Abstract Background Low-vision rehabilitative support for children with multiple-disability conditions is underexplored. We conduct a pilot study of an assistive device in children with CLN3 disease, a multisystemic pediatric blindness and neurodegenerative condition. The prospective, pilot study (NCT04974307) evaluated the safety, feasibility and preliminary efficacy of the OrCam MyEye 2 in aiding daily living tasks. We used multimodal assessments of feasibility and efficacy to assess nine participants with CLN3 disease and one with non-CLN3 low vision (age 8.1-17.4 years; females:males 2:8) at baseline (Day 1, without the device) and Day 5 (with the device). Results Surveyed parents and affected children reported desire for future research addressing the vision loss in CLN3 disease, and lower quality of life in vision-related domains. One grade 1 adverse event was recorded during the study. Feasibility and Function assessments showed that > 90% of evaluable participants scored above thresholds on feasibility assessments and > 25% had improved scores and performance time on device-specific tasks. Conclusions The data provide indications for the safety, feasibility and task-specific efficacy for the OrCam MyEye 2. They support further, including longitudinal, evaluation and consideration of such optic-to-audio devices as part of the toolbox for low vision therapy for children with multiple disabilities such as CLN3 disease. Trial registration clinicaltrials.gov, NCT04974307. Registered 23 July 2021, https//clinicaltrials.gov/study/NCT04974307 .

Examples of system-driven implementation of multiple evidence-based practices (EBPs) are becoming more frequent in efforts to improve community mental health care, but there is limited understanding of how these efforts change community therapist practice. Within one such implementation effort in the Los Angeles County Department of Mental Health, this observational study sought to: (1) examine observer ratings of therapist delivery of EBP strategies in sessions where therapists claimed reimbursement to one of six youth mental health EBPs; and (2) explore factors associated with extensiveness of EBP strategy delivery. Data were drawn from 680 sessions with 273 youth delivered by 103 therapists in 14 agencies. Sessions were audio recorded and rated by trained observers for extensiveness of therapist delivery of EBP technique and content strategies. Therapists were observed to use EBP techniques (Structuring Treatment Techniques and Skill Building Techniques) in the majority of sessions. Consistent with expectations, use of specific EBP content strategies were more targeted and less commonly observed at every session. Finally, the following factors were associated with higher observed EBP strategy extensiveness: sessions completed in a non-English language (compared with sessions completed in English), sessions using an EBP with a prescribed session content/order (compared with sessions using an EBP without a prescribed session content/order), higher levels of therapist reported self-efficacy with the EBP being delivered, older client age, and therapists with a cognitive behavioral theoretical orientation (compared with therapists with an orientation other than cognitive behavioral). Patterns of therapist EBP strategy delivery followed expected patterns, with techniques strategies used in the majority of sessions and specific content strategies used in a more targeted fashion. Given the dearth of observational measurement of EBP implementation-as-usual, these findings contribute to our understanding of key outcomes of scale-up efforts. Predictors of EBP strategy use have implications for targeting efforts to promote sustainment, such as improving provider EBP self-efficacy.

The National Institute of Health (NIH) Undiagnosed Diseases Program (UDP) is an NIH project with the goal of providing both a comprehensive diagnosis and a better understanding of the many mechanisms of disease for patients with rare and undiagnosed conditions. Patients accepted to the program receive a careful review of their medical records and a tailored inpatient evaluation at the NIH Clinical Center in Bethesda, MD. For the pediatric population, systematic neurodevelopmental phenotypic evaluations are included. Here we report neurodevelopmental phenotyping data on pediatric participants enrolled in the NIH UDP from 2009 to 2019, with genetic findings reported through 2025. Results for 219 pediatric participants included a high rate of intellectual disability, with 27% of the sample in the severe-to-profound range. The phenotype often included multisystemic involvement, with motor impairments as well as vision and hearing concerns. For the 46% for whom a genetic diagnosis was made, there was greater impairment, including more severe intellectual disability and more frequent motor impairments as well as minimal verbal status. This study documented that severe neurodevelopmental impairments are frequently present in the unique pediatric undiagnosed patients enrolled in NIH UDP; the diagnosis of a genetic condition was associated with greater impairment.

