Ribosome Quality Control mitigates the cytotoxicity of ribosome collisions induced by 5-Fluorouracil.

Ribosome quality control (RQC) resolves collided ribosomes, thus preventing their cytotoxic effects. The chemotherapeutic agent 5-Fluorouracil (5FU) is best known for its misincorporation into DNA and inhibition of thymidylate synthase. However, while a major determinant of 5FU's anticancer activity is its misincorporation into RNAs, the mechanisms by which cancer cells overcome the RNA-dependent 5FU toxicity remain ill-defined. Here, we report a role for RQC in mitigating the cytotoxic effects of 5FU. We show that 5FU treatment results in rapid induction of the mTOR signalling pathway, enhanced rate of mRNA translation initiation, and increased ribosome collisions. Consistently, a defective RQC exacerbates the 5FU-induced cell death, which is mitigated by blocking mTOR pathway or mRNA translation initiation. Furthermore, 5FU treatment enhances the expression of the key RQC factors ZNF598 and GIGYF2 via an mTOR-dependent post-translational mechanism. This adaptation likely mitigates the cytotoxic consequences of increased ribosome collisions upon 5FU treatment.

Contrast-Enhanced In-Phase Dixon Sequence: Impact on Biopsy Clip Detection on Breast MRI.

BACKGROUND. Identification of breast biopsy clips using conventional MRI sequences may be challenging. A contrast-enhanced in-phase Dixon sequence may have greater conspicuity for areas of susceptibility compared with standard clinical sequences. OBJECTIVE. The purpose of this article is to compare detection of breast biopsy clips on MRI between the contrast-enhanced in-phase Dixon sequence and three routine clinical sequences. METHODS. This retrospective study included 164 patients (mean age, 50.3 years) with a total of 281 breast biopsy clips who underwent contrast-enhanced breast MRI between January 2, 2019, and April 16, 2020. Three radiologists, blinded to the clip location and sequence used, independently annotated biopsy clip locations on three clinical sequences (T1-weighted non-fat-suppressed [NFS], STIR, and first phase from dynamic contrast-enhanced T1-weighted fat-suppressed [FS]) and on a contrast-enhanced in-phase Dixon sequence and then recorded confidence scores (1-4 scale). A study coordinator used all available imaging and reports to localize clips on MRI, which served as the reference standard. A physicist measured clip CNR. Sequences were compared using the McNemar test and two-tailed Wilcoxon signed rank tests. RESULTS. Among the three readers, pooled sensitivity and PPV were 78.2% and 96.2% for T1-weighted NFS, 26.6% and 92.7% for STIR, 61.7% and 95.9% for contrast-enhanced T1-weighted FS, and 85.1% and 95.1% for contrast-enhanced in-phase Dixon sequence. Pooled sensitivity was higher for contrast-enhanced in-phase Dixon sequence than for the other sequences (all p < .05); pooled PPV was not significantly different between contrast-enhanced in-phase Dixon and the other sequences (all p > .05). Mean confidence scores (pooled across readers for true-positive assessments) and mean CNR were 3.0 ± 0.9 (SD) and 1.21 ± 0.61 for T1-weighted NFS, 1.7 ± 0.9 and 0.57 ± 0.69 for STIR, 2.5 ± 1.0 and 0.54 ± 0.61 for contrast-enhanced T1-weighted FS, and 3.5 ± 0.8 and 4.05 ± 2.6 for the contrast-enhanced in-phase Dixon sequence. Pooled mean confidence scores and CNR were higher for contrast-enhanced in-phase Dixon than for the other sequences (all p < .001). CONCLUSION. Compared with clinical sequences, the contrast-enhanced in-phase Dixon sequence had higher sensitivity for detecting breast biopsy clips on MRI and higher reader confidence and CNR, without change in PPV. CLINICAL IMPACT. The contrast-enhanced in-phase Dixon sequence may help address a current challenge in clinical breast MRI interpretation.

Patient and Radiologist Demographics Influence Perceptions of Screening Mammography Reports.

