TRAIP resolves DNA replication-transcription conflicts during the S-phase of unperturbed cells.

Cell division is the basis for the propagation of life and requires accurate duplication of all genetic information. DNA damage created during replication (replication stress) is a major cause of cancer, premature aging and a spectrum of other human disorders. Over the years, TRAIP E3 ubiquitin ligase has been shown to play a role in various cellular processes that govern genome integrity and faultless segregation. TRAIP is essential for cell viability, and mutations in TRAIP ubiquitin ligase activity lead to primordial dwarfism in patients. Here, we have determined the mechanism of inhibition of cell proliferation in TRAIP-depleted cells. We have taken advantage of the auxin induced degron system to rapidly degrade TRAIP within cells and to dissect the importance of various functions of TRAIP in different stages of the cell cycle. We conclude that upon rapid TRAIP degradation, specifically in S-phase, cells cease to proliferate, arrest in G2 stage of the cell cycle and undergo senescence. Our findings reveal that TRAIP works in S-phase to prevent DNA damage at transcription start sites, caused by replication-transcription conflicts.

Further Evidence of an Association Between a Positive Child Behavior Checklist-Bipolar Profile and a Diagnosis of Pediatric Bipolar Disorder: A Meta-Analysis.

Background: Previous research has found that a unique profile of the Child Behavior Checklist comprising of aggregate elevations of the Attention, Anxiety/Depression and Aggression scales (A-A-A profile, CBCL-Bipolar (BP) profile, CBCL-Dysregulation profile (DP); henceforth CBCL-BP/DP profile) is associated with a clinical diagnosis of pediatric bipolar (BP) disorder. Objective: The main aim of the study is to evaluate the strength of the association between the CBCL-BP/DP profile and the clinical diagnosis of pediatric BP disorder through a meta-analysis. Methods: A literature search was performed to identify studies that examined the association between a positive CBCL-BP/DP profile and a clinical diagnosis of pediatric BP disorder. The meta-analyses first examined studies assessing the rates of a positive CBCL-BP/DP profile in youth with BP disorder versus those with 1) ADHD, anxiety/depression, or disruptive behavior disorders (DBDs), and 2) non-bipolar controls. The second analysis evaluated studies examining the rates of pediatric BP disorder in youth with and without a positive CBCL-BP/DP profile. Results: Eighteen articles met our inclusion and exclusion criteria, and fifteen articles had adequate data for meta-analysis. Results showed that BP youth were at significantly increased odds of having a positive CBCL-BP/DP profile compared to those with other psychiatric disorders (i.e., ADHD, anxiety/depression, or DBDs) (pooled OR=4.34, 95% CI=2.82, 8.27; p<0.001) and healthy control groups (pooled OR=34.77, 95% CI=2.87, 420.95; p=0.005). Further, meta-analysis results showed that youth with a positive CBCL-BP/DP profile were at significantly increased odds of having a BP disorder diagnosis compared to those without (pooled OR=4.25, 95% CI=2.12, 8.52; p<0.001). Conclusion: Our systematic review and meta-analysis of the extant literature provides strong support for the association between the CBCL-BP/DP profile and pediatric BP disorder.

An Evaluation of the Structure of Attention in Adolescence.

This study evaluated the factor structure of attention, considering internal and external attention, and juxtaposed alongside processing speed (PS) and working memory (WM). We expected the hypothesized model to fit better than unitary or method factors. We included 27 measures with 212 Hispanic middle schoolers from Spanish-speaking backgrounds, where a substantial proportion were at risk for learning difficulties. Confirmatory factor analytic models separated factors of PS and WM, but the final model did not align with theoretical predictions; rather only measurement factors emerged. Findings extend and refine our understanding of the structure of attention in adolescents.

A Randomized, Double-Blind, Controlled Clinical Trial of Omega-3 Fatty Acids and Inositol as Monotherapies and in Combination for the Treatment of Pediatric Bipolar Spectrum Disorder in Children Age 5-12.