OBJECTIVE:This study tests the effectiveness of leader- and provider-level implementation strategies to implement evidence-based interventions (EBIs) in 2 of the service systems caring for autistic children. The TEAMS Leadership Institute (TLI) targets implementation leadership and climate, and TEAMS Individualized Provider Strategy (TIPS) targets provider motivation and engagement. METHOD:A cluster randomized hybrid type 3 implementation-effectiveness trial tested the effects of the implementations strategies when paired with AIM HI (An Individualized Mental Health Intervention for Autism) in mental health programs (study 1) and CPRT (Classroom Pivotal Response Teaching) in classrooms (study 2). The combined sample included 65 programs/districts across 4 training cohorts (2018-2019 to 2020-2021). Organizations were randomized to receive a leader-level strategy, provider strategy, both strategies, or neither strategy (EBI provider training only). Leader and provider participants were recruited from enrolled programs/districts, and child participants were recruited from providers' caseloads or classrooms. Data from a total of 387 providers (mean age = 36.39 years; 91% female participants; 30% Latino/a/x participants) and 385 children (mean age = 8 years; 80% male participants; 45% Latino/a/x participants) were analyzed. Outcomes were assessed over 6 months. Provider outcome measures included provider EBI certification and observed EBI fidelity. Clinical outcome measures included the Eyberg Child Behavior Inventory (ECBI) (study 1) and the Pervasive Developmental Disorder Behavior Inventory (PDD-BI) (study 2). Outcomes were analyzed using intent-to-treat models. RESULTS:There was no significant effect of TLI on EBI Certification. TLI was associated with significantly higher EBI fidelity compared to non-TLI (B = 0.37, p = .04). Moreover, a statistically significant TLIxTime interaction was found for child outcome T scores (B = -10.47, p = .03), with a significant reduction in T scores across time only for those in the TLI condition. There were no significant effects of TIPS on any outcomes. CONCLUSION:Findings support the effectiveness of leader-focused strategies to promote implementation and clinical outcomes of autism EBIs in multiple public service systems and for multiple EBIs. PLAIN LANGUAGE SUMMARY:Although many evidence-based interventions have been developed for autistic children, they are not routinely delivered in usual-care services. This randomized controlled trial tested two implementation strategies, one focused on leadership and climate, the other focused on provider motivation and engagement. These implementation strategies were paired with two different autism interventions (An Individualized Mental Health Intervention for Autism [AIM HI], and Classroom Pivotal Response Teaching [CPRT]). The study took place in 65 mental health programs and school districts in California with 387 providers and 385 child participants. The authors found that the leadership and climate-focused implementation strategy, but not the provider-focused strategy, increased providers' use of the autism interventions and improved child outcome over 6 months. The study highlights the important role of organizational and district leaders in improving intervention delivery and child outcomes in usual care. CLINICAL TRIAL REGISTRATION INFORMATION:Translating Evidence-based Interventions for ASD: Multi-Level Implementation Strategy (TEAMS); https://clinicaltrials.gov/study/NCT03380078.

Williams syndrome is caused by a microdeletion of genes on chromosome 7q11.23. It is estimated that 75% of individuals with Williams syndrome meet criteria for intellectual disability. The existing literature, primarily using the Differential Ability Scales, supports a pattern of relative weakness in visuospatial construction and language abilities commensurate with or slightly stronger than overall cognitive functioning. However, it is unclear how cognitive profile patterns are captured by current versions of the Wechsler system of assessment, which is more commonly used in community settings. Further, few longitudinal data on cognitive profiles exist, limiting conclusions about developmental trends. The current study included 59 individuals with Williams syndrome aged 4-24 years assessed with the age-appropriate Wechsler test a median of twice over 3 ± 1.5 years. The results of this study confirmed the profile found in the extant literature, but there was evidence of heterogeneity in relative strengths and weaknesses that necessitates individual evaluation. Careful longitudinal modeling of between- and within-person effects suggested stability of standard scores in all domains. The results of this study inform a developmental understanding of the Williams syndrome cognitive profile and improve the interpretability of research findings for clinical and school settings where the Wechsler system is commonly used.

