Adaptive DNA amplification of synthetic gene circuit opens a way to overcome cancer chemoresistance.

Drug resistance continues to impede the success of cancer treatments, creating a need for experimental model systems that are broad, yet simple, to allow the identification of mechanisms and novel countermeasures applicable to many cancer types. To address these needs, we investigated a set of engineered mammalian cell lines with synthetic gene circuits integrated into their genome that evolved resistance to Puromycin. We identified DNA amplification as the mechanism underlying drug resistance in 4 out of 6 replicate populations. Triplex-forming oligonucleotide (TFO) treatment combined with Puromycin could efficiently suppress the growth of cell populations with DNA amplification. Similar observations in human cancer cell lines suggest that TFOs could be broadly applicable to mitigate drug resistance, one of the major difficulties in treating cancer.

Nonmonotone invasion landscape by noise-aware control of metastasis activator levels.

A major pharmacological assumption is that lowering disease-promoting protein levels is generally beneficial. For example, inhibiting metastasis activator BACH1 is proposed to decrease cancer metastases. Testing such assumptions requires approaches to measure disease phenotypes while precisely adjusting disease-promoting protein levels. Here we developed a two-step strategy to integrate protein-level tuning, noise-aware synthetic gene circuits into a well-defined human genomic safe harbor locus. Unexpectedly, engineered MDA-MB-231 metastatic human breast cancer cells become more, then less and then more invasive as we tune BACH1 levels up, irrespective of the native BACH1. BACH1 expression shifts in invading cells, and expression of BACH1's transcriptional targets confirm BACH1's nonmonotone phenotypic and regulatory effects. Thus, chemical inhibition of BACH1 could have unwanted effects on invasion. Additionally, BACH1's expression variability aids invasion at high BACH1 expression. Overall, precisely engineered, noise-aware protein-level control is necessary and important to unravel disease effects of genes to improve clinical drug efficacy.

Engineered IL13 variants direct specificity of IL13Rα2-targeted CAR T cell therapy.

IL13Rα2 is an attractive target due to its overexpression in a variety of cancers and rare expression in healthy tissue, motivating expansion of interleukin 13 (IL13)-based chimeric antigen receptor (CAR) T cell therapy from glioblastoma into systemic malignancies. IL13Rα1, the other binding partner of IL13, is ubiquitously expressed in healthy tissue, raising concerns about the therapeutic window of systemic administration. IL13 mutants with diminished binding affinity to IL13Rα1 were previously generated by structure-guided protein engineering. In this study, two such variants, termed C4 and D7, are characterized for their ability to mediate IL13Rα2-specific response as binding domains for CAR T cells. Despite IL13Rα1 and IL13Rα2 sharing similar binding interfaces on IL13, mutations to IL13 that decrease binding affinity for IL13Rα1 did not drastically change binding affinity for IL13Rα2. Micromolar affinity to IL13Rα1 was sufficient to pacify IL13-mutein CAR T cells in the presence of IL13Rα1-overexpressing cells in vitro. Interestingly, effector activity of D7 CAR T cells, but not C4 CAR T cells, was demonstrated when cocultured with IL13Rα1/IL4Rα-coexpressing cancer cells. While low-affinity interactions with IL13Rα1 did not result in observable toxicities in mice, in vivo biodistribution studies demonstrated that C4 and D7 CAR T cells were better able to traffic away from IL13Rα1+ lung tissue than were wild-type (WT) CAR T cells. These results demonstrate the utility of structure-guided engineering of ligand-based binding domains with appropriate selectivity while validating IL13-mutein CARs with improved selectivity for application to systemic IL13Rα2-expressing malignancies.

A High Threshold of Biotherapeutic Aggregate Numbers is Needed to Induce an Immunogenic Response In Vitro, In Vivo, and in the Clinic.