Objectives: The aim of this study was to assess the efficacy and tolerability of omega-3 fatty acids (FAs) and inositol alone and in combination for the treatment of pediatric bipolar (BP) spectrum disorder in young children. Methods: Participants were male and female children ages 5-12 meeting DSM-IV diagnostic criteria for a BP spectrum disorder and displaying mixed, manic, or hypomanic symptoms without psychotic features at the time of evaluation. Results: Participants concomitantly taking psychotropic medication were excluded from efficacy analyses. There were significant reductions in YMRS and HDRS mean scores in the inositol and combination treatment groups (all p < 0.05) and in CDRS mean scores in the combination treatment group (p < 0.001), with the largest changes seen in the combination group. Those receiving the combination treatment had the highest rates of antimanic and antidepressant response. The odds ratios for the combination group compared to the omega-3 FAs and inositol groups were clinically meaningful (ORs ≥2) for 50% improvement on the YMRS, normalization of the YMRS (score <12) (vs. inositol group only), 50% improvement on the HDRS, 50% improvement on CDRS (vs. omega-3 FAs group only), and CGI-I Mania, CGI-I MDD, and CGI-I Anxiety scores <2. Conclusion: The antimanic and antidepressant effects of the combination treatment of omega-3 FAs and inositol were consistently superior to either treatment used alone. This combination may offer a safe and effective alternative or augmenting treatment for youth with BP spectrum disorder, but more work is needed to confirm the statistical significance of this finding.

A systematic review of the literature on telepsychiatry for bipolar disorder.

OBJECTIVE: Bipolar (BP) disorder is a highly morbid disorder that is often misdiagnosed or undiagnosed and affects a large number of adults and children. Due to the coronavirus disease 2019 public health emergency stay at home orders, most outpatient mental health care was provided via telepsychiatry, and the many benefits of virtual care ensure that this will continue as an ongoing practice. The main aim of this review was to investigate what is currently known about the use of telepsychiatry services in the diagnosis and treatment of BP disorder across the lifespan. METHOD: A systematic literature review assessing the use of telepsychiatry in BP disorder was conducted in PubMed, PsychINFO, and Medline. RESULTS: Six articles were included in the final review. All included articles assessed populations aged 17 years or older. The literature indicates that BP disorder was addressed in telepsychiatry services at a similar rate as in-person services, reliable diagnoses can be made using remote interviews, satisfaction rates are comparable to in-person services, telepsychiatry services are able to reach and impact patients with BP disorder, are sustainable, and patient outcomes can improve using a telepsychiatry intervention. CONCLUSIONS: Given the morbidity of BP disorder, the research addressing the telepsychiatry diagnosis and treatment of BP disorder is sparse, with only emerging evidence of its reliability, effectiveness, and acceptance. There is no research assessing the safety and efficacy of telepsychiatry in pediatric populations with BP disorder. Given the morbidity associated with BP disorder at any age, further research is needed to determine how to safely and effectively incorporate telepsychiatry into clinical care for BP adult and pediatric patients.

Long term outcomes of pediatric Bipolar-I disorder: A prospective follow-up analysis attending to full syndomatic, subsyndromal and functional types of remission.

OBJECTIVE: To examine patterns of remission of pediatric bipolar I (BP-I) disorder attending to syndromatic, symptomatic, and functional outcomes from childhood to adolescent and young adult years. METHODS: We analyzed data from a six-year prospective follow-up study of youths aged 6-17 years with BP-I disorder. Subjects were comprehensively assessed at baseline and subsequently at four, five, and six years thereafter. Assessments included structured diagnostic interviews and measures of psychosocial and educational functioning. Patterns of remission were calculated attending to whether syndromatic, symptomatic, and functional remission were achieved. RESULTS: Kaplan-Meier failure functions revealed that the probability of functional recovery from pediatric BP-I disorder was very low. Of the 88 youths assessed, only 6% (N = 5) of the sample were euthymic with normal functioning during the year prior to their last follow-up assessment (average follow-up time = 5.8 ± 1.8 years). CONCLUSIONS: These results provide compelling evidence of the high level of persistence of pediatric BP-I disorder. Symptomatic and functional remission were uncommon and most subjects continued to demonstrate high morbidity into late adolescence and early adulthood.

