Shyness discriminates between children with 22q11.2 deletion syndrome and Williams syndrome and predicts emergence of psychosis in 22q11.2 deletion syndrome

BACKGROUND: 22q11.2 deletion syndrome (22q11.2DS) is a common neurogenetic syndrome associated with high rates of psychosis. The aims of the present study were to identify the unique temperament traits that characterize children with 22q11.2DS compared to children with Williams syndrome (WS) and typically developing (TD) controls, and to examine temperamental predictors of the emergence of psychosis in 22q11.2DS. METHODS: The temperament of 55 children with 22q11.2DS, 36 with WS, and 280 TD children was assessed using the Emotionality, Activity, Sociability (EAS) Temperament Survey, Parental Ratings. The presence of a psychotic disorder was evaluated in 49 children and adolescents with 22q11.2DS at baseline and again 5.43 ± 2.23 years after baseline temperament assessment. RESULTS: Children with 22q11.2DS scored higher on Shyness compared to WS and TD controls. Children with 22q11.2DS and WS scored higher on Emotionality and lower on Activity compared to TD controls. Shyness was more severe in older compared to younger children with 22q11.2DS. Baseline Shyness scores significantly predicted the later emergence of a psychotic disorder at follow-up, in children with 22q11.2DS. CONCLUSIONS: Our results suggest that shyness is an early marker associated with the later emergence of psychosis in 22q11.2DS

Subthreshold psychosis in 22q11.2 deletion syndrome: multisite naturalistic study

Nearly one-third of individuals with 22q11.2 deletion syndrome (22q11.2DS) develop a psychotic disorder during life, most of them by early adulthood. Importantly, a full-blown psychotic episode is usually preceded by subthreshold symptoms. In the current study, 760 participants (aged 6-55 years) with a confirmed hemizygous 22q11.2 microdeletion have been recruited through 10 medical sites worldwide, as part of an international research consortium. Of them, 692 were nonpsychotic and with complete measurement data. Subthreshold psychotic symptoms were assessed using the Structured Interview for Prodromal Syndromes (SIPS). Nearly one-third of participants met criteria for positive subthreshold psychotic symptoms (32.8%), less than 1% qualified for acute positive subthreshold symptoms, and almost a quarter met criteria for negative/disorganized subthreshold symptoms (21.7%). Adolescents and young adults (13-25 years) showed the highest rates of subthreshold psychotic symptoms. Additionally, higher rates of anxiety disorders and attention deficit/hyperactivity disorder (ADHD) were found among the study participants with subthreshold psychotic symptoms compared to those without. Full-scale IQ, verbal IQ, and global functioning (GAF) scores were negatively associated with participants' subthreshold psychotic symptoms. This study represents the most comprehensive analysis reported to date on subthreshold psychosis in 22q11.2DS. Novel findings include age-related changes in subthreshold psychotic symptoms and evidence that cognitive deficits are associated with subthreshold psychosis in this population. Future studies should longitudinally follow these symptoms to detect whether and how early identification and treatment of these manifestations can improve long-term outcomes in those that eventually develop a psychotic disorder

miRNA profiling of NurOwn®: mesenchymal stem cells secreting neurotrophic factors

