratory cell phenotypes that occurs in hypoxic microenvironments. Our mathematical modeling and statistical analysis platform provides a rational method for comparing treatment schedules in search for optimal dosing strategies for glioblastoma and other cancer types.</p></div