OBJECTIVE:Publicly funded mental health services play an important role in caring for children with mental health needs, including children with autism spectrum disorder (ASD). This study assessed the associations between individual family- and neighborhood-level sociodemographic factors and baseline family functioning and long-term outcomes when community therapists were trained to deliver An Individualized Mental Health Intervention for ASD (AIM HI). METHOD:Participants included 144 children with ASD (ages 5 to 13 years; 58.3% Latinx) and their caregivers whose therapists received AIM HI training within a cluster-randomized effectiveness-implementation trial in publicly funded mental health services. Sociodemographic strain (e.g., low income, less education, single-parent status, minoritized status) was coded at the individual family and neighborhood level, and caregivers rated caregiver strain at baseline. Child interfering behaviors and caregiver sense of competence were assessed at baseline and 6-, 12- and 18-months after baseline. RESULTS:Higher caregiver strain was associated with higher intensity of child behaviors (B = 5.17, p < .001) and lower caregiver sense of competence (B = -6.59, p < 001) at baseline. Child and caregiver outcomes improved over time. Higher caregiver strain (B = 1.50, p < .001) and lower family sociodemographic strain (B = -0.58, p < .01) were associated with less improvements in child behaviors. Lower caregiver strain (B = -2.08, p < .001) and lower neighborhood sociodemographic strain (B = -0.51, p < .01) were associated with greater improvements in caregiver sense of competence. CONCLUSIONS:Findings corroborate the importance of considering both family and neighborhood context in the community delivery of child-focused EBIs. TRIAL REGISTRATION:Clinical Trials NCT02416323.

Propionic acidemia (PA) is an autosomal recessive condition (OMIM #606054), wherein pathogenic variants in PCCA and PCCB impair the activity of propionyl-CoA carboxylase. PA is associated with neurodevelopmental disorders, including intellectual disability (ID) and autism spectrum disorder (ASD); however, the correlates and mechanisms of these outcomes remain unknown. Using data from a subset of participants with PA enrolled in a dedicated natural history study ( n = 33), we explored associations between neurodevelopmental phenotypes and laboratory parameters. Twenty (61%) participants received an ID diagnosis, and 12 of the 31 (39%) who were fully evaluated received the diagnosis of ASD. A diagnosis of ID, lower full-scale IQ (sample mean = 65 ± 26), and lower adaptive behavior composite scores (sample mean = 67 ± 23) were associated with several biomarkers. Higher concentrations of plasma propionylcarnitine, plasma total 2-methylcitrate, serum erythropoietin, and mitochondrial biomarkers plasma FGF21 and GDF15 were associated with a more severe ID profile. Reduced 1- 13 C-propionate oxidative capacity and decreased levels of plasma and urinary glutamine were also associated with a more severe ID profile. Only two parameters, increased serum erythropoietin and decreased plasma glutamine, were associated with ASD. Plasma glycine, one of the defining features of PA, was not meaningfully associated with either ID or ASD. Thus, while both ID and ASD were commonly observed in our PA cohort, only ID was robustly associated with metabolic parameters. Our results suggest that disease severity and associated mitochondrial dysfunction may play a role in CNS complications of PA and identify potential biomarkers and candidate surrogate endpoints.

The purpose of this study was to: (1) confirm the factor structure of a therapist-report measure of adaptations to an autism evidence-based intervention (EBI), (2) identify predictors of adaptation types, and (3) examine associations of adaptation types with observed therapist fidelity. Participants included a subset of therapists (N = 70; 31.4 Trial Registration ClinicalTrials.gov identifier NCT02416323.