BACKGROUND AND PURPOSE: There is concern that subvisible aggregates in biotherapeutic drug products pose a risk to patient safety. We investigated the threshold of biotherapeutic aggregates needed to induce immunogenic responses. METHODS AND RESULTS: Highly aggregated samples were tested in cell-based assays and induced cellular responses in a manner that depended on the number of particles. The threshold of immune activation varied by disease state (cancer, rheumatoid arthritis, allergy), concomitant therapies, and particle number. Compared to healthy donors, disease state patients showed an equal or lower response at the late phase (7 days), suggesting they may not have a higher risk of responding to aggregates. Xeno-het mice were used to assess the threshold of immune activation in vivo. Although highly aggregated samples (~ 1,600,000 particles/mL) induced a weak and transient immunogenic response in mice, a 100-fold dilution of this sample (~ 16,000 particles/mL) did not induce immunogenicity. To confirm this result, subvisible particles (up to ~ 18,000 particles/mL, containing aggregates and silicone oil droplets) produced under representative administration practices (created upon infusion of a drug product through an IV catheter) did not induce a response in cell-based assays or appear to increase the rate of adverse events or immunogenicity during phase 3 clinical trials. CONCLUSION: The ability of biotherapeutic aggregates to elicit an immune response in vitro, in vivo, and in the clinic depends on high numbers of particles. This suggests that there is a high threshold for aggregates to induce an immunogenic response which is well beyond that seen in standard biotherapeutic drug products.

Measurement of adolescent psychological wellbeing: A test of factor structure and measurement invariance.

Gains in holistic approaches to adult mental health have been associated with increasing interest in understanding psychological wellbeing (PWB) among adolescents. Empirical examination of measurement models for PWB in adolescence is lacking. Thus, the current study examined PWB in a longitudinal, diverse sample of 433 adolescents (non-Latinx Black: 37.6%; non-Latinx White: 25.9%; Latinx: 36.5%; Male adolescents: 50.1%). A one-factor, correlated six-factor and hierarchical models were examined across racial/ethnic (White, Black, and Hispanic) and gender (female, male) identities, after which the best fitting model was selected to undergo invariance testing. A one-factor structure was superior, and exhibited strict invariance across racial/ethnic and gender identities at each wave of the study, as well as longitudinal invariance within the entire sample.

BigBrain 3D atlas of cortical layers: Cortical and laminar thickness gradients diverge in sensory and motor cortices.

Histological atlases of the cerebral cortex, such as those made famous by Brodmann and von Economo, are invaluable for understanding human brain microstructure and its relationship with functional organization in the brain. However, these existing atlases are limited to small numbers of manually annotated samples from a single cerebral hemisphere, measured from 2D histological sections. We present the first whole-brain quantitative 3D laminar atlas of the human cerebral cortex. It was derived from a 3D histological atlas of the human brain at 20-micrometer isotropic resolution (BigBrain), using a convolutional neural network to segment, automatically, the cortical layers in both hemispheres. Our approach overcomes many of the historical challenges with measurement of histological thickness in 2D, and the resultant laminar atlas provides an unprecedented level of precision and detail. We utilized this BigBrain cortical atlas to test whether previously reported thickness gradients, as measured by MRI in sensory and motor processing cortices, were present in a histological atlas of cortical thickness and which cortical layers were contributing to these gradients. Cortical thickness increased across sensory processing hierarchies, primarily driven by layers III, V, and VI. In contrast, motor-frontal cortices showed the opposite pattern, with decreases in total and pyramidal layer thickness from motor to frontal association cortices. These findings illustrate how this laminar atlas will provide a link between single-neuron morphology, mesoscale cortical layering, macroscopic cortical thickness, and, ultimately, functional neuroanatomy.

Testing the temporal precedence of family functioning and child psychopathology in the LONGSCAN sample.

