Efficient reconstruction of cell lineage trees for cell ancestry and cancer.

Mosaic mutations can be used to track cell ancestries and reconstruct high-resolution lineage trees during cancer progression and during development, starting from the first cell divisions of the zygote. However, this approach requires sampling and analyzing the genomes of multiple cells, which can be redundant in lineage representation, limiting the scalability of the approach. We describe a strategy for cost- and time-efficient lineage reconstruction using clonal induced pluripotent stem cell lines from human skin fibroblasts. The approach leverages shallow sequencing coverage to assess the clonality of the lines, clusters redundant lines and sums their coverage to accurately discover mutations in the corresponding lineages. Only a fraction of lines needs to be sequenced to high coverage. We demonstrate the effectiveness of this approach for reconstructing lineage trees during development and in hematologic malignancies. We discuss and propose an optimal experimental design for reconstructing lineage trees.

Cognitive training for children with ADHD: composite cognitive score outcome in a randomized controlled trial.

PURPOSE OF THE ARTICLE: Cognitive training for Attention Deficit/Hyperactivity Disorder (ADHD) has shown promising, although mixed results. In post-hoc analyses, we evaluate effects of cognitive training using a novel composite cognition score as the outcome for children attending at least 16 sessions of training, dose-response of training and associations between symptoms and cognitive functioning. MATERIALS AND METHODS: Children (age 6-13) with ADHD were randomized to intervention (n = 26) or control (n = 34). For the current analysis, we restricted the intervention group to children, who completed at least 16 sessions of cognitive training (n = 26) and examined a dose response within that group. RESULTS: Cognition improved significantly in the intervention, but not control group. Amount of the completed training sessions correlated significantly with the amount of cognitive improvement. CONCLUSION: Variations in dose and frequency of training may be an important source of the variance in previous studies.

Functional connectivity during tic suppression predicts reductions in vocal tics following behavior therapy in children with Tourette syndrome.

BACKGROUND: Comprehensive Behavioral Intervention for Tics (CBIT) is recommended as a first-line treatment for Tourette syndrome in children and adults. While there is strong evidence proving its efficacy, the mechanisms of reduction in tic severity during CBIT are still poorly understood. In a recent study, our group identified a functional brain network involved in tic suppression in children with TS. We reasoned that voluntary tic suppression and CBIT may share some mechanisms and thus we wanted to assess whether functional connectivity during tic suppression was associated with CBIT outcome. METHODS: Thirty-two children with TS, aged 8 to 13 years old, participated in a randomized controlled trial of CBIT v. a treatment-as-usual control condition. EEG was recorded during tic suppression in all participants at baseline and endpoint. We used a source-reconstructed EEG connectivity pipeline to assess functional connectivity during tic suppression. RESULTS: Functional connectivity during tic suppression did not change from baseline to endpoint. However, baseline tic suppression-related functional connectivity specifically predicted the decrease in vocal tic severity from baseline to endpoint in the CBIT group. Supplementary analyses revealed that the functional connectivity between the right superior frontal gyrus and the right angular gyrus was mainly driving this effect. CONCLUSIONS: This study revealed that functional connectivity during tic suppression at baseline predicted reduction in vocal tic severity. These results suggest probable overlap between the mechanisms of voluntary tic suppression and those of behavior therapy for tics.

Mispatterning and interneuron deficit in Tourette Syndrome basal ganglia organoids.

Tourette Syndrome (TS) is a neuropsychiatric disorder thought to involve a reduction of basal ganglia (BG) interneurons and malfunctioning of the BG circuitry. However, whether interneurons fail to develop or are lost postnatally remains unknown. To investigate the pathophysiology of early development in TS, induced pluripotent stem cell (iPSC)-derived BG organoids from TS patients and healthy controls were compared on multiple levels of measurement and analysis. BG organoids from TS individuals manifested an impaired medial ganglionic eminence fate and a decreased differentiation of cholinergic and GABAergic interneurons. Transcriptome analyses revealed organoid mispatterning in TS, with a preference for dorsolateral at the expense of ventromedial fates. Our results point to altered expression of GLI transcription factors downstream of the Sonic Hedgehog signaling pathway with cilia disruption at the earliest stages of BG organoid differentiation as a potential mechanism for the BG mispatterning in TS. This study uncovers early neurodevelopmental underpinnings of TS neuropathological deficits using organoids as a model system.

