Risk Factors and Clinical Correlates of Pediatric Serotonin Syndrome in Hospitalized Suicide Attempters.

Objective: To evaluate the risk factors and clinical correlates of pediatric serotonin syndrome (SS) given that research on SS in adults exists, there is a dearth of literature on pediatric SS. Study design: We conducted a retrospective chart review of 183 pediatric patients who were medically hospitalized after a suicide attempt. We investigated associations between SS and several of its risk factors and clinical correlates. We also assessed the sensitivity/specificity of Hunter's criteria and criterion symptoms in predicting SS. Results: SS occurred in 21.7% of patients with a serotonergic overdose. Recent marijuana use and overdose on a selective serotonin reuptake inhibitor were significantly associated with SS. Individuals with SS required a greater number of days to be medically stabilized and had a greater likelihood of being placed on a ventilator during treatment. Hunter's criteria had 66.7% sensitivity and 92.3% specificity in diagnosing SS. Conclusions: Our study reveals both novel risk factors associated with SS (eg, recent marijuana use) and clinical correlates for patients with pediatric SS. In children, Hunter's criteria appeared to have good specificity but poor sensitivity in identifying SS. Our results set the stage for future work aimed at enhancing clinicians' ability to more rapidly identify and treat pediatric SS.

Examining Longitudinal Associations Between Future Orientation and Multiple Forms of Youth Violence Perpetration.

PURPOSE: Future orientation, defined as hopes and aspirations for the future, is gaining promise as a cross-cutting protective factor against youth violence. This study assessed how future orientation longitudinally predicted multiple forms of violence perpetration among minoritized male youth in neighborhoods made vulnerable by concentrated disadvantage. METHODS: Data were drawn from a sexual violence (SV) prevention trial among 817 predominately African American male youth, ages 13 to 19, residing in neighborhoods disproportionately impacted by community violence. We used latent class analysis to create baseline future orientation profiles of participants. Mixed effects models examined how future orientation classes predicted multiple forms of violence perpetration (i.e., weapon violence, bullying, sexual harassment, non-partner SV, and intimate partner SV) at 9-month follow-up. RESULTS: Latent class analysis yielded four classes, with nearly 80% of youth belonging to moderately high and high future orientation classes. We found significant overall associations between latent class and weapon violence, bullying, sexual harassment, non-partner SV, and SV (all p < .01). While patterns of association differed across each type of violence, violence perpetration was consistently highest among youth in the low-moderate future orientation class. Compared to youth in the low future orientation class, youth in the low-moderate class had higher odds of bullying (odds ratio 3.51, 95% confidence interval: 1.56-7.91) and sexual harassment perpetration (odds ratio 3.44, 95% confidence interval: 1.49-7.94). DISCUSSION: The longitudinal relationship between future orientation and youth violence may not be linear. Greater attention to nuanced patterns of future orientation may better inform interventions seeking to harness this protective factor to reduce youth violence.

Exploring the Impact of Racism on Black Youth: A Multidimensional Examination of Discriminatory Experiences Across Place and Time.

PURPOSE: Community violence disproportionally impacts Black youth. Experiences of racism and discrimination may create additional challenges for youth recovering from violence exposure. This study used ecological momentary assessment to elucidate how perceptions of racism and social support influence health and safety outcomes among Black youth following violence exposure. METHODS: Twenty-five Black youth (14-19 years old, 60% female) who had witnessed violence within the past three months completed a baseline survey that assessed discrimination experiences, social support, post-traumatic stress symptoms (PTS), and perceived safety. Youth completed ecological momentary assessments three times daily for two weeks about the place they were in, people they were with, their current emotional state, and in-the-moment racism perceptions. Multilevel models estimated the relationship between overall and time-varying perceptions of racism and social support, PTS symptoms, and perceived safety. RESULTS: Overall, 76% of youth reported at least one discrimination experience at baseline. Prior discrimination was associated with higher PTS (B = 1.86, p = .001) and depressive symptoms (B = 0.13, p = .013) at baseline. Youth who reported higher overall perceptions of racism in-the-moment reported higher PTS (B = 0.50, p = .002) and lower perceived safety (B = -0.53, p = .001). In-the-moment perceptions of racism were associated with lower perceived safety in that place (B = -0.09, p < .01). Emotional and instrumental support were associated with lower PTS and higher perceived safety (p < .05). DISCUSSION: Experiences of racism and being in discriminatory places impacted youth's depressive symptoms, PTS symptoms, and perceived safety. Interventions attuned to in-the-moment experiences of racism, and that leverage social support, are needed to support Black youth exposed to violence and discrimination.

Transition age youth mental health: addressing the gap with telemedicine.