Family functioning may serve as protective or risk factors in the development of youth psychopathology. However, few studies have examined the potentially reciprocal relation between child psychopathology and family functioning. To fill this gap in the literature, this study tested for time-ordered associations between measures of family functioning (e.g., cohesion, conflict, and emotional expressiveness) and child psychopathology (e.g., total behavior problems, externalizing, and internalizing problems) using data from the Longitudinal Studies of Child Abuse and Neglect (LONGSCAN; N = 1143, 52.3% female, Nwaves = 5). We used a random-intercept cross-lagged panel model to identify whether child psychopathology preceded and predicted family functioning, the reverse, or both processes occurred simultaneously. At the between-person level, families who tended to have more cohesion, who lacked conflict, and who expressed their emotions had lower levels of child psychopathology. At the within-person level in childhood, we found minimal evidence for time-ordered associations. In adolescence, however, a clear pattern whereby early psychopathology consistently predicted subsequent family functioning emerged, and the reverse direction was rarely found. Results indicate a complex dynamic relation between the family unit and child that have important implications for developmental models that contextualize risk and resilience within the family unit.

Hospital transfer and delayed reduction of traumatic hip dislocations.

INTRODUCTION: Native hip dislocations are high energy injuries that cause substantial patient morbidity. Expedient reduction has been demonstrated to improve patient outcomes. The objective of our study was to compare complication rates in patients with native hip dislocations who presented directly to a level-one trauma center with those transferred from an outside hospital (OSH). Our hypothesis was that those transferred from an OSH would experience a delay in reduction and subsequently would experience higher rates of avascular necrosis (AVN), post-traumatic arthritis (PTA), and need for secondary surgery. MATERIAL AND METHODS: We conducted a retrospective chart review of all native hip dislocations from our level-one trauma center between January 2007 and December 2020. The initial query resulted 628 patients which was refined to 90 patients after excluding patients for incorrect diagnosis code or less than 6 months of follow-up. Our primary outcome was the development of AVN, PTA, and need for secondary surgery. Time from injury to reduction was recorded for all patients included. RESULTS: For every one hour of delay in time to reduction, there was a 3.4% increase in the risk of developing AVN (p = 0.004) and a 4.3% increase in risk for developing PTA (p = 0.01). The risk of requiring a secondary surgery increased 4.6% for each hour of delay in reduction (p = 0.03). The average time to reduction of transferred patients was higher compared to those who presented directly to our center (13.8 h vs 5.7 h); however, transfer status was not found to be an independent risk factor for the measured outcomes. CONCLUSIONS: Transfer status is not an independent risk factor for the development of AVN, PTA, or the need for a secondary surgery. However, transferred patients did experience an average delay of 8 h in time to reduction compared to those who presented directly to a trauma center. Of the 27 patients with a reduction delay greater than 12 h, 26 (96%) were transferred.

Short-Term and Long-Term Resilience Among At-Risk Adolescents: The Role of Family and Community Settings.

Objective: Given the severe consequences associated with maltreatment, establishing an understanding of pathways to resilience among trauma-exposed youth is a critical public health aim. Longitudinal research has either examined short-term or long-term responses to traumatic events, which prevents testing for a) individual differences between resilience subtypes and b) consistency of short-term, resilient responses over time. Additionally, post-traumatic stress and depression represent the two most common symptom patterns in youth exposed to maltreatment, however few studies have simultaneously investigated resilience to these outcomes. In response, the current study employs a dimensional analytic approach to distinguish between short-term (the ability to demonstrate adaptive responses to ongoing adversities) and long-term (lack of distress over several years in response to a prior adversity) resilience. Consistent with an ecological perspective, the study examines whether family- and community-level protective factors are similarly or uniquely associated with different resilience subtypes.Method: Participants included 943 individuals (469 male, 474 female) from a nationally-representative, at-risk sample of adolescents who completed self-report measures of maltreatment exposure, depressive symptoms and post-traumatic stress symptoms at ages 12, 16, and 18. During the age 12 visit, participants' caregivers completed self-report measures of family routines and neighborhood social cohesion.Results: Overall, we found that family routines uniquely buffered against trauma-related distress across resilience conceptualizations, while social cohesion played a role in short-term resilience to depressive symptoms (p <.05). Participant gender did not moderate these results (p > .05).Conclusion: These findings highlight the importance of understanding resilience dimensionally for adolescents exposed to maltreatment.