PURPOSE: The aim of this study was to test whether patient and radiologist demographics influence perceptions of screening mammography reports and the interpreting radiologist. METHODS: Patients presenting for breast imaging were surveyed. Demographics were collected, and each participant was shown five mock screening mammography reports with BI-RADS category 2 findings, each with a recommendation for 1-year screening. Each report included a picture of the interpreting radiologist, who was Black or White and male or female. Participants answered seven questions, on a Likert-type scale, about understanding, satisfaction, and trust in the report and radiologist. Generalized estimating equation ordinal logistic regression compared responses on the basis of participant and radiologist demographics. RESULTS: A total of 178 women participated, with a mean age of 55.1 ± 10.2 years. Most participants self-identified as White (71%) or Black (20%) and non-Hispanic (98%), with broad educational representation (28% with bachelor's degrees and 28% with master's degrees). After controlling for demographics, Black participants reported greater agreement regarding trust in the report's finding (P = .037) if the radiologist was also Black. Black participants were less likely to be satisfied in the report quality (P = .043). Additionally, participants without any college education reported lower agreement that they were satisfied with the report quality (P = .020) and felt the radiologist cares about his or her patients (P = .037). There were no significant associations for radiologist sex or participant age. CONCLUSIONS: Participant perceptions of screening mammography reports and the interpreting radiologist can be influenced by participant and provider race as well as participant education. These findings could have implications for mammography adherence, breast radiologist recruitment, and developing patient-centric reports.

Perceived Risk of Harm Mediates the Effects of Primary Care Alcohol Use Screening and Brief Advice in Adolescents.

PURPOSE: A previous trial found lower alcohol use risk during follow-up among adolescent primary care patients receiving computer-facilitated Screening and provider Brief Advice (cSBA) compared to treatment-as-usual (TAU). We tested whether the effect was mediated by alcohol-related perceived risk of harm (PRoH). METHODS: We analyzed data from the cSBA trial on 12- to 18-year-old patients at 9 New England practices (n = 2,096, 58% females). The trial used a quasi-experimental pre-post design with practices being their own controls (TAU followed by cSBA). Because prior alcohol experience could modify effects, we stratified analyses by baseline past 12-month drinking. Among baseline nondrinkers, we tested baseline to 3-month trajectories in PRoH of "trying alcohol" as an effect mediator for drinking at 3- and 12-month follow-up. Similarly, among those with prior drinking, we examined baseline to 3-month trajectories in PRoH of "weekly binge drinking" as an effect mediator for drinking and binge drinking. We used the Hayes product of coefficients mediation approach. RESULTS: Among baseline nondrinkers (n = 1,449), cSBA had higher PRoH compared to TAU for "trying alcohol," and higher PRoH in turn was associated with lower follow-up drinking risk. PRoH mediated their cSBA effect at 12 months, but not 3 months. Among adolescents with prior drinking (n = 647), cSBA had higher PRoH for "weekly binge drinking," which was associated with lower drinking risk at both follow-ups, and lower binge drinking risk at 3 months. PRoH mediated their cSBA effect on drinking at both follow-ups, and binge drinking at 3 months. CONCLUSION: A computer-facilitated primary care intervention enhanced adolescents' perceived alcohol risks which in turn was associated with lower drinking risk.

Tuning protein synthesis for cancer therapy.

~50% of colorectal cancers have an activating mutation in KRAS (encoding the KRAS proto-oncogene) and remain difficult to target in the clinic. We have recently shown that activation of KRAS protein alters the regulation of mRNA translation, increasing total protein synthesis, and maintaining elevated c-MYC (MYC proto-oncogene) expression. Targeting these pathways downstream of KRAS reveals a striking dependency that has potential for clinical translation.

Adolescent Gender and Age Differences in Religiously and Spiritually Motivated Types of Forgiveness and the Relationship to Depressive Symptoms.

We examined three religiously/spiritually motivated forgiveness types, forgiveness of self, others, and divine forgiveness, and their association with depressive symptoms, across adolescent gender and age groups. Twelve- to 18-year-old patients arriving for primary care completed a 3-item Forgiveness measure and the Beck Depression Inventory-II. Girls reported a higher tendency to forgive others compared to boys, and self-forgiveness and divine forgiveness tended to decline with age in both genders. We found no significant associations between forgiveness and depression among boys. Among girls, higher self-forgiveness was associated with fewer depressive symptoms. Forgiveness of others was associated with less depression only among 17-18-year-old girls. Divine forgiveness showed no association with depression in either gender. Forgiveness of self and others appears to be protective factors for depression among adolescent girls.

The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer.