Abstract Background MSC-NTF cells are Mesenchymal Stromal Cells (MSC) induced to express high levels of neurotrophic factors (NTFs) using a culture-medium based approach. MSC-NTF cells have been successfully studied in clinical trials for Amyotrophic Lateral Sclerosis (ALS) patients. MicroRNAs (miRNA) are short non-coding RNA molecules that coordinate post-transcriptional regulation of multiple gene targets. The purpose of this study was to determine whether the miRNA profile could provide a tool for MSC-NTF cell characterization and to distinguish them from the matched MSC from which they are derived. Methods NTF secretion in the culture supernatant of MSC-NTF cells was evaluated by ELISA assays. The Agilent microarray miRNA platform was used for pairwise comparisons of MSC-NTF cells to MSC. The differentially expressed miRNAs and putative mRNA targets were validated using qPCR analyses. Results Principal component analysis revealed two distinct clusters based on cell type (MSC and MSC-NTFs). Nineteen miRNAs were found to be upregulated and 22 miRNAs were downregulated in MSC-NTF cells relative to the MSC cells of origin. Further validation of differentially expressed miRNAs confirmed that miR-3663 and miR-132 were increased 18.5- and 4.06-fold, respectively while hsa-miR-503 was reduced more than 15-fold, suggesting that miRNAs could form the basis of an MSC-NTF cell characterization assay. In an analysis of the miRNA mRNA targets, three mRNA targets of hsa-miR-132-3p (HN-1, RASA1 and KLH-L11) were found to be significantly downregulated. Conclusions We have demonstrated that MSC-NTF cells can be distinguished from their MSCs of origin by a unique miRNA expression profile. Trial Registration Clinicaltrial.gov identifier NCT01777646 . Registered 12 December 2012

Education and employment trajectories from childhood to adulthood in individuals with 22q11.2 deletion syndrome

22q11.2 deletion syndrome (22q11.2DS) is the most common known microdeletion in humans occurring in 1 out of 2000-4000 live births, with increasing numbers of individuals with the microdeletion living into adulthood. The aim of the study was to explore the education and employment trajectories of individuals with 22q11.2DS from childhood to adulthood in a large cohort composed of two significant samples. 260 individuals with 22q11.2DS, 134 male and 126 female, aged 5-59 years (mean age 21.3 ± 10.8 years) were evaluated at two sites, Geneva (GVA) and Tel Aviv (TA). Psychiatric comorbidities, IQ score, and adaptive functioning were assessed using gold-standard diagnostic tools. Demographic factors, such as data about education, employment, marital status, and living status, were collected. Children entering elementary school (5-12 years) were significantly more likely to attend a mainstream school, while adolescents were significantly more likely to attend special education schools (p < 0.005). Cognitive abilities, and not adaptive functioning, predicted school placement. Among adults with 22q11.2DS (n = 138), 57 (41.3%) were unemployed, 46 (33.3%) were employed in open market employment, and 35 (25.4%) worked in assisted employment. In adulthood, adaptive functioning more than cognitive abilities predicted employment. Surprisingly, psychotic spectrum disorders were not found to be associated with employment. Individuals with 22q11.2DS are characterized by heterogeneity in educational and employment profiles. We found that cognitive abilities and adaptive functioning, and not the presence of psychiatric disorders, are key factors in school placement and employment. These factors should, therefore, be taken into account when planning optimal development of individuals with 22q11.2DS

Pediatric psychiatric emergency rooms during COVID-19: a multi-center study

Abstract Background The COVID-19 (SARS-CoV-2) pandemic has been a major stressor for the mental health and well-being of children and adolescents. Surveys and reports from hotlines indicate a significant rise in mental health problems. As the psychiatric emergency room (ER) is a first-line free-of-charge facility for psychiatric emergencies, we expected to see a significant increase in visits, specifically of new patients suffering from anxiety, depression, or stress-related disorders. Methods Data from two psychiatric hospital ERs and one general hospital were included. All visits of children and adolescents from the computerized files between March and December of 2019 were analyzed anonymously and compared to the same months in 2020, using multilevel linear modeling. Results There was a significant decline in the total number of visits (p = .017), specifically among those diagnosed as suffering from stress-related, anxiety, and mood disorder groups (p = .017), and an incline in the proportion of visits of severe mental disorders (p = .029). Discussion The limited use of child and adolescent psychiatric emergency facilities during the pandemic highlights the importance of tele-psychiatry as part of emergency services. It also suggests the importance of the timeline of the emergence of clinically relevant new psychiatric diagnoses related to the pandemic. Future studies are needed to establish the long-term effects of the pandemic and the expeditious use of tele-psychiatry

Child and Adolescent Mental Health during the COVID-19 Pandemic: Challenges of Psychiatric Outpatient Clinics.