Transition age youth (TAY), a demographic spanning ages 15-26, navigate a myriad of developmental transitions, ranging from identity formation and intimate relationships to substance use. Unfortunately, many young adults continue to have a dearth of mental health services and programing tailored to their unique developmental needs. Moreover, the systems of care in place are generally designed for treating traditional pediatric and adult patients but not ideally suited to meet the needs of TAY. Given the additional stressors from the COVID-19 pandemic, TAY are now, more than ever, in need of routine mental health care. We posit that the rapid expansion of telemedicine programming developed in response to the pandemic could be beneficial in mitigating this historic gap in care. In this commentary, we call on mental health providers and researchers to expand and invest in the growing number of telemedicine interventions and programming for this population so that TAY can begin to receive the care they so desperately need.

Associations Between Parental Monitoring and Multiple Types of Youth Violence Victimization: A Brief Report.

Youth violence victimization continues to be pervasive and a significant cause of adolescent mortality. Since their 2014 "Connecting the Dots" report, the Centers for Disease Control and Prevention have encouraged researchers to identify shared protective factors that prevent multiple forms of youth violence. Parental monitoring, a bidirectional construct encompassing parental knowledge and regulation of their child's activities with children's concurrent perception of their parent's awareness of such activities, could be such a cross-cutting protective factor. In this study, we examined associations between parental monitoring and multiple types of violence victimization among a school-based sample of adolescents. We conducted a cross-sectional analysis of an anonymous survey of health risk and protective behaviors completed by students across Pittsburgh Public Schools (N = 2,426). In separate analyses, we used logistic regression to examine associations between youth-reported parental monitoring and multiple experiences of youth violence victimization, ranging from school- and electronic-based bullying to different forms of sexual and physical violence. We found that many experiences of youth violence victimization were consistent with nationally representative data. In addition, we determined that higher parental monitoring was significantly and inversely associated with all violence victimization outcomes examined (school-based bullying, electronic-based bullying, threatening someone with a weapon, adolescent relationship abuse, sexual assault, and exchange sex) at the p < .05 threshold. Overall, this study is one of the first that examines how parental monitoring relates to multiple forms of youth violence victimization, including exchange sex, which is a critical but less-studied violence experience. This work adds to the growing literature on how parental monitoring may serve as a shared protective factor for multiple forms of violence victimization.

Parent ADHD Is Associated With Greater Parenting Distress in the First Year Postpartum.

OBJECTIVE: Little is known about the experience of parenting infants when a mother or father has ADHD. This study examined cross-sectional predictors of parenting distress experienced by parents with and without ADHD who also have infants. METHODS: Participants were 73 mother-father pairs (N = 146) of infants 6 to 10 months old. Half of the families included a parent with ADHD. Psychosocial predictors were tested using multilevel modeling. RESULTS: Parent or partner ADHD, lower parent sleep quality, fewer social supports, and less infant surgency and effortful control were associated with greater parental distress. Infant negative affect and sleep were not associated. CONCLUSIONS: Parents with ADHD and their partners experience greater parenting distress in the first year of their child's life than parents without ADHD. Addressing parent ADHD symptoms and co-occurring difficulties, including sleep disturbances, are potential targets for early interventions to maximize both parent and infant mental health outcomes.

Protective Factors Against Vaping and Other Tobacco Use.

BACKGROUND AND OBJECTIVES: Vaping has gained popularity among adolescents despite negative health consequences. Few studies have focused on factors that may protect against vaping. We sought to determine if future orientation, parental monitoring, school connectedness, and social support are associated with decreased risk of vaping and other forms of tobacco use. METHODS: Data were obtained via anonymous school-based health behavior surveys among ninth- through 12th-graders in Pittsburgh, PA (n = 2487). Protective factors were assessed through validated Likert scale instruments. The primary outcome was recent (past 30-day) vaping. Additional outcomes included other forms of tobacco use and intention to quit tobacco products. Poisson regression models examined associations between protective factors and vaping and tobacco use outcomes. RESULTS: Mean age was 15.7 years, 1446 (58.1%) respondents were female, and 671 youth (27.0%) reported recent vaping. Positive future orientation and high parental monitoring were associated with significantly lower prevalence of recent vaping (adjusted prevalence ratio: 0.84 [95% confidence interval: 0.73-0.97] and adjusted prevalence ratio: 0.73 [95% confidence interval: 0.62-0.85], respectively). There were no significant relationships between social support or school connectedness and vaping. All 4 protective factors were inversely associated with other forms of tobacco use. No factors were significantly associated with intent to quit tobacco products. CONCLUSIONS: Findings reveal significant inverse associations between future orientation, parental monitoring, and vaping but no relationship between protective factors and intent to quit tobacco products. Developing interventions to foster protective factors in youth and their parental supports may inform primary prevention efforts to reduce vaping and other tobacco use.