Oncogenic KRAS mutations and inactivation of the APC tumor suppressor co-occur in colorectal cancer (CRC). Despite efforts to target mutant KRAS directly, most therapeutic approaches focus on downstream pathways, albeit with limited efficacy. Moreover, mutant KRAS alters the basal metabolism of cancer cells, increasing glutamine utilization to support proliferation. We show that concomitant mutation of Apc and Kras in the mouse intestinal epithelium profoundly rewires metabolism, increasing glutamine consumption. Furthermore, SLC7A5, a glutamine antiporter, is critical for colorectal tumorigenesis in models of both early- and late-stage metastatic disease. Mechanistically, SLC7A5 maintains intracellular amino acid levels following KRAS activation through transcriptional and metabolic reprogramming. This supports the increased demand for bulk protein synthesis that underpins the enhanced proliferation of KRAS-mutant cells. Moreover, targeting protein synthesis, via inhibition of the mTORC1 regulator, together with Slc7a5 deletion abrogates the growth of established Kras-mutant tumors. Together, these data suggest SLC7A5 as an attractive target for therapy-resistant KRAS-mutant CRC.

Translation initiation in cancer at a glance.

Cell division, differentiation and function are largely dependent on accurate proteome composition and regulated gene expression. To control this, protein synthesis is an intricate process governed by upstream signalling pathways. Eukaryotic translation is a multistep process and can be separated into four distinct phases: initiation, elongation, termination and recycling of ribosomal subunits. Translation initiation, the focus of this article, is highly regulated to control the activity and/or function of eukaryotic initiation factors (eIFs) and permit recruitment of mRNAs to the ribosomes. In this Cell Science at a Glance and accompanying poster, we outline the mechanisms by which tumour cells alter the process of translation initiation and discuss how this benefits tumour formation, proliferation and metastasis.

MNK Inhibition Sensitizes KRAS-Mutant Colorectal Cancer to mTORC1 Inhibition by Reducing eIF4E Phosphorylation and c-MYC Expression.

KRAS-mutant colorectal cancers are resistant to therapeutics, presenting a significant problem for ∼40% of cases. Rapalogs, which inhibit mTORC1 and thus protein synthesis, are significantly less potent in KRAS-mutant colorectal cancer. Using Kras-mutant mouse models and mouse- and patient-derived organoids, we demonstrate that KRAS with G12D mutation fundamentally rewires translation to increase both bulk and mRNA-specific translation initiation. This occurs via the MNK/eIF4E pathway culminating in sustained expression of c-MYC. By genetic and small-molecule targeting of this pathway, we acutely sensitize KRASG12D models to rapamycin via suppression of c-MYC. We show that 45% of colorectal cancers have high signaling through mTORC1 and the MNKs, with this signature correlating with a 3.5-year shorter cancer-specific survival in a subset of patients. This work provides a c-MYC-dependent cotargeting strategy with remarkable potency in multiple Kras-mutant mouse models and metastatic human organoids and identifies a patient population that may benefit from its clinical application. SIGNIFICANCE: KRAS mutation and elevated c-MYC are widespread in many tumors but remain predominantly untargetable. We find that mutant KRAS modulates translation, culminating in increased expression of c-MYC. We describe an effective strategy targeting mTORC1 and MNK in KRAS-mutant mouse and human models, pathways that are also commonly co-upregulated in colorectal cancer.This article is highlighted in the In This Issue feature, p. 995.

Pediatric Primary Care Provider Perspectives on a Computer-Facilitated Screening and Brief Intervention System for Adolescent Substance Use.

PURPOSE: This study aimed to elicit pediatric primary care providers' (PCPs) feedback on the acceptability and feasibility of implementing a tablet computer-facilitated Screening and Brief Intervention (cSBI) system for adolescent substance use in their practices. METHODS: We trained PCPs at five Boston area practices and enrolled their 12- to 18-year-old patients in a pilot randomized trial of cSBI versus usual care. PCPs completed an 18-item poststudy questionnaire. We computed frequencies and thematically coded open-ended responses. RESULTS: The analysis sample included 49 of 54 participating PCPs (90.7%). Overall, 89.8% of participants agreed the cSBI system was useful, and 81.6% reported increased confidence in providing brief counseling. Most useful were the immediate availability of screen results, talking points on substance use risks, and counseling prompts. Challenges included time and unfamiliarity with tablet computers. Many suggested electronic health record integration of cSBI to improve efficiency. CONCLUSIONS: cSBI showed high acceptability and increased confidence among pediatric PCPs. Feasibility could be enhanced by electronic health record integration.