Towards a definitive symptom structure of obsessive-compulsive disorder: a factor and network analysis of 87 distinct symptoms in 1366 individuals.

BACKGROUND: The symptoms of obsessive-compulsive disorder (OCD) are highly heterogeneous and it is unclear what is the optimal way to conceptualize this heterogeneity. This study aimed to establish a comprehensive symptom structure model of OCD across the lifespan using factor and network analytic techniques. METHODS: A large multinational cohort of well-characterized children, adolescents, and adults diagnosed with OCD (N = 1366) participated in the study. All completed the Dimensional Yale-Brown Obsessive-Compulsive Scale, which contains an expanded checklist of 87 distinct OCD symptoms. Exploratory and confirmatory factor analysis were used to outline empirically supported symptom dimensions, and interconnections among the resulting dimensions were established using network analysis. Associations between dimensions and sociodemographic and clinical variables were explored using structural equation modeling (SEM). RESULTS: Thirteen first-order symptom dimensions emerged that could be parsimoniously reduced to eight broad dimensions, which were valid across the lifespan: Disturbing Thoughts, Incompleteness, Contamination, Hoarding, Transformation, Body Focus, Superstition, and Loss/Separation. A general OCD factor could be included in the final factor model without a significant decline in model fit according to most fit indices. Network analysis showed that Incompleteness and Disturbing Thoughts were most central (i.e. had most unique interconnections with other dimensions). SEM showed that the eight broad dimensions were differentially related to sociodemographic and clinical variables. CONCLUSIONS: Future research will need to establish if this expanded hierarchical and multidimensional model can help improve our understanding of the etiology, neurobiology and treatment of OCD.

Prevalence of mental disorders in school children and adolescents in China: diagnostic data from detailed clinical assessments of 17,524 individuals.

BACKGROUND: To date, no national-scale psychiatric epidemiological survey for children and adolescents has been conducted in China. In order to inform government officials and policymakers and to develop a comprehensive plan for service providers, there was a clear need to conduct an up-to-date systematic nationwide psychiatric epidemiological survey. METHODS: We conducted a two-stage large-scale psychiatric point prevalence survey. Multistage cluster stratified random sampling was used as the sampling strategy. Five provinces were selected by comprehensively considering geographical partition, economic development, and rural/urban factors. In Stage 1, the Child Behavior Checklist was used as the screening tool. In Stage 2, Mini-International Neuropsychiatric Interview for Children and Adolescents and a diagnostic process based on the Diagnostic and Statistical Manual were used to make the diagnoses. Sampling weights and poststratification weights were employed to match the population distributions. Exploratory analyses were also performed using socio-demographic factors. Prevalence in socio-demographic factor subgroups and overall were estimated. Rao-Scott adjusted chi-square tests were utilized to determine if between-group differences were present. Factor interactions were checked by logistic regression analyses. RESULTS: A total of 73,992 participants aged 6-16 years of age were selected in Stage 1. In Stage 2, 17,524 individuals were screened and diagnosed. The weighted prevalence of any disorder was 17.5% (95% CI: 17.2-18.0). Statistically significant differences in prevalence of any psychiatric disorder were observed between sexes [χ2 (1, N = 71,929) = 223.0, p < .001], age groups [χ2 (1, N = 71,929) = 18.6, p < .001] and developed vs. developing areas [χ2 (1, N = 71,929) = 2,129.6, p < .001], while no difference was found between rural and urban areas [χ2 (1, N = 71,929) = 1.4, p = .239]. Male, younger individuals, children, and adolescents from developed areas had higher prevalence of any psychiatric disorder. The prevalence of any psychiatric disorder was found to decrease with the age in the male group, while the female group increased with the age. Individuals diagnosed with attention-deficit hyperactivity disorder, oppositional defiant disorder, a tic disorder, conduct disorder, and major depression disorder had the highest rates of comorbidity. CONCLUSIONS: The prevalence of any psychiatric disorder we found is the highest ever reported in China. These results urgently need to be addressed by public mental health service providers and policymakers in order to provide access to the necessary treatments and to reduce the long-term negative impact of these conditions on families and the society as a whole.