Is ACEs Screening for Adolescent Mental Health Accurate and Fair?

Increasingly, adversity-focused assessment tools are being introduced into preventive mental health screening protocols. However, few studies have explicitly examined whether use of these instruments serves as equitable, clinically useful measures of mental health risk in adolescents. In response, the present study examined whether an adverse childhood experiences (ACEs) measure was accurate and fair as an index of environmental risk for adolescent mental health diagnoses. Secondary data analyses were conducted on the National Comorbidity Survey-Adolescent Supplement. Adolescents (N = 10,148; AgeMean = 15.20; 51.3% male; 65.6% White, 15.1% Black, and 14.4% Hispanic) answered ten questions concerning childhood adversities and completed diagnostic interviews for PTSD, depression, and externalizing disorders. In the overall sample, ACEs showed some clinical utility (e.g., area under the curve (AUCs) ≥ 0.64), diagnostic likelihood ratios (DLRs) > 4.0) and acceptable calibration (i.e., expected/observed indices' confidence intervals included 1) across diagnoses. Within subpopulations, however, predictive validity varied. The AUCs were lower for multiple diagnoses in Black male and Hispanic female adolescents and DLRs suggested greater clinical utility for indexing mental health in White, female adolescents. Finally, models were not well-calibrated between adolescent subpopulations, suggesting recommended ACEs screening can potentially produce biased results when used to inform mental health policy and prevention. Reasons for why results from ACEs screening may vary across adolescent subpopulations and the importance of testing statistical fairness for preventive mental health screening are discussed.

The role of hopelessness and procedural justice on depressogenic outcomes in serious adolescent offenders.

OBJECTIVE: Despite increasing depression and suicide rates in justice-system-involved youth, little is known about depressogenic risk factors in this population. Therefore, we explored how levels of and changes in hopelessness and perceptions of procedural justice predicted depressive and suicidal outcomes in justice-system-involved youth. HYPOTHESES: We hypothesized that higher levels and increasing trajectories of hopelessness, as well as of perceived injustice, would predict depressive symptoms and suicidal ideation across adolescence and emerging adulthood. We also expected that procedural injustice would explain the relation between hopelessness and these outcomes. Finally, we hypothesized that gender and race/ethnicity would moderate the influence of hopelessness and perceived injustice. METHOD: Data for the present study were collected as part of the Pathways to Desistance study. In total, 1,354 adolescents (Mage = 16.04 years; 86.4% male; 41.4% non-Hispanic Black, 33.5% Hispanic, 20.2% non-Hispanic White) convicted of serious offenses participated. For the present study, participants answered questions on measures of procedural justice, hopelessness, depression, and suicidal ideation across 11 time points over 7 years. RESULTS: Using latent growth curve modeling, we found partial support for our hypotheses. Specifically, baseline levels of hopelessness predicted depression levels and increases in depression during adolescence (ps < .01). Further, changes in hopelessness predicted corresponding changes in depression throughout adolescence and emerging adulthood (ps < .001). Similarly, procedural justice levels predicted levels of depression (p < .001), and changes in procedural justice corresponded to changes in depression during emerging adulthood (p = .01). With regard to suicidal ideation, levels of and changes in hopelessness in emerging adulthood predicted corresponding suicidal ideation outcomes (ps ≤ .01). Meanwhile, we found only marginal support for our mediation model (p = .05). Collectively, results did not vary across gender or race/ethnicity. CONCLUSIONS: Hopelessness and perceived injustice are unique predictors of depression for juvenile-justice-system-involved youth. Preventive interventions targeting both hopelessness and procedural justice could help attenuate elevated depression rates in this population. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Wealth, Income, and Preferences for Redistribution: Evidence from 30 countries.

This analysis probes the relationship between individuals' preferences for redistribution and their economic self-interest. We analyze personal finance and preferences data from 30 countries included in the 2009 ISSP to analyze whether respondents' personal income, financial wealth, or housing wealth are related to their opinions about economic redistribution, poor aid, and unemployment support. We find evidence of a relationship between income and preferences in English-speaking OECD countries, and between home equity, financial wealth, and preferences in Nordic countries. However, that linkage varies by policy attitude and asset type, and is also non-existent in some countries.

