Cognitive bias modification of interpretations for anxiety and depression in children and adolescents: A meta-analysis.

Background: Evidence suggests that cognitive bias modification of interpretations (CBM-I) is effective in modifying interpretation biases and has a small effect on reducing anxiety in children and adolescents. However, most evidence to date is based on studies which report anxiety or general distress using ad-hoc Likert-type or Visual Analogue Scales, which are useful but do not reliably index symptoms of clinical importance. This meta-analysis aimed to establish the effects of CBM-I for children and adolescents on both anxiety and depression using psychometrically validated symptom measures, as well as state negative affect and negative and positive interpretation bias. Methods: We identified studies through a systematic search. To be eligible for inclusion, studies needed to target interpretation biases, not combine CBM-I with another intervention, randomly allocate participants to CBM-I or a control condition, assess a mental health outcome (i.e., anxiety or depression symptoms using validated measures or state measures of negative affect) and/or interpretation bias and have a mean age less than 18 years. Results: We identified 36 studies for inclusion in the meta-analysis. CBM-I had a small and non-significant unadjusted effect on anxiety symptoms (g = 0.16), no effect on depression symptoms (g = -0.03), and small and non-significant unadjusted effects on state negative affect both at post-training (g = 0.16) and following a stressor task (g = 0.23). In line with previous findings, CBM-I had moderate to large unadjusted effects on negative and positive interpretations (g = 0.78 and g = 0.52). No significant moderators were identified. Conclusions: CBM-I is effective at modifying interpretation bias, however there were no effects on mental health outcomes. The substantial variability across studies and paucity of studies using validated symptom measures highlight the need to establish randomized controlled trial protocols that evaluate CBM-I in clinical youth samples to determine its future as a clinical intervention.

Estimated Prevalence of Depressive Disorders in Children From 2004 to 2019: A Systematic Review and Meta-Analysis.

Importance: Depression during childhood (ie, age <13 years) poses a major health burden. Recent changes in environmental and lifestyle factors may increase children's risk of mental health problems. This has been reported for anxiety disorders, but it is unclear whether this occurs for depressive disorders. Objective: To provide prevalence estimates for the depressive disorders (ie, major depressive disorder [MDD], dysthymia, disruptive mood dysregulation disorder [DMDD], and overall) in children, and whether they have changed over time. Data Sources: The MEDLINE, PsycINFO, Embase, Scopus, and Web of Science databases were searched using terms related to depressive disorders, children, and prevalence. This was supplemented by a systematic gray literature search. Study Selection: Studies were required to provide population prevalence estimates of depressive disorder diagnoses (according to an established taxonomy and standardized interviews) for children younger than 13 years, information about participants' year of birth, and be published in English. Data Extraction and Synthesis: Data extraction was compliant with the Meta-Analysis of Observational Studies in Epidemiology guidelines. A total of 12 985 nonduplicate records were retrieved, and 154 full texts were reviewed. Data were analyzed from 2004 (the upper limit of a previous review) to May 27, 2023. Multiple proportional random-effects meta-analytic and mixed-effects meta-regression models were fit. Main Outcomes and Measures: Pooled prevalence rates of depressive disorders, prevalence rate differences between males vs females and high-income countries (HICs) vs low-and middle-income countries (LMICs), and moderating effects of time or birth cohort. Results: A total of 41 studies were found to meet the inclusion criteria. Pooled prevalence estimates were obtained for 1.07% (95% CI, 0.62%-1.63%) for depressive disorders overall, 0.71% (95% CI, 0.48%-0.99%) for MDD, 0.30% (95% CI, 0.08%-0.62%) for dysthymia, and 1.60% (95% CI, 0.28%-3.90%) for DMDD. The meta-regressions found no significant evidence of an association with birth cohort, and prevalence rates did not differ significantly between males and females or between HICs and LMICs. There was a low risk of bias overall, except for DMDD, which was hindered by a lack of studies. Conclusions and Relevance: In this systematic review and meta-analysis, depression in children was uncommon and did not increase substantially between 2004 and 2019. Future epidemiologic studies using standardized interviews will be necessary to determine whether this trend will continue into and beyond the COVID-19 pandemic.

Everolimus downregulates STAT3/HIF-1α/VEGF pathway to inhibit angiogenesis and lymphangiogenesis in TP53 mutant head and neck squamous cell carcinoma (HNSCC).

TP53 mutant head and neck squamous cell carcinoma (HNSCC) patients exhibit poor clinical outcomes with 50-60% recurrence rates in advanced stage patients. In a recent phase II clinical trial, adjuvant therapy with everolimus (mTOR inhibitor) significantly increased 2-year progression-free survival in p53 mutated patients. TP53-driven mTOR activation in solid malignancies causes upregulation of HIF-1α and its target, downstream effector VEGF, by activating STAT3 cell signaling pathway. Here, we investigated the effects of everolimus on the STAT3/HIF-1α/VEGF pathway in TP53 mutant cell lines and xenograft models. Treatment with everolimus significantly inhibited cell growth in vitro and effectively reduced the growth of TP53 mutant xenografts in a minimal residual disease (MRD) model in nude mice. Everolimus treatment was associated with significant downregulation of STAT3/HIF-1α/VEGF pathway in both models. Further, treatment with everolimus was associated with attenuation in tumor angiogenesis and lymphangiogenesis as indicated by decreased microvessel density of vascular and lymphatic vessels in HN31 and FaDu xenografts. Everolimus downregulated the STAT3/HIF-1α/VEGF pathway to inhibit growth and in vitro tube formation of HMEC-1 (endothelial) and HMEC-1A (lymphatic endothelial) cell lines. Our studies demonstrated that everolimus inhibits the growth of TP53 mutant tumors by inhibiting angiogenesis and lymphangiogenesis through the downregulation of STAT3/HIF-1α/VEGF signaling.