Control of translation elongation in health and disease.

Regulation of protein synthesis makes a major contribution to post-transcriptional control pathways. During disease, or under stress, cells initiate processes to reprogramme protein synthesis and thus orchestrate the appropriate cellular response. Recent data show that the elongation stage of protein synthesis is a key regulatory node for translational control in health and disease. There is a complex set of factors that individually affect the overall rate of elongation and, for the most part, these influence either transfer RNA (tRNA)- and eukaryotic elongation factor 1A (eEF1A)-dependent codon decoding, and/or elongation factor 2 (eEF2)-dependent ribosome translocation along the mRNA. Decoding speeds depend on the relative abundance of each tRNA, the cognate:near-cognate tRNA ratios and the degree of tRNA modification, whereas eEF2-dependent ribosome translocation is negatively regulated by phosphorylation on threonine-56 by eEF2 kinase. Additional factors that contribute to the control of the elongation rate include epigenetic modification of the mRNA, coding sequence variation and the expression of eIF5A, which stimulates peptide bond formation between proline residues. Importantly, dysregulation of elongation control is central to disease mechanisms in both tumorigenesis and neurodegeneration, making the individual key steps in this process attractive therapeutic targets. Here, we discuss the relative contribution of individual components of the translational apparatus (e.g. tRNAs, elongation factors and their modifiers) to the overall control of translation elongation and how their dysregulation contributes towards disease processes.

Effect of Computer-Based Substance Use Screening and Brief Behavioral Counseling vs Usual Care for Youths in Pediatric Primary Care: A Pilot Randomized Clinical Trial.

Importance: Annual preventive health visits provide an opportunity to screen youths for unhealthy substance use and intervene before serious harm results. Objectives: To assess the feasibility and acceptability and estimate the efficacy of a primary care computer-facilitated screening and practitioner-delivered brief intervention (CSBI) system compared with usual care (UC) for youth substance use and associated risk of riding with an impaired driver. Design, Setting, and Participants: An intent-to-treat pilot randomized clinical trial compared CSBI with UC among 965 youths aged 12 to 18 years at 5 pediatric primary care offices and 54 practitioners. Patients were randomized to CSBI (n = 628) or usual care (n = 243) groups within practitioner with 12 months of follow-up. Data were collected from February 1, 2015, to December 31, 2017. Data analysis was performed January 1, 2018, to March 30, 2019. Interventions: Patients self-administered a computer-facilitated substance use screening questionnaire before their annual preventive health visits. Immediately after completing the screening, they received their score and level of risk and viewed 10 pages of scientific information and true-life vignettes illustrating health risks associated with substance use. Trained practitioners received the screening results, patients' risk levels, talking points designed to prompt brief counseling, and recommended follow-up plans. Main Outcomes and Measures: Feasibility and acceptability were assessed using adolescents' postvisit ratings. Days of alcohol use, cannabis use, and heavy episodic drinking were assessed at baseline and 3-, 6-, 9-, and 12-month follow-ups using Timeline Followback, and riding in the past 3 months with a driver who was impaired by use of alcohol or other drugs was assessed using 2 self-report items. The primary outcome was the intervention effect among at-risk youths who reported using alcohol or other drugs in the past 12 months or riding with an impaired driver in the past 3 months at baseline. The secondary outcome was the prevention effect among those with no prior use or risk. Results: Among 871 youths screened, 869 completed the baseline assessment; 211 of the 869 reported alcohol or cannabis use in the past 12 months at baseline (mean [SD] age, 16.4 [1.3] years; 114 [54.1%] female; 105 [49.8%] non-Hispanic white). Of the 211 youths, 148 (70.1%) were assigned to the CSBI group and 63 (29.9%) were assigned to the UC group. Among youths in the CSBI group, 105 (70.9%) reported receiving counseling about alcohol, 122 (82.4%) reported receiving counseling about cannabis, and 129 (87.2%) reported receiving counseling about not riding with an impaired driver. Adjusted hazard ratios for time to first postvisit use of alcohol or other drugs for CSBI vs UC were as follows: alcohol use, 0.69 (95% CI, 0.47-1.02); heavy episodic drinking, 0.66 (95% CI, 0.40-1.10); and cannabis use, 0.62 (95% CI, 0.41-0.94). At 12-month follow-ups among 99 youths who reported having ridden in the past 3 months at baseline with an impaired driver (64 in the CSBI group; 35 in the UC group), adjusted relative risk ratio of riding in the past 3 months with an impaired driver for CSBI vs UC groups was 0.58 (95% CI, 0.37-0.91). No intervention effect was observed among youths who reported no prior use of alcohol or other drugs (n = 658) or not having ridden with an impaired driver (n = 769) at baseline. Conclusions and Relevance: The CSBI system is a feasible and acceptable option for screening youths in primary care practice for use of alcohol and other drugs and for risk of riding with an impaired driver, and the estimated efficacy in this sample warrants further testing in larger samples. Trial Registration: ClinicalTrials.gov identifier: NCT00227877.