An integrated program of computer-presented and physical cognitive training exercises for children with attention-deficit/hyperactivity disorder.

BACKGROUND: This study integrated an experimental medicine approach and a randomized cross-over clinical trial design following CONSORT recommendations to evaluate a cognitive training (CT) intervention for attention deficit hyperactivity disorder (ADHD). The experimental medicine approach was adopted because of documented pathophysiological heterogeneity within the diagnosis of ADHD. The cross-over design was adopted to provide the intervention for all participants and make maximum use of data. METHODS: Children (n = 93, mean age 7.3 +/- 1.1 years) with or sub-threshold for ADHD were randomly assigned to CT exercises over 15 weeks, before or after 15 weeks of treatment-as-usual (TAU). Fifteen dropped out of the CT/TAU group and 12 out of the TAU/CT group, leaving 66 for cross-over analysis. Seven in the CT/TAU group completed CT before dropping out making 73 available for experimental medicine analyses. Attention, response inhibition, and working memory were assessed before and after CT and TAU. RESULTS: Children were more likely to improve with CT than TAU (27/66 v. 13/66, McNemar p = 0.02). Consistent with the experimental medicine hypotheses, responders improved on all tests of executive function (p = 0.009-0.01) while non-responders improved on none (p = 0.27-0.81). The degree of clinical improvement was predicted by baseline and change scores in focused attention and working memory (p = 0.008). The response rate was higher in inattentive and combined subtypes than hyperactive-impulsive subtype (p = 0.003). CONCLUSIONS: Targeting cognitive dysfunction decreases clinical symptoms in proportion to improvement in cognition. Inattentive and combined subtypes were more likely to respond, consistent with targeted pathology and clinically relevant heterogeneity within ADHD.

Promoting mother-infant relationships and underlying neural correlates: Results from a randomized controlled trial of a home-visiting program for adolescent mothers in Brazil.

Poverty and teenage pregnancy are common in low-and-middle-income countries and can impede the development of healthy parent-child relationships. This study aimed to test whether a home-visiting intervention could improve early attachment relationships between adolescent mothers and their infants living in poverty in Brazil. Analyses were conducted on secondary outcomes from a randomized controlled trial (NCT0280718) testing the efficacy of a home-visiting program, Primeiros Laços, on adolescent mothers' health and parenting skills and their infants' development. Pregnant youth were randomized to intervention (n = 40) or care-as-usual (CAU, n = 40) from the first trimester of pregnancy until infants were aged 24 months. Mother-infant attachment was coded during a mother-infant interaction when the infants were aged 12 months. Electrophysiological correlates of social processing (mean amplitude of the Nc component) were measured while infants viewed facial images of the mother and a stranger at age 6 months. Infants in the intervention group were more securely attached and more involved with their mothers than those receiving CAU at 12 months. Smaller Nc amplitudes to the mother's face at 6 months were associated with better social behavior at 12 months. Our findings indicate that the Primeiros Laços Program is effective in enhancing the development of mother-infant attachment.

A Phase-2 Pilot Study of a Therapeutic Combination of Δ9-Tetrahydracannabinol and Palmitoylethanolamide for Adults With Tourette's Syndrome.

OBJECTIVE: There are few effective pharmacological treatments for Tourette's syndrome. Many patients with Tourette's syndrome experience impairing tic symptoms despite use of available evidence-based treatments. The investigators conducted a small, uncontrolled trial to examine the safety, tolerability, and dosing of THX-110, a combination of Δ9-tetrahydracannabinol (Δ9-THC) and palmitoylethanolamide (PEA), in Tourette's syndrome. METHODS: A 12-week uncontrolled trial of THX-110 (maximum daily Δ9-THC dose, 10 mg, and a constant 800-mg dose of PEA) in 16 adults with Tourette's syndrome was conducted. The primary outcome was improvement on the Yale Global Tic Severity Scale (YGTSS) total tic score. Secondary outcomes included measures of comorbid conditions and the number of participants who elected to continue treatment in the 24-week extension phase. RESULTS: Tic symptoms significantly improved over time with THX-110 treatment. Improvement in tic symptoms was statistically significant within 1 week of starting treatment compared with baseline. THX-110 treatment led to an average improvement in tic symptoms of more than 20%, or a 7-point decrease in the YGTSS score. Twelve of the 16 participants elected to continue to the extension phase, and only two participants dropped out early. Side effects were common but were generally managed by decreasing Δ9-THC dosing, slowing the dosing titration, and shifting dosing to nighttime. CONCLUSIONS: Although the initial data from this trial in adults with refractory Tourette's syndrome are promising, future randomized double-blind placebo-controlled trials are necessary to demonstrate efficacy of THX-110 treatment. The challenges raised by the difficulty in blinding trials due to the psychoactive properties of many cannabis-derived compounds need to be further appreciated in these trial designs.

