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.

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.

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).

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.

The "Heart" of depression during early adolescence.

This study examined the concurrent associations linking youths' parasympathetic nervous system activity, specifically baseline respiratory sinus arrhythmia (RSA) and respiratory sinus arrhythmia reactivity (RSAR; vagal withdrawal), with youth depression risk in a community sample of young adolescents. Youth gender was examined as a moderator of associations. Participants included 100 youth (53% boys; M age = 11.05 years, SD = 0.33; 43% ethnic minorities), along with their mothers and teachers. Youth and mothers participated in a laboratory protocol involving a peer problem-solving conversation, during which youths' physiological activity was measured. Youth reported on their depressive symptoms. Teachers reported on youth depression risk via internalizing symptoms and emotion regulation (e.g., emotion lability/negativity). Results from regression analyses revealed that youths' vagal withdrawal during the mother-youth peer problem conversation was associated with lower youth-reported depressive symptoms. Further, gender moderated the associations linking youth baseline RSA and RSAR with youth depression risk. Specifically, among girls but not boys, higher baseline RSA was associated with lower depressive symptoms and emotion lability/negativity, and higher RSAR (i.e., vagal withdrawal) was linked with lower internalizing symptoms. Findings contribute to the relatively small literature linking youth parasympathetic functioning with depression risk, and point to specific implications for girls.

Youth Depression Screening with Parent and Self-Reports: Assessing Current and Prospective Depression Risk.

Few studies have examined the incremental validity of multi-informant depression screening approaches. In response, we examined how recommendations for using a multi-informant approach may vary for identifying concurrent or prospective depressive episodes. Participants included 663 youth (AgeM = 11.83; AgeSD = 2.40) and their caregiver who independently completed youth depression questionnaires, and clinical diagnostic interviews, every 6 months for 3 years. Receiver operating characteristic (ROC) analyses showed that youth-report best predicted concurrent episodes, and that both youth and parent-report were necessary to adequately forecast prospective episodes. More specifically, youth-reported negative mood symptoms and parent-reported anhedonic symptoms incrementally predicted future depressive episodes. Findings were invariant to youth's sex and age, and results from person and variable-centered analyses suggested that discrepancies between informants were not clinically meaningful. Implications for future research and evidence-based decision making for depression screening initiatives are discussed.

Emerging Adulthood and Prospective Depression: A Simultaneous Test of Cumulative Risk Theories.

Past research indicates that a history of depression and exposure to abuse and neglect represent some of the most robust predictors of depression in emerging adults. However, studies rarely test the additive or interactive risk associated with these distinct risk factors. In response, the present study explored how these three risk factors (prior depression, abuse, and neglect) synergistically predicted prospective depressive symptoms in a sample of 214 emerging adults (Mage = 21.4 years; SDage = 2.4; 78% females). Subtypes of maltreatment and lifetime history of depression were assessed through semi-structured interviews, and depressive symptoms were assessed annually for three years via self-report measures. The results indicated that for both males and females, a lifetime history of depression, abuse, and neglect-exposure uniquely conferred risk for elevated depressive symptoms. Furthermore, the interaction between neglect and prior depression forecasted increasing depressive symptoms, and a history of abuse also predicted increasing depressive symptoms, but only in females. These findings are contextualized within extant developmental psychopathology theories, and translational implications for trauma-informed depression prevention efforts are discussed.

The Impact of Intimate Partner Violence Exposure in Adolescence and Emerging Adulthood: A Developmental Psychopathology Approach.

Despite increased attention on parental intimate partner violence (IPV) exposure, a relative paucity of research has examined the developmental consequences of this traumatic experience within a life span approach. The aim of the present study was to examine how parental IPV exposure may relate to mental health during the transition from adolescence to emerging adulthood. Furthermore, we examined whether the impact of parental IPV exposure was unique from more commonly studied maltreatment experiences, specifically neglect and physical abuse. A large, racially and ethnically diverse sample (Nbaseline = 1,042; 56% female; Mage = 15.1, SD = 0.79; 31.4% Hispanic, 29.4% White, 27.9% African American, 3.6% Asian, 7.7% biracial or other) of adolescents completed a baseline assessment for parental physical IPV exposure and maltreatment as well as measures for symptoms of depression, posttraumatic stress, and substance use, annually for 6 consecutive years. Mixed-level modeling was used to examine how parental IPV exposure was uniquely associated with different patterns of mental health across developmental epochs. Findings demonstrated a multifaceted relation with mental health. For internalizing symptoms, the effect was pronounced during adolescence, and neglect increased the risk for depression symptomatology. Meanwhile, parental-IPV-exposed adolescents were at increasing risk for substance use as they aged into adulthood. Symptom levels and trajectories were independent and distinct from maltreatment experiences. This study helps illuminate parental IPV exposure's unique influence on well-being during vulnerable developmental periods. It also calls attention to the importance of developing suitable intervention/prevention programs to target this vulnerable population.

Does change in perceptions of peer teen dating violence predict change in teen dating violence perpetration over time?

Research has previously demonstrated that perceptions of peer's teen dating violence (TDV) is associated with one's own perpetration of TDV, although little research has examined whether this relationship is consistent across developmental time periods (i.e., mid-to-late adolescence). The present study examined whether changes in perceptions of peer's TDV predicted change in one's own perpetration of TDV in a sample of ethnically diverse adolescents from ages 15 to 18 (N = 1,042). Parallel process modeling demonstrated that decreases in perceptions of peer's TDV predicted decreases in TDV perpetration over time, and this relationship was more pronounced for males than females. These findings lend further support to the need for TDV prevention and intervention programs to include peer influence in their programs.

Age of onset for physical and sexual teen dating violence perpetration: A longitudinal investigation.

Teen dating violence (TDV) is a serious and prevalent public health problem. TDV is associated with a number of negative health consequences for victims and predicts violence in adult relationships. Thus, efforts should be devoted to the primary prevention of TDV. However, only a few studies have examined when the risk for the first occurrence of TDV is greatest. Continued research in this area would inform the timing of, as well as developmentally appropriate strategies for, TDV primary prevention efforts. The current study examined at which age(s) the risk for TDV perpetration onset was greatest. Utilizing a panel-based design, a sample of racially/ethnically diverse high school students (N=872; 56% female) from the Southwestern United States completed self-report surveys on physical and sexual TDV perpetration annually for six years (2010 to 2016). Findings suggested that the physical TDV risk of onset was at or before ages 15 to 16 for females and at or before age 18 for males. For sexual TDV perpetration, risk was similar for males and females during adolescence, before uniquely increasing for males, and not females in emerging adulthood. Findings highlight the need for TDV primary prevention programs to be implemented early in high school, and potentially in middle school.