Pragmatic measures of evidence-based practice (EBP) implementation can support and evaluate implementation efforts. We examined the predictive validity of therapist reports of EBP strategy delivery for children’s mental health outcomes. Data were obtained from 1,380 sessions with 248 children delivered by 76 therapists in two county systems. Children (Mage=11.8 years, SD = 3.7) presented with internalizing (52

Objective: The aim of this study was to characterize patterns of and factors associated with psychotropic medication use in children with autism spectrum disorder (ASD) receiving publicly funded mental health services. Method: Data were extracted from 202 children with ASD participating in a cluster randomized trial of An Individualized Mental Health Intervention for ASD conducted in 29 publicly funded mental health programs. Children with ASD were aged 5 to 13 years (M = 9.1 years, SD = 2.4), and were 84.2% male and 59.9% Latinx. Child ASD and cognitive functioning were determined by standardized assessment. Caregivers reported child psychotropic medication use, behavior problems, ASD symptom severity, mental health symptoms, family demographics, and caregiver strain at the baseline. Results: Nearly half (49.5%) of participants used psychotropic medication(s) within the past 6 months, with stimulants being most commonly reported. Child co-occurring attention-deficit/hyperactivity disorder (ADHD) (B = 1.55, p < 0.01; 95% confidence interval [CI]: 0.53-2.57), lower cognitive functioning (B = -0.03, p = 0.02; 95% CI: -0.05 to <0.00), and non-Hispanic White ethnicity (vs Hispanic/Latinx; B = 1.02, p = 02; 95% CI: -1.89 to -0.14) were associated with a greater likelihood of using any type of medication. Factors associated with medication use varied by class: stimulants-ADHD, lower ASD symptom severity, and more intensive behavior problems; SSRIs-higher ASD symptom severity; alpha-2 agonists-ADHD, higher ASD symptom severity, lower cognitive functioning, and higher caregiver strain; and antipsychotics-none. Conclusion: The findings highlight factors associated with psychotropic medication use for a clinically complex population, which may inform community care improvement efforts.

The Eyberg Child Behavior Inventory (ECBI) is a frequently used measure to assess interfering behaviors in children and psychometric properties have recently been examined in children with autism spectrum disorder (ASD). There is a need to confirm the identified factors and examine the factor structure in a racially/ethnically diverse, community-based sample. The current study conducts a psychometric analysis of the ECBI in a sample of children with ASD receiving publicly-funded mental health services. Data were collected from 201 children with ASD ages 5–13 years (60% Hispanic/Latinx) participating in a community effectiveness trial . Confirmatory factor analysis indicated poor model fit using previously identified factors and a new four-factor solution was identified. Clinical and research implications of these findings are discussed.

This study examines therapist and caregiver report of evidence-based intervention (EBI) strategy use in the context of a community effectiveness trial of An Individualized Mental Health Intervention for Autism (AIM HI), a caregiver and child skill-building mental health intervention for school-aged children with autism. This study explores whether child, caregiver, or therapist characteristics or therapist training are associated with agreement between caregiver and therapist raters. Data were drawn from a cluster randomized effectiveness trial of AIM HI, in which therapists were trained and delivered AIM HI or treatment as usual. Therapists and caregivers completed assessments at baseline. At 6 months post baseline, therapists and caregivers reported on perceptions of therapist EBI delivery across sessions. Caregiver-therapist agreement on therapist EBI strategy use was generally high, with both reporters indicating trained therapists used more extensive EBI strategies than usual care therapists. When there were significant differences between therapists and caregivers, caregivers tended to rate therapists higher on EBI strategy delivery. The presence of an internalizing co-occurring mental health diagnosis and higher levels of child behavior problems were associated with lower caregiver-therapist agreement. Therapists with more years of experience and those with self-identified autism expertise had higher levels of therapist-caregiver disagreement. Results suggest that therapist EBI training results in increased report of therapist EBI strategy delivery from multiple reporters. There was general agreement between therapists and caregiver reporters. Examination of strategy ratings provides critical information about how stakeholders experience the delivery of EBI strategies in routine mental health services.