Factorized embeddings learns rich and biologically meaningful embedding spaces using factorized tensor decomposition.

MOTIVATION: The recent development of sequencing technologies revolutionized our understanding of the inner workings of the cell as well as the way disease is treated. A single RNA sequencing (RNA-Seq) experiment, however, measures tens of thousands of parameters simultaneously. While the results are information rich, data analysis provides a challenge. Dimensionality reduction methods help with this task by extracting patterns from the data by compressing it into compact vector representations. RESULTS: We present the factorized embeddings (FE) model, a self-supervised deep learning algorithm that learns simultaneously, by tensor factorization, gene and sample representation spaces. We ran the model on RNA-Seq data from two large-scale cohorts and observed that the sample representation captures information on single gene and global gene expression patterns. Moreover, we found that the gene representation space was organized such that tissue-specific genes, highly correlated genes as well as genes participating in the same GO terms were grouped. Finally, we compared the vector representation of samples learned by the FE model to other similar models on 49 regression tasks. We report that the representations trained with FE rank first or second in all of the tasks, surpassing, sometimes by a considerable margin, other representations. AVAILABILITY AND IMPLEMENTATION: A toy example in the form of a Jupyter Notebook as well as the code and trained embeddings for this project can be found at: https://github.com/TrofimovAssya/FactorizedEmbeddings. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Evaluation for septic arthritis of the native adult knee is aided by multivariable assessment.

INTRODUCTION: Evaluation of suspected septic arthritis of the native adult knee is a common diagnostic dilemma. Pre-aspirate criteria predictive of septic arthritis do not exist for the adult knee and investigations of aspiration results (cell count, differential, gram stain and crystal analysis) have been limited to univariate analyses. Given numerous clinical variables inform the risk of septic arthritis, multivariable analysis that incorporates all clinically available information is critical to allowing accurate decision-making. METHODS: We retrospectively identified 455 cases of potential septic arthritis of a native adult knee at a tertiary health system from 2012 to 2017, of which 281 underwent aspiration. We recorded demographics, comorbidities, history, exam, laboratory, and radiographic data. Among aspirated cases, we performed univariate analyses of all variables for association with septic arthritis followed by multivariable logistic regression analysis. RESULTS: Septic arthritis was confirmed in 61 of 281 patients who underwent aspiration. Independent associations of risk for septic arthritis included synovial fluid WBC ≥ 30,000 (Odds Ratio 90.8, 95% Confidence Interval 26.6-310.1, p < 0.001), bacteria reported on synovial fluid gram stain (OR 21.5, 95% CI 3.9-119.2, p < 0.001), duration of pain >2 days (OR 6.9, 95% CI. 2.3-20.9, p < 0.001), history of septic arthritis at any joint (OR 5.0, 95% CI 1.1-23.4, p = 0.039), clinical effusion (OR 4.8, 95% CI 1.2-20.0, p = 0.030). Independent associations protective against septic arthritis included presence of synovial fluid crystals (OR 0.1, 95% CI 0.1-0.4, p < 0.001). The multivariable model was highly accurate in discriminating between septic and aseptic cases (AUC = 0.942). A web-based tool was created to aid clinical decision-making. CONCLUSION: When evaluating for septic arthritis of a native adult knee, several independent associations were identified for variables related and unrelated to joint aspiration. The associated multivariable model discriminated very well between patients with and without septic arthritis, outperforming previous univariate assessments. A web-based tool was created that estimates the probability of septic arthritis based on this model. This may aid decision-making in complex clinical scenarios.

Psychological Distress and Well-Being in Trauma-Exposed Adolescents: A Residualized, Person-Centered Approach to Resilience.