Brf1 loss and not overexpression disrupts tissues homeostasis in the intestine, liver and pancreas.

RNA polymerase III (Pol-III) transcribes tRNAs and other small RNAs essential for protein synthesis and cell growth. Pol-III is deregulated during carcinogenesis; however, its role in vivo has not been studied. To address this issue, we manipulated levels of Brf1, a Pol-III transcription factor that is essential for recruitment of Pol-III holoenzyme at tRNA genes in vivo. Knockout of Brf1 led to embryonic lethality at blastocyst stage. In contrast, heterozygous Brf1 mice were viable, fertile and of a normal size. Conditional deletion of Brf1 in gastrointestinal epithelial tissues, intestine, liver and pancreas, was incompatible with organ homeostasis. Deletion of Brf1 in adult intestine and liver induced apoptosis. However, Brf1 heterozygosity neither had gross effects in these epithelia nor did it modify tumorigenesis in the intestine or pancreas. Overexpression of BRF1 rescued the phenotypes of Brf1 deletion in intestine and liver but was unable to initiate tumorigenesis. Thus, Brf1 and Pol-III activity are absolutely essential for normal homeostasis during development and in adult epithelia. However, Brf1 overexpression or heterozygosity are unable to modify tumorigenesis, suggesting a permissive, but not driving role for Brf1 in the development of epithelial cancers of the pancreas and gut.

Hypoxic cancer-associated fibroblasts increase NCBP2-AS2/HIAR to promote endothelial sprouting through enhanced VEGF signaling.

Intratumoral hypoxia causes the formation of dysfunctional blood vessels, which contribute to tumor metastasis and reduce the efficacy of therapeutic treatments. Blood vessels are embedded in the tumor stroma of which cancer-associated fibroblasts (CAFs) constitute a prominent cellular component. We found that hypoxic human mammary CAFs promoted angiogenesis in CAF-endothelial cell cocultures in vitro. Mass spectrometry-based proteomic analysis of the CAF secretome unraveled that hypoxic CAFs contributed to blood vessel abnormalities by altering their secretion of various pro- and anti-angiogenic factors. Hypoxia induced pronounced remodeling of the CAF proteome, including proteins that have not been previously related to this process. Among those, the uncharacterized protein NCBP2-AS2 that we renamed HIAR (hypoxia-induced angiogenesis regulator) was the protein most increased in abundance in hypoxic CAFs. Silencing of HIAR abrogated the pro-angiogenic and pro-migratory function of hypoxic CAFs by decreasing secretion of the pro-angiogenic factor VEGFA and consequently reducing VEGF/VEGFR downstream signaling in the endothelial cells. Our study has identified a regulator of angiogenesis and provides a map of hypoxia-induced molecular alterations in mammary CAFs.

Empirical validation of the CRAFFT Abuse Screening Test in a Spanish sample. / Validación empírica del CRAFFT Abuse Screening Test en una muestra de adolescentes españoles.