Pathways to a more peaceful and sustainable world: The transformative power of children in families.

This article provides an overview of selected ongoing international efforts that have been inspired by Edward Zigler's vision to improve programs and policies for young children and families in the United States. The efforts presented are in close alignment with three strategies articulated by Edward Zigler: (a) conduct research that will inform policy advocacy; (b) design, implement, and revise quality early childhood development (ECD) programs; and (c) invest in building the next generation of scholars and advocates in child development. The intergenerational legacy left by Edward Zigler has had an impact on young children not only in the United States, but also across the globe. More needs to be done. We need to work together with a full commitment to ensure the optimal development of each child.

The prevalence of behavioral and emotional problems among Chinese school children and adolescents aged 6-16: a national survey.

Improving the mental health of children and adolescents is a critical priority in China. However, only minimal information is available concerning the prevalence of mental disorders. In the present study, a two-stage national survey has been completed in five regions of China. In the first stage, data from the Achenbach Child Behavior Checklist (CBCL) were collected for each participant to identify the prevalence of the behavioral and emotional problems in China. A multistage cluster stratified random sampling design was used, and a total of 71,929 individuals aged 6-16 years were collected. In this large cohort, 36,893 (49.86%) were males, and 49,015 (66.24%) were living in urban communities. Overall, 17.6% (90% confidence interval 17.4%, 17.9%) of the children and adolescents were identified as having behavioral and emotional problems. Moreover, age and sex effect was found for the CBCL scores. The boys' cohort had a higher prevalence of behavioral and emotional problems than girls (18.6% versus 16.6%). In the older cohort aged 12-16, the prevalence was higher than for the younger cohort aged 6-11 (19.0% versus 15.9%). Notably, it seems that the prevalence of the behavioral and emotional problems for children and adolescents had a rise in the past 30 years, but the scarcity of pediatric psychiatrists in China needs to be addressed. To reduce the behavioral and emotional problems, the whole society, including mental health providers, educators, and parents, needs to focus on and pay more attention to it. It will have long-term benefits for China.

Risk factors for obsessive-compulsive symptoms. Follow-up of a community-based youth cohort.

Environmental factors are at least as important as genetic factors for the development of obsessive-compulsive symptoms (OCS), but the identification of such factors remain a research priority. Our study aimed to investigate the association between a broad scope of potential risk factors and OCS in a large community cohort of children and adolescents. We evaluated 1877 participants and their caregivers at baseline and after 3 years to assess various demographic, prenatal, perinatal, childhood adversity, and psychopathological factors. Mean age at baseline was 10.2 years (SD 1.9) and mean age at follow-up was 13.4 years (SD 1.9). Reports of OCS at baseline and follow-up were analyzed using latent variable models. At preliminary regression analysis, 15 parameters were significantly associated with higher OCS scores at follow-up. At subsequent regression analysis, we found that eight of these parameters remained significantly associated with higher follow-up OCS scores while being controlled by each other and by baseline OCS scores. The significant predictors of follow-up OCS were: lower socioeconomic status (p = 0.033); lower intelligence quotient (p = 0.013); lower age (p < 0.001); higher maternal stress level during pregnancy (p = 0.028); absence of breastfeeding (p = 0.017); parental baseline OCS (p = 0.038); youth baseline anxiety disorder (p = 0.023); and youth baseline OCS scores (p < 0.001). These findings may better inform clinicians and policymakers engaged in the mental health assessment and prevention in children and adolescents.