Positive adaptation manifests differently in the aftermath of traumatic events. Methodological limitations, however, impede the ability to test conceptualizations of resilience that emphasize the multifaceted nature of these responses. In response, an approach that synthesized a residualized and person-centered conceptualization of resilience examined associations between aspects of resilience in an adolescent sample. In total, 584 racially/ethnically diverse adolescents (age range: 12-17 years; M = 14.98 years; SD = 1.05; 50.9% female; 30.1% White, 29.6% African American, 19.5% Hispanic) self-reported lifetime emotional maltreatment and community violence exposure as well as current levels of depression, posttraumatic stress symptoms (PTSS), violent behavior, and psychological well-being (PWB). Each mental health outcome was regressed on lifetime trauma exposure to create residuals used as indices of resilience. Correlations between the residuals suggested that PWB was more closely related to resilience to depression and PTS, rs = .17-.30, than violent behavior, r = .00. Residuals were subsequently entered into person-centered analyses to identify representative well-being profiles. Cluster analysis identified four groups, including two adaptive profiles defined by (a) lower distress and higher PWB and (b) lower psychopathology and lower PWB, based on adolescents' levels of trauma exposure. These two profiles did not vary regarding impairment, p > .999, suggesting both profiles represent positive adaption to lifetime trauma exposure. Theoretical and clinical implications of distinguishing between these two profiles by assessing PWB in adolescents are discussed, as well as how PWB may manifest within the context of different patterns of psychological distress.

The development and validation of an algorithm to predict future depression onset in unselected youth.

BACKGROUND: Universal depression screening in youth typically focuses on strategies for identifying current distress and impairment. However, these protocols also play a critical role in primary prevention initiatives that depend on correctly estimating future depression risk. Thus, the present study aimed to identify the best screening approach for predicting depression onset in youth. METHODS: Two multi-wave longitudinal studies (N = 591, AgeM = 11.74; N = 348, AgeM = 12.56) were used as the 'test' and 'validation' datasets among youth who did not present with a history of clinical depression. Youth and caregivers completed inventories for depressive symptoms, adversity exposure (including maternal depression), social/academic impairment, cognitive vulnerabilities (rumination, dysfunctional attitudes, and negative cognitive style), and emotional predispositions (negative and positive affect) at baseline. Subsequently, multi-informant diagnostic interviews were completed every 6 months for 2 years. RESULTS: Self-reported rumination, social/academic impairment, and negative affect best predicted first depression onsets in youth across both samples. Self- and parent-reported depressive symptoms did not consistently predict depression onset after controlling for other predictors. Youth with high scores on the three inventories were approximately twice as likely to experience a future first depressive episode compared to the sample average. Results suggested that one's likelihood of developing depression could be estimated based on subthreshold and threshold risk scores. CONCLUSIONS: Most pediatric depression screening protocols assess current manifestations of depressive symptoms. Screening for prospective first onsets of depressive episodes can be better accomplished via an algorithm incorporating rumination, negative affect, and impairment.

Emotional Maltreatment and Adolescent Depression: Mediating Mechanisms and Demographic Considerations in a Child Welfare Sample.

Emotional maltreatment is a risk factor for adolescent depression. Yet, it remains unclear whether commissions and omissions of emotional maltreatment (a) confer vulnerability via distinct mechanisms and (b) demonstrate similar risk across adolescent subpopulations. The present, multiwave study examined whether school engagement and peer relationships explain the depressive effects of distinct emotional maltreatment subtypes in an at-risk child welfare sample (N = 657; ages 11-14, AgeMean  = 12.49). The findings indicated that commission subtypes of emotional maltreatment predicted increasing depressive symptoms via increasing peer relationship problems, especially for girls. Meanwhile, decreasing school engagement was a depressogenic risk pathway for Hispanic adolescents reporting omission subtypes of emotional maltreatment. The results emphasize the importance of distinguish between emotional maltreatment subtypes to identify specific risk pathways for adolescent depression.

Offspring Self-Disclosure Predicts Substance-Related Outcomes in an Emergency Department Sample of Young Adults with Traumatic Injury.