The CRAFFT Substance Abuse Screening Instrument, developed by the Center for Adolescents Substance Abuse Research (CeASAR) (Knight et al., 1999), is a screening tool for high-risk alcohol and drug risk consumption designed for use with adolescents. Since its publication it has been the subject of translations and validations in different countries, populations and contexts that have demonstrated its enormous potential. However, there is still no empirical validation study that would ensure its good psychometric performance in Spain. The aim of this paper is to develop an adapted version of the CRAFFT in Spanish and to analyze its psychometric properties in a sample of Spanish adolescents. For this purpose an individual interview was conducted on 312 adolescents aged between 12 and 18 years of age (M = 15.01; SD = 1.83) from the Galician community. The interview included a part of the Adolescent Diagnostic Interview (ADI) and the Problem Oriented Screening Instrument for Teenagers (POSIT). The results obtained, similar to those found in other countries, allow us to report that the Spanish version of the CRAFFT has a good psychometric behaviorproperties. It was found to have a satisfactory internal consistency with a Cronbach’s alpha value of .74. In terms of sensitivity and specificity, values of 74.4% and 96.4% respectively, were obtained and the area under the ROC curve was .946. The Spanish version of the CRAFFT is made available to researchers and professionals in the field of addictive behaviors, so that it can be used with the necessary psychometric guarantees.

El CRAFFT Abuse Screening Test, desarrollado por el Center for Adolescents Substance Abuse Research (CeASAR) (Knight et al., 1999), es una herramienta de cribado del consumo de riesgo de alcohol y otras sustancias diseñada para su uso con adolescentes. Desde su publicación ha sido objeto de numerosas traducciones y validaciones en diferentes países, poblaciones y contextos que han dado cuenta de su enorme potencial. No obstante, seguimos sin disponer de estudios de validación empírica que garanticen su adecuado comportamiento psicométrico en España. El objetivo del presente trabajo consiste en desarrollar una versión adaptada del CRAFFT en castellano y analizar sus propiedades psicométricas en una muestra de adolescentes españoles. Para ello, se realizó una entrevista individual a 312 adolescentes de entre 12 y 18 años (M = 15,01; DT = 1,83) de la comunidad gallega, que incluyó una parte de la Adolescent Diagnostic Interview (ADI) y del Problem Oriented Screening Instrument for Teenagers (POSIT). Los resultados obtenidos, similares a los encontrados en otros países, permiten informar que la versión española del CRAFFT presenta un buen comportamiento psicométrico. A nivel de consistencia interna se obtuvo un a de Cronbach satisfactorio de ,74. En cuanto a la sensibilidad y especificidad se obtuvieron unos valores del 74,4% y el 96,4% respectivamente, con un área bajo la curva COR de ,946. Por lo tanto, queda a disposición de investigadores y profesionales del ámbito de las conductas adictivas la versión española del CRAFFT, para que pueda ser utilizada en adelante con las garantías psicométricas necesarias.

Screening and Brief Advice to Reduce Adolescents' Risk of Riding With Substance-Using Drivers.

OBJECTIVE: Alcohol- and drug-related car crashes are a leading cause of death for adolescents in the United States. This analysis tested the effects of a computer-facilitated Screening and Brief Advice (cSBA) system for primary care on adolescents' reports of driving after drinking or drug use (driving) and riding with substance-using drivers (riding). METHOD: Twelve- to 18-year-old patients (N = 2,096) at nine New England pediatric offices completed assessments only during the initial 18-month treatment-as-usual (TAU) phase. Subsequently, the 18-month cSBA intervention phase began with a 1-hour provider training and implementation of the cSBA system at all sites. cSBA included a notebook-computer with self-administered screener, immediate scoring and feedback, and 10 pages of scientific information and true-life stories illustrating substance-related harms. Providers received screening results, "talking points" for 2 to 3 minutes of counseling, and a Contract for Life handout. Logistic regression with generalized estimating equations generated adjusted relative risk ratios (aRRR) for past-90-day driving and riding risk at 3- and 12-month follow-ups, controlling for significant covariates. RESULTS: We found no significant effects on driving outcomes. At 3 months, cSBA youth were less likely than TAU to report riding with a drinking driver (aRRR = 0.70, 95% CI [0.49, 1.00]), and less likely to report riding with a driver who had used cannabis or other drugs (aRRR = 0.46, 95% CI [0.29, 0.74]). The effect was even greater (aRRR = 0.34, 95% CI [0.16, 0.71]) for riding with drinking drivers who were adult family members. All effects dissipated by 12-month follow-up. CONCLUSIONS: Screening and pediatrician brief advice shows promise for reducing adolescents' risk of riding with substance-using drivers.