Peer reviewed: TrueFunder: Gates Cambridge TrustBACKGROUND: Worldwide national surveys show a rising mental health burden among children and adolescents (C&A) during COVID-19. The objective of the current study is to verify the expected rise in visits to psychiatric outpatient clinics of C&A, especially of new patients. METHODS: a cross-sectional study focusing on visits as recorded in electronic medical records of eight heterogeneous C&A psychiatric outpatient clinics. The assessment was based on visits held from March to December of 2019 (before the pandemic) in comparison to visits held in 2020 (during the pandemic). RESULTS: The number of visits was similar for both periods. However, in 2020, 17% of the visits used telepsychiatry (N = 9885). Excluding telepsychiatry reveals a monthly decrease in traditional in-person activities between 2020 and 2019 (691.6 ± 370.8 in 2020 vs. 809.1 ± 422.8 in 2019, mean difference = -117.5, t (69) = -4.07, p = 0.0002, Cohen's d = -0.30). Acceptation of new patients declined during 2020, compared to 2019 (50.0 ± 38.2 in 2020 vs. 62.8 ± 42.9 in 2019; Z = -3.12, p = 0.002, r = 0.44). Telepsychiatry was not used for new patients. CONCLUSIONS: The activity of C&A psychiatric outpatient clinics did not rise but was guarded due to the use of telepsychiatry. The decline in visits of new patients was explained by the lack of use of telepsychiatry for these patients. This calls for expanding the use of telepsychiatry, especially for new patients

Addressing heterogeneity in amyotrophic lateral sclerosis CLINICAL TRIALS.

Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder with complex biology and significant clinical heterogeneity. Many preclinical and early phase ALS clinical trials have yielded promising results that could not be replicated in larger phase 3 confirmatory trials. One reason for the lack of reproducibility may be ALS biological and clinical heterogeneity. Therefore, in this review, we explore sources of ALS heterogeneity that may reduce statistical power to evaluate efficacy in ALS trials. We also review efforts to manage clinical heterogeneity, including use of validated disease outcome measures, predictive biomarkers of disease progression, and individual clinical risk stratification. We propose that personalized prognostic models with use of predictive biomarkers may identify patients with ALS for whom a specific therapeutic strategy may be expected to be more successful. Finally, the rapid application of emerging clinical and biomarker strategies may reduce heterogeneity, increase trial efficiency, and, in turn, accelerate ALS drug development

Child and Adolescent Mental Health during the COVID-19 Pandemic: Challenges of Psychiatric Outpatient Clinics.

BACKGROUND: Worldwide national surveys show a rising mental health burden among children and adolescents (C&A) during COVID-19. The objective of the current study is to verify the expected rise in visits to psychiatric outpatient clinics of C&A, especially of new patients. METHODS: a cross-sectional study focusing on visits as recorded in electronic medical records of eight heterogeneous C&A psychiatric outpatient clinics. The assessment was based on visits held from March to December of 2019 (before the pandemic) in comparison to visits held in 2020 (during the pandemic). RESULTS: The number of visits was similar for both periods. However, in 2020, 17% of the visits used telepsychiatry (N = 9885). Excluding telepsychiatry reveals a monthly decrease in traditional in-person activities between 2020 and 2019 (691.6 ± 370.8 in 2020 vs. 809.1 ± 422.8 in 2019, mean difference = -117.5, t (69) = -4.07, p = 0.0002, Cohen's d = -0.30). Acceptation of new patients declined during 2020, compared to 2019 (50.0 ± 38.2 in 2020 vs. 62.8 ± 42.9 in 2019; Z = -3.12, p = 0.002, r = 0.44). Telepsychiatry was not used for new patients. CONCLUSIONS: The activity of C&A psychiatric outpatient clinics did not rise but was guarded due to the use of telepsychiatry. The decline in visits of new patients was explained by the lack of use of telepsychiatry for these patients. This calls for expanding the use of telepsychiatry, especially for new patients