BACKGROUND: Hundreds of thousands of individuals visit the emergency department (ED) every year, with many visits occurring following alcohol misuse. Parent-child relationship factors are associated with alcohol-related outcomes. For example, offspring choice to self-disclose information about their lives to parents, rather than parents actively soliciting this information, is associated with substance use. However, it is unclear whether self-disclosure uniquely predicts alcohol-related outcomes in a young adult ED sample. METHODS: Data were collected from young adults (age 18-30 years) visiting an ED for a traumatic injury (n=79). Participants were about 24.4 years old, majority male (53.7%), and Caucasian (76%; 24% African-American). A bifactor model within a structural equation model tested unique effects of self-disclosure on age at first drink, propensity for risky drinking, and likelihood of consuming substances prior to ED visit, over and above parental solicitation and a general factor and gender. RESULTS: Those who shared more information with their caregivers reported an older age at first drink, lower propensity for risky drinking and lower propensity to consume substances prior to their ED visit. CONCLUSIONS: These findings suggest that self-disclosure may be a unique risk factor in the initiation of alcohol use, development of problem use, and consequences following use.

Predicting sexual behaviors from mid-adolescence to emerging adulthood: The roles of dating violence victimization and substance use.

The purpose of the present study was to determine whether dating violence victimization (psychological, physical, and sexual) and substance use (alcohol and marijuana) predicted sexual behaviors that increase risk for poor outcomes from ages 15-19. Adolescents (N = 1042; 56% female) were recruited from high schools in Southeast Texas in 2010 and followed annually for six years. The mean age of the sample at baseline was 15.09 (SD = 0.79). Participants primarily identified as Hispanic (31.4%), White (29.4%), and Black/African American (27.9%). Participants completed measures of dating violence victimization, substance use, and sexual behaviors annually. We examined unique and interactive associations between substance use and dating violence victimization with sexual behaviors that increase risk for poor outcomes. Multilevel modeling demonstrated that, when examining predictors simultaneously, marijuana use and psychological victimization predicted sexual behaviors over time for males. For females, marijuana use, and physical and psychological victimization all predicted sexual behaviors over time, with marijuana exerting the strongest effect, particularly among females who also used alcohol. Prevention efforts for adolescent sexual behaviors that increase risk for poor outcomes should include a focus on reducing substance use, particularly marijuana, and the effects of dating violence victimization.

Translating Cognitive Vulnerability Theory Into Improved Adolescent Depression Screening: A Receiver Operating Characteristic Approach.

Traditionally, screening research tests how well a given symptom inventory can identify a concurrent depressive episode. Although developmental psychopathology could inform screening protocols for a myriad of depression outcomes (e.g., prospective depressive episodes), approaches typically used in research make it difficult to translate these findings. Using a translational analytic approach and multiwave longitudinal study design, we examined how screening for cognitive vulnerabilities (rumination, dysfunctional attitudes, and attributional style) may improve our ability to identify concurrent depressive episodes, prospective depressive episodes, first lifetime episodes of depression, and recurrent major depressive episodes. There were 473 sixth-grade (early adolescents) and ninth-grade (middle adolescents; AgeM = 13.15, AgeSD = 1.62) students who completed baseline self-report cognitive vulnerability and depressive symptom measures. At baseline and every 6 months for 3 years, pediatric depression interviews were completed by the caregiver and youth. A receiver operating characteristic (ROC) approach was utilized to test our aims. Distinct algorithms best forecasted our depression outcomes. Rumination and attributional style emerged as unique and incrementally valid predictors for prospective episodes after controlling for baseline depressive symptoms. Rumination was the only unique predictor for first lifetime depressive episodes. For recurrent major depression, rumination in early adolescence and attributional style in middle adolescence served as incremental predictors beyond baseline depressive symptoms. Proposed cutoffs and diagnostic likelihood ratios are offered for algorithms for each depression outcome. Assessing cognitive vulnerability represents a feasible method to improve depression screening initiatives. Using an ROC-informed approach can help prevention initiatives better leverage the considerable gains made within developmental psychopathology research.