An examination of the relationship between regulatory T cells and symptom flare-ups in children and adolescents diagnosed with chronic tic disorder and Tourette syndrome.

BACKGROUND: Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder characterized by several motor and phonic tics. AIMS: In this study, we aimed to compare activated regulatory T cell (Treg) values between patients with TS/chronic tic disorder (CTD) and age- and sex-matched healthy controls (HCs). MATERIALS AND METHOD: Patients with TS/CTD and age- and sex-matched HCs were included in the study. The severity of the disease was evaluated using the Yale Global Tic Severity Scale. CD4+CD25+CD127low Tregs from the patient group and the control group were compared using flow cytometry. RESULTS: The study included 48 patients diagnosed with TS/CTD (36 males and 12 females, mean age: 11.58 ± 2.61) and 24 HCs (18 males and 6 females, mean age: 11.63 ± 2.60). The TS/CTD group had significantly higher activated regulatory T percentile with respect to the T helper value compared to the HCs (p = 0.010). Lymphocyte count, T lymphocyte count, T lymphocyte percentage, T-helper lymphocyte count, and T-helper lymphocyte percentage were lower in the patient group compared to the control group (p = 0.024, 0.003, 0.007, <0.001, <0.001, respectively). The comparison of three groups (mild, moderate-severe, and HCs) revealed that T lymphocyte number and percentage and the T helper number and percentage were significantly higher in the HC group compared to the moderate-severe group, whereas the activated Treg percentage with respect to the T helper value was significantly higher in the moderate-severe group compared to the HC group (0.002, 0.026, <0.001, <0.001, 0.027, respectively). CONCLUSION: Our results suggest that Tregs may have a role in the pathogenesis of TS/CTD.

Manifesto for new directions in developmental science.

Although developmental science has always been evolving, these times of fast-paced and profound social and scientific changes easily lead to disorienting fragmentation rather than coherent scientific advances. What directions should developmental science pursue to meaningfully address real-world problems that impact human development throughout the lifespan? What conceptual or policy shifts are needed to steer the field in these directions? The present manifesto is proposed by a group of scholars from various disciplines and perspectives within developmental science to spark conversations and action plans in response to these questions. After highlighting four critical content domains that merit concentrated and often urgent research efforts, two issues regarding "how" we do developmental science and "what for" are outlined. This manifesto concludes with five proposals, calling for integrative, inclusive, transdisciplinary, transparent, and actionable developmental science. Specific recommendations, prospects, pitfalls, and challenges to reach this goal are discussed.

The impact of attention deficit hyperactivity disorder in obsessive-compulsive disorder subjects.

BACKGROUND: Recent findings suggest an association between attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). Thus, we evaluated the clinical associated features of ADHD in a large sample of adult OCD patients. METHODS: A cross-sectional study including 955 adult patients with OCD from the Brazilian Research Consortium of Obsessive-Compulsive Spectrum Disorders (C-TOC). Clinical characteristics in adult OCD patients with and without comorbid ADHD were compared using Fisher's exact test, t-tests or Mann-Whitney tests. Bivariate analyses were followed by logistic regression analysis to identify clinical characteristics independently associated with ADHD comorbidity. RESULTS: The lifetime prevalence of ADHD in adult OCD patients was 13.7%. The current results indicate that OCD + ADHD patients were more severe, had an earlier onset of the obsessive-compulsive symptoms, a higher history of rheumatic fever, with higher frequencies of sensory phenomena and comorbidity with Tourette syndrome. They also had an increased risk for academic impairment and suicide attempts. CONCLUSION: Adult OCD patients with ADHD present some specific clinical features and may represent a special subgroup of adult OCD. Future studies should focus on the development of interventions more tailored to the phenotype of this subgroup of patients.

Implementation Evaluation of the Mother-Child Education Program Among Refugee and Other Vulnerable Communities in Lebanon.