An Individualized Mental Health Intervention for ASD (AIM HI) was developed in collaboration with community stakeholders for delivery in mental health services in response to therapist- and caregiver-identified need to improve services for children with autism spectrum disorder (ASD). Primary findings from a cluster randomized Hybrid Type 1 effectiveness-implementation trial conducted in publicly funded mental health programs demonstrated the effectiveness of AIM HI therapist training on child and caregiver outcomes. This study examined therapist outcomes and therapist experience as a moderator of training effects. Mental health programs were randomized to immediate AIM HI training or usual care. Therapists and child/caregiver clients were recruited from participating programs. Therapists in the AIM HI training condition received consultation for 6 months while delivering AIM HI. Differences between training conditions were examined using multilevel modeling. Therapists receiving AIM HI training were observed to use more extensive active teaching strategies with caregivers, engagement strategies with children, strategies promoting continuity of care, and had more structured sessions with more extensively pursued skill building. Therapist licensure moderated some training outcomes. The current study provides support for evidence-based practice implementation in usual care mental health services. Lay abstract Publicly funded mental health services play an important role in caring for school-age children with autism spectrum disorder (ASD); however, therapists report a lack of specialized ASD training, which families identity as a barrier in obtaining mental health services for their children. An Individualized Mental Health Intervention for ASD (AIM HI) was developed in collaboration with community stakeholders to respond to identified needs of children and community therapists. The current study examined the effects of therapist training in AIM HI on the changes in therapist practice, including therapists’ use of evidence-based intervention strategies in session. Data were collected from a study conducted in community outpatient and school based mental health programs randomly assigned to receive AIM HI therapist training or observation of routine care. Therapist and child clients were enrolled from participating programs. Therapists in AIM HI training received training and consultation for 6 months while delivering the AIM HI intervention to a participating client; therapists in usual care delivered routine care. Both groups of therapists video recorded psychotherapy sessions which were scored by trained raters. Differences between training groups were examined using multilevel modeling. Therapists trained in AIM HI were observed to use more extensive active teaching strategies with caregivers, engagement strategies with children, strategies promoting continuity of care, and had more structured sessions with more effective pursuit of caregiver and children skill teaching. Therapist licensure moderated some training outcomes.

The NIH Toolbox Cognition Battery (NIHTB-CB) was developed for epidemiological and longitudinal studies across a wide age span. Such a tool may be useful for intervention trials in conditions characterized by intellectual disability (ID), such as Williams syndrome (WS). Three NIHTB-CB tasks, including two executive functioning (Flanker, Dimensional Change Card Sort) and one episodic memory (Picture Sequence Memory) task, were given to 47 individuals with WS, ages 4 to 50, to evaluate feasibility (i.e., proportion of valid administrations) in this population. Findings indicated that NIHTB-CB tests showed good feasibility. Flanker and DCCS age-corrected scores were negatively correlated with age and showed floor effects, indicating these scores may not be useful for quantifying performance on these NIHTB-CB tests in ID.