Can pediatric bipolar disorder be successfully treated when comorbid with conduct disorder? A secondary analysis of clinical trials of risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole.

BACKGROUND: Pediatric bipolar disorder (BP) is frequently comorbid with conduct disorder (CD) and its presence adds to the morbidity of BP. While there are no known pharmacological treatments for CD, pediatric BP is responsive to treatment with medications initially indicated for the treatment of psychosis, several of which have Food and Drug Administration (FDA) approval for the treatment of pediatric mania. AIMS: The main aim of this secondary analysis was to examine whether pediatric BP comorbid with CD responds similarly to treatment with such selected medications. Considering the well-documented morbidity of CD, this finding could have important clinical and public health significance. METHODS: We conducted a secondary analysis of six prospective 8-week open-label trials of selected medications (risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole) using identical methodology in youth with BP with and without comorbid CD. Results: Of 165 youths with BP, 54% (N = 89) met criteria for comorbid CD. The antimanic effects observed did not significantly differ between BP youths with and without comorbid CD, as measured either by a reduction in Young Mania Rating Scale (YMRS) ⩾ 30% or Clinical Global Impression (CGI)-Improvement ⩽ 2 (p = 0.23), or by the more stringent definition of a reduction in YMRS ⩾ 50% (p = 0.61). CONCLUSION: Pediatric BP can be effectively treated with the abovementioned medications in the context of comorbid CD. Based on previous research showing that remission of BP is associated with remission of CD, if confirmed, these findings raise the possibility that antimanic treatment of youth with BP comorbid with CD could have secondary benefits in mitigating the morbidity associated with CD. This is a pilot scale finding, the results of which are promising and should be confirmed by larger and long-term follow-up studies.

Findings from a pilot open-label trial of N-acetylcysteine for the treatment of pediatric mania and hypomania.

BACKGROUND: Pediatric bipolar disorder is a highly prevalent and morbid disorder and is considered a prevalent public health concern. Currently approved treatments often pose the risk of serious side effects. Therefore, this study assessed the efficacy and tolerability of N-acetylcysteine (NAC), in children and adolescents with bipolar spectrum disorder. METHODS: We conducted a 12-week open-label trial of NAC for treatment of mania and hypomania in children and adolescents ages 5-17 with bipolar spectrum disorder including participants with full and subthreshold manic symptoms, accepting those with and without mixed states with co-occurring depression, and Young Mania Rating Scale scores ≥ 20 and < 40. Symptoms of mania and depression were assessed using the Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HDRS), Children's Depression Rating Scale (CDRS), and Clinical Global Impression (CGI) Severity (CGI-S) and Improvement (CGI-I) scales for mania and depression. RESULTS: This study had a high drop-out rate with only 53% completing all 12 weeks. There was a significant reduction in YMRS, HDRS, and CDRS mean scores from baseline to endpoint. Of the 24 exposed participants, 54% had an anti-manic response measured by a reduction in YMRS ≥ 30% and 46% had a CGI-I mania score ≤ 2 at endpoint. Additionally, 62% of participants had an anti-depressive response measured by a reduction in HDRS ≥ 30%, 31% had an anti-depressive response measured by a reduction in CDRS ≥ 30%, and 38% had a CGI-I depression score ≤ 2 at endpoint. CONCLUSIONS: These pilot open-label findings in a small sample provide preliminary data supporting the tolerability and safety of NAC in a pediatric population. The findings of this pilot scale study indicating improvement in mania and depression are promising, but require replication with a monotherapy randomized placebo controlled clinical trial and larger sample. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02357290 . First Registration 06/02/2015.

Using a Digital Meditation Application to Mitigate Anxiety and Sleep Problems in Children with ADHD.