Despite the knowledge that quality early childhood development programs, including those that target parental knowledge and behaviors, are essential for ameliorating the negative effects of early-life adversity, robust analyses of their implementation and impact in highly vulnerable settings are scarce. To address this knowledge gap, we conducted a pilot wait-list randomized controlled trial (RCT) to assess the impact and the process of implementing and evaluating the Mother-Child Education Program (MOCEP) among refugee families and one low-income community in Beirut, Lebanon. This paper focuses on the analysis of MOCEP's implementation (i.e., key enablers of and barriers to the application and evaluation of the program). Our analysis suggests that, despite multiple challenges, implementation and robust evaluations of early childhood parenting programs in fragile contexts are feasible and urgently needed. This study illustrates how implementation evaluations are a key component of RCTs and crucial to identifying strategies to optimize program uptake and maximize impact.

Nurturing care: promoting early childhood development.

The UN Sustainable Development Goals provide a historic opportunity to implement interventions, at scale, to promote early childhood development. Although the evidence base for the importance of early childhood development has grown, the research is distributed across sectors, populations, and settings, with diversity noted in both scope and focus. We provide a comprehensive updated analysis of early childhood development interventions across the five sectors of health, nutrition, education, child protection, and social protection. Our review concludes that to make interventions successful, smart, and sustainable, they need to be implemented as multi-sectoral intervention packages anchored in nurturing care. The recommendations emphasise that intervention packages should be applied at developmentally appropriate times during the life course, target multiple risks, and build on existing delivery platforms for feasibility of scale-up. While interventions will continue to improve with the growth of developmental science, the evidence now strongly suggests that parents, caregivers, and families need to be supported in providing nurturing care and protection in order for young children to achieve their developmental potential.

Differential binding of antibodies in PANDAS patients to cholinergic interneurons in the striatum.

Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus, or PANDAS, is a syndrome of acute childhood onset of obsessive-compulsive disorder and other neuropsychiatric symptoms in the aftermath of an infection with Group A beta-hemolytic Streptococcus (GABHS). Its pathophysiology remains unclear. PANDAS has been proposed to result from cross-reactivity of antibodies raised against GABHS with brain antigens, but the targets of these antibodies are unclear and may be heterogeneous. We developed an in vivo assay in mice to characterize the cellular targets of antibodies in serum from individuals with PANDAS. We focus on striatal interneurons, which have been implicated in the pathogenesis of tic disorders. Sera from children with well-characterized PANDAS (n = 5) from a previously described clinical trial (NCT01281969), and matched controls, were infused into the striatum of mice; antibody binding to interneurons was characterized using immunofluorescence and confocal microscopy. Antibodies from children with PANDAS bound to ∼80% of cholinergic interneurons, significantly higher than the <50% binding seen with matched healthy controls. There was no elevated binding to two different populations of GABAergic interneurons (PV and nNOS-positive), confirming the specificity of this phenomenon. Elevated binding to cholinergic interneurons resolved in parallel with symptom improvement after treatment with intravenous immunoglobulin. Antibody-mediated dysregulation of striatal cholinergic interneurons may be a locus of pathology in PANDAS. Future clarification of the functional consequences of this specific binding may identify new opportunities for intervention in children with this condition.

Attention and executive functions computer training for attention-deficit/hyperactivity disorder (ADHD): results from a randomized, controlled trial.

Multicenter randomized clinical superiority single-blind trial investigated the effect of a computer training program targeting multiple cognitive functions. Seventy children with ADHD, aged 6-13, were randomized to intervention or control group. The intervention group used ACTIVATE™ for 8 weeks and both groups received treatment as usual and were assessed in regard to cognitive functions, symptoms, behavioral and functional outcome measures after 8, 12 and 24 weeks. There was no significant effect on the primary outcome, sustained attention (ß = - 0.047; CI - 0.247 to 0.153) or the secondary outcomes [parent-rated ADHD-RS, ß = - 0.037; CI (- 0.224 to 0.150); teacher-rated-ADHD-RS, ß = 0.093; CI (- 0.107 to 0.294); parent-rated-BRIEF, ß = - 0.119; CI (- 0.307 to 0.069); and teacher-rated-BRIEF, ß = 0.136; CI (- 0.048 to 0.322)]. This multicenter randomized clinical trial found no significant beneficial effects of cognitive training using the computer program ACTIVATE on the primary or secondary outcome measures in children with ADHD. Nevertheless, our study was likely underpowered to detect small to moderate changes.Trial registration ClinicalTrials.gov: NCT01752530, date of registration: December 10, 2012.