This study identified patterns of therapist delivery of evidence-based intervention strategies with children with autism spectrum disorder within publicly funded mental health services and compared patterns for therapists delivering usual care to those trained in AIM HI ("An Individualized Mental Health Intervention for ASD"). Data were drawn from a randomized community effectiveness trial and included a subsample of 159 therapists (86% female) providing outpatient or school-based psychotherapy. Therapist strategies were measured via observational coding of psychotherapy session recordings. Exploratory factor analysis used to examine patterns of strategy delivery showed that among therapists in the usual care condition, strategies loaded onto the single factor, General Strategies, whereas for therapists in the AIM HI training condition, strategies grouped onto two factors, Autism Engagement Strategies and Active Teaching Strategies. Among usual care therapists, General Strategies were associated with an increase in child behavior problems, whereas for AIM HI therapists, Active Teaching Strategies were associated with reductions in child behavior problems over 18 months. Results support the effectiveness of training therapists in evidence-based interventions to increase the specificity of strategies delivered to children with autism spectrum disorder served in publicly funded mental health settings. Findings also support the use of active teaching strategies in reducing challenging behaviors. Lay abstract This study was conducted to identify patterns of therapist delivery of evidence-based intervention strategies with children with autism spectrum disorder receiving publicly funded mental health services and compare strategy use for therapists delivering usual care to those trained to deliver AIM HI ("An Individualized Mental Health Intervention for ASD"), an intervention designed to reduce challenging behaviors in children with autism spectrum disorder. For therapists trained in AIM HI, intervention strategies grouped onto two factors, Autism Engagement Strategies and Active Teaching Strategies, while strategies used by usual care therapists grouped onto a broader single factor, General Strategies. Among usual care therapists, General Strategies were related to an increase in child behavior problems, whereas for AIM HI therapists, Active Teaching Strategies were related with reductions in child behavior problems over 18 months. Findings support the use of active teaching strategies in reducing challenging behaviors in children with autism spectrum disorder and provide support for the effectiveness of training therapists in evidence-based interventions to promote the delivery of targeted, specific intervention strategies to children with autism spectrum disorder in mental health services.

Purpose To conduct a proof-of-principle study to identify subtypes of propionic acidemia (PA) and associated biomarkers. Methods Data from a clinically diverse PA patient population ( https://clinicaltrials.gov/ct2/show/NCT02890342 ) were used to train and test machine learning models, identify PA-relevant biomarkers, and perform validation analysis using data from liver-transplanted participants. k -Means clustering was used to test for the existence of PA subtypes. Expert knowledge was used to define PA subtypes (mild and severe). Given expert classification, supervised machine learning (support vector machine with a polynomial kernel, svmPoly) performed dimensional reduction to define relevant features of each PA subtype. Results Forty participants enrolled in the study; five underwent liver transplant. Analysis with k -means clustering indicated that several PA subtypes may exist on the biochemical continuum. The conventional PA biomarkers, plasma total 2-methylctirate and propionylcarnitine, were not statistically significantly different between nontransplanted and transplanted participants motivating us to search for other biomarkers. Unbiased dimensional reduction using svmPoly revealed that plasma transthyretin, alanine:serine ratio, GDF15, FGF21, and in vivo 1- 13 C-propionate oxidation, play roles in defining PA subtypes. Conclusion Support vector machine prioritized biomarkers that helped classify propionic acidemia patients according to severity subtypes, with important ramifications for future clinical trials and management of PA. Graphical Abstract

Progressive vision loss and neurocognitive impairment are early and frequent presentations in CLN3 disease. This highlights neurodevelopmental functioning as critical to the disease, but limits the neuropsychological test repertoire. We evaluated the convergent validity of the Vineland Adaptive Behavior Scales as a potential outcome measure. In a prospective observational study of 22 individuals (female:male 11:11; 6-20 years-old) with a molecular diagnosis of CLN3, we used generalized linear models and Spearman correlations to quantify the relationship of the adaptive behavior composite (ABC) standard score with established outcomes of verbal IQ (VIQ) and disease severity (Unified Batten Disease Rating Scale, UBDRS) scores. We analyzed ABC changes in 1-year follow-up data in a subset of the same cohort (n = 17). The ABC and VIQ, both standard scores, exhibited a strong positive correlation in cross-sectional data (r = 0.81). ABC and UBDRS scores were strongly and positively correlated in cross-sectional data (rrange  = 0.87-0.93). Participants' ABC scores decreased slightly over the 1-year follow-up period (mean change, 95% CI: -5.23, -2.16). The convergent validity of the Vineland-3 for use in CLN3 is supported by its relationships with the established outcomes of VIQ and UBDRS. Future longitudinal research, including replication in other cohorts and evaluation of sensitivity to change, will be important to establish utility of the Vineland-3 for monitoring change in CLN3.