Objective: ADHD affects 11% of children in the United States and is associated with significant levels of anxiety. Although the literature supports mindfulness-based interventions as a promising strategy for managing anxiety, it falls short in the feasibility of digital mindfulness interventions. Method: This study investigated the usefulness of the pediatric version of Headspace, a digital mindfulness program, for reducing stress in 18 children with ADHD. We conducted a 4-week pilot study to evaluate the Headspace digital mindfulness application for children ages 6 to 12 with ADHD. Parents completed the Beck Anxiety Inventory and the Children's Sleep Habits Questionnaire at baseline and endpoint. Results: Participants had an average age of 9.2 years and were 78% male. The Headspace intervention significantly reduced anxiety and sleep problems in children with ADHD. Conclusion: Children with ADHD and comorbid anxiety and/or sleep problems could benefit from a digitally based meditation application. (J. of Att. Dis. XXXX; XX(X) XX-XX).

Psychopharmacology of Treating Explosive Behavior.

Explosive and aggressive behavior in children can pose safety risks, disturb family functioning, and lead to significant impairments. Pharmacologic management should be based on the first-line treatment of the primary psychiatric diagnoses of the patient and initiated in combination with appropriate psychosocial interventions. Review of the literature suggests that risperidone has the most supporting evidence in the treatment of explosive behavior. Stimulants have been shown to be helpful in the treatment of explosive behavior in attention-deficit/hyperactivity disorder. Medication treatment can be associated with significant side effects and therefore the risks and benefits of medication management must be weighed carefully.

The child behavior checklist can aid in characterizing suspected comorbid psychopathology in clinically referred youth with ADHD.

OBJECTIVE: To examine the utility of the Child Behavior Checklist (CBCL) to aid in the identification of comorbid psychopathological conditions affecting referred youth with suspected ADHD prior to the evaluation. The CBCL is an easy-to-use assessment tool that may provide invaluable information regarding the severity and characteristics of the presenting complaints. METHODS: The sample included 332 youths consecutively referred to an ADHD program for the assessment of suspected ADHD. Parents completed the CBCL, parent-rated ADHD Self-Report Scale (ASRS), Social Responsiveness Scale (SRS), and Behavior Rating Inventory of Executive Function (BRIEF). Because of the established association between the CBCL Attention Problems scale and a structured diagnostic interview of ADHD, all youths analyzed had abnormal Attention Problems T-scores (≥60). RESULTS: Seventy-six percent of youths with elevated Attention Problems T-scores had ≥3 additional abnormal CBCL scales, suggesting they were likely affected with multiple comorbid psychopathological conditions. Moreover, 44% had ≥1 CBCL clinical scale with a T-score more severe than their Attention Problems T-score, suggesting the putative comorbid condition was more severe than the ADHD symptoms. Additional CBCL scale elevations were associated with more severe functional impairments as assessed by the ASRS, SRS, BRIEF, and CBCL competence scales. CONCLUSION: The CBCL obtained before the clinical assessment identified high rates of comorbid psychopathology in youths referred for the assessment of ADHD. It provided detailed information about the types and severity of suspected psychopathological conditions impacting a particular youth, which is critical to guide the assessing clinician on likely differing needs of the affected child.

Looking for more food or more people? Task context influences basic numerosity perception.

Approximate numerical magnitude (or numerosity) is thought to represent one of the fundamental sensory properties driving perceptual choices. Recent studies indicate that numerosity judgment on a dot array is primarily driven by its numerical magnitude, largely independent from its other non-numerical visual dimensions. Nevertheless, these findings do not preclude the possibility that non-numerical cues such as size or spacing of a dot array influence numerosity judgment. Here, we test the hypothesis that numerosity judgment is influenced by non-numerical dimensions of a dot array depending on the context to which those non-numerical cues could be useful. Participants were asked to choose the more numerous of two dot arrays in two different contexts that differed only in one aspect. In one condition, the task was framed as choosing a set with more fruits to consume. In the other condition, the task was framed as choosing a group with more people to join. The results demonstrate that the influence of non-numerical cues - and particularly of the dimension of size - was significantly smaller when participants made quantitative choices about people than when they made choices about food, illustrating that the representation of discrete magnitude is more pronounced in the former case. These findings suggest that the information pooled to reach a decision about numerosity is flexibly determined according to the context and the goals of such judgment.