Future Orientation as a Cross-Cutting Protective Factor Against Multiple Forms of Violence.

Among 9th-to 12th-grade students who completed an anonymous health risk and protective behavior survey (n = 2346), positive future orientation was significantly and inversely associated with multiple forms of interpersonal violence including youth, community, and sexual/relationship violence. Designing interventions to promote future orientation holds promise as a cross-cutting violence prevention strategy.

Targeting the EMT transcription factor TWIST1 overcomes resistance to EGFR inhibitors in EGFR-mutant non-small-cell lung cancer.

Patients with EGFR-mutant non-small-cell lung cancer (NSCLC) have significantly benefited from the use of EGFR tyrosine kinase inhibitors (TKIs). However, long-term efficacy of these therapies is limited due to de novo resistance (~30%) as well as acquired resistance. Epithelial-mesenchymal transition transcription factors (EMT-TFs), have been identified as drivers of EMT-mediated resistance to EGFR TKIs, however, strategies to target EMT-TFs are lacking. As the third generation EGFR TKI, osimertinib, has now been adopted in the first-line setting, the frequency of T790M mutations will significantly decrease in the acquired resistance setting. Previously less common mechanisms of acquired resistance to first generation EGFR TKIs including EMT are now being observed at an increased frequency after osimertinib. Importantly, there are no other FDA approved targeted therapies after progression on osimertinib. Here, we investigated a novel strategy to overcome EGFR TKI resistance through targeting the EMT-TF, TWIST1, in EGFR-mutant NSCLC. We demonstrated that genetic silencing of TWIST1 or treatment with the TWIST1 inhibitor, harmine, resulted in growth inhibition and apoptosis in EGFR-mutant NSCLC. TWIST1 overexpression resulted in erlotinib and osimertinib resistance in EGFR-mutant NSCLC cells. Conversely, genetic and pharmacological inhibition of TWIST1 in EGFR TKI-resistant EGFR-mutant cells increased sensitivity to EGFR TKIs. TWIST1-mediated EGFR TKI resistance was due in part to TWIST1 suppression of transcription of the pro-apoptotic BH3-only gene, BCL2L11 (BIM), by directly binding to BCL2L11 intronic regions and promoter. As such, pan-BCL2 inhibitor treatment overcame TWIST1-mediated EGFR TKI resistance and were more effective in the setting of TWIST1 overexpression. Finally, in a mouse model of autochthonous EGFR-mutant lung cancer, Twist1 overexpression resulted in erlotinib resistance and suppression of erlotinib-induced apoptosis. These studies establish TWIST1 as a driver of resistance to EGFR TKIs and provide rationale for use of TWIST1 inhibitors or BCL2 inhibitors as means to overcome EMT-mediated resistance to EGFR TKIs.

A First-in-Class TWIST1 Inhibitor with Activity in Oncogene-Driven Lung Cancer.

TWIST1, an epithelial-mesenchymal transition (EMT) transcription factor, is critical for oncogene-driven non-small cell lung cancer (NSCLC) tumorigenesis. Given the potential of TWIST1 as a therapeutic target, a chemical-bioinformatic approach using connectivity mapping (CMAP) analysis was used to identify TWIST1 inhibitors. Characterization of the top ranked candidates from the unbiased screen revealed that harmine, a harmala alkaloid, inhibited multiple TWIST1 functions, including single-cell dissemination, suppression of normal branching in 3D epithelial culture, and proliferation of oncogene driver-defined NSCLC cells. Harmine treatment phenocopied genetic loss of TWIST1 by inducing oncogene-induced senescence or apoptosis. Mechanistic investigation revealed that harmine targeted the TWIST1 pathway through its promotion of TWIST1 protein degradation. As dimerization is critical for TWIST1 function and stability, the effect of harmine on specific TWIST1 dimers was examined. TWIST1 and its dimer partners, the E2A proteins, which were found to be required for TWIST1-mediated functions, regulated the stability of the other heterodimeric partner posttranslationally. Harmine preferentially promoted degradation of the TWIST1-E2A heterodimer compared with the TWIST-TWIST1 homodimer, and targeting the TWIST1-E2A heterodimer was required for harmine cytotoxicity. Finally, harmine had activity in both transgenic and patient-derived xenograft mouse models of KRAS-mutant NSCLC. These studies identified harmine as a first-in-class TWIST1 inhibitor with marked anti-tumor activity in oncogene-driven NSCLC including EGFR mutant, KRAS mutant and MET altered NSCLC.Implications: TWIST1 is required for oncogene-driven NSCLC tumorigenesis and EMT; thus, harmine and its analogues/derivatives represent a novel therapeutic strategy to treat oncogene-driven NSCLC as well as other solid tumor malignancies. Mol Cancer Res; 15(12); 1764-76. ©2017 AACR.