A cluster randomized controlled trial comparing the effectiveness of two school-based interventions for autistic youth with anxiety.

BACKGROUND: Recent systematic reviews have indicated that cognitive behavioral therapy (CBT) is effective in reducing anxiety symptoms for autistic and non-autistic children. However, the vast majority of CBT research for autistic youth has been implemented within university settings and primarily by mental health providers. Schools hold great promise to equitably manage the mental health symptoms of autistic youth. Although preliminary research evaluating CBT within schools has been promising, CBT has not yet been compared to another readily available school mental health program. The goal of this protocol paper is to describe a multi-site study comparing two school-based interventions, Facing Your Fears-School Based (FYF-SB) and Zones of Regulation (ZOR) via a cluster randomized controlled type 1 hybrid effectiveness-implementation trial to determine which of the two interventions will best support autistic youth with anxiety in schools. METHODS: Up to 100 elementary and middle schools will be randomized into FYF-SB or ZOR. Once schools are randomized, a minimum of two interdisciplinary school providers at each school will be trained to deliver either FYF-SB or ZOR over the course of 12 weeks to groups of 2-5 autistic students ages 8-14 years. Over the course of two years, a total of 200 autistic students will receive either ZOR or FYF-SB. The primary outcome of this trial is child anxiety, as rated by masked evaluators and via caregiver- and student-report, which will be measured at baseline, post-treatment, and 6-month follow-up. Semi-structured interviews will also be conducted with a purposive sample of students, caregivers, and school providers to understand the acceptability, appropriateness, and feasibility of either ZOR or FYF-SB. Stakeholder engagement is a central component of this project via two stakeholder advisory boards that will directly inform and oversee the project. DISCUSSION: Results of this study will provide evidence about the relative impact of two school-based mental health interventions on outcomes reported as meaningful by caregivers and school providers. The additional focus on evaluating factors that support the implementation of FYF-SB and ZOR will allow future studies to test targeted implementation strategies that support mental health programming uptake and implementation within public schools. TRIAL REGISTRATION: This trial is registered with clinicaltrials.gov (NCT05863520).

Reanalysis of Trio Whole-Genome Sequencing Data Doubles the Yield in Autism Spectrum Disorder: De Novo Variants Present in Half.

Autism spectrum disorder (ASD) is a common condition with lifelong implications. The last decade has seen dramatic improvements in DNA sequencing and related bioinformatics and databases. We analyzed the raw DNA sequencing files on the Variantyx® bioinformatics platform for the last 50 ASD patients evaluated with trio whole-genome sequencing (trio-WGS). "Qualified" variants were defined as coding, rare, and evolutionarily conserved. Primary Diagnostic Variants (PDV), additionally, were present in genes directly linked to ASD and matched clinical correlation. A PDV was identified in 34/50 (68%) of cases, including 25 (50%) cases with heterozygous de novo and 10 (20%) with inherited variants. De novo variants in genes directly associated with ASD were far more likely to be Qualifying than non-Qualifying versus a control group of genes (p = 0.0002), validating that most are indeed disease related. Sequence reanalysis increased diagnostic yield from 28% to 68%, mostly through inclusion of de novo PDVs in genes not yet reported as ASD associated. Thirty-three subjects (66%) had treatment recommendation(s) based on DNA analyses. Our results demonstrate a high yield of trio-WGS for revealing molecular diagnoses in ASD, which is greatly enhanced by reanalyzing DNA sequencing files. In contrast to previous reports, de novo variants dominate the findings, mostly representing novel conditions. This has implications to the cause and rising prevalence of autism.

A Prospective Cohort of Alcohol Use and Alcohol-related Problems Before and After Metabolic and Bariatric Surgery in Adolescents.

OBJECTIVE: To describe alcohol use, alcohol-related harm, and alcohol-related problems preoperatively and up to 8 years following metabolic and bariatric surgery (MBS) in adolescents. BACKGROUND: Risk for alcohol use and alcohol use disorders (AUD) increases post-Roux-en-Y gastric bypass and vertical sleeve gastrectomy in adults. However, data are lacking in adolescents who undergo MBS. METHODS: This study includes 217 adolescents (aged 13-19 y) enrolled in a 5-center prospective cohort study who underwent Roux-en-Y gastric bypass or vertical sleeve gastrectomy (2007-2011) and reported alcohol use preoperatively and annually postoperatively for up to 8 years. Time to elevated Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) score, alcohol-related harm, and alcohol-related problems were analyzed with Kaplan-Meier estimates of cumulative incidence. RESULTS: Preoperatively, the median age was 17 years; the median body mass index was 51 kg/m 2 . Alcohol use frequency and average quantity of drinks per drinking day increased postoperatively (2% consumed alcohol 2-4 times/month 6 months versus 24% 8 years postoperatively, P <0.001; 2% consumed≥3 drinks per drinking day 6 months versus 35% 8 years postoperatively, P <0.001). Cumulative incidence of postoperative onset elevated AUDIT-C score, alcohol-related harm, and alcohol-related problems at year 8 were 45% (95% CI:37-53), 43% (95% CI:36-51), and 47% (95% CI:40-55), respectively. CONCLUSIONS: Nearly half of those who underwent MBS as adolescents screened positively for AUD, symptoms of alcohol-related harm, or alcohol-related problems 8 years post-MBS, highlighting the risk for alcohol use and AUD after MBS in adolescents. AUD evaluation and treatment should be integrated into routine long-term care for adolescents undergoing MBS.

The Role of Maternal Anxiety in Treatment Response for Youth with ASD and Co-occurring Anxiety.

Anxiety disorders occur at higher rates in youth with ASD than in neurotypical youth. Although the efficacy of CBT for anxiety in children with ASD is widely supported, factors that influence treatment outcomes are not well understood. This study examined the role of maternal anxiety in treatment outcomes for youth with ASD. Youth with ASD and anxiety (ages 8 to 14), along with their mothers (n = 87), participated in a group CBT intervention. Results indicated that maternal anxiety did not improve over the course of treatment. However, findings suggest that high levels of maternal anxiety at pre-treatment predicted higher levels of youth anxiety post-treatment. Importantly, the relationship between parent anxiety and youth outcomes was moderated by child age. The findings of the present study may provide initial insight into the role that maternal anxiety plays in treatment outcomes for children with ASD and co-occurring anxiety, particularly when considering child age.

Group Cognitive Behavioural Treatment for Anxiety in Autistic Adolescents with Intellectual Disability: A Pilot and Feasibility Study.

BACKGROUND: Adolescents with Autism Spectrum Disorder (ASD) and intellectual disability evidence significant anxiety. This study aimed to adapt a group cognitive behaviour therapies (CBT) programme designed for youth with ASD and anxiety to meet the cognitive, communication, and behavioural needs of adolescents with intellectual disability, and assess initial feasibility and efficacy of the intervention. METHODS: Structural, content and procedural adaptations were made to a 14-week family-focused CBT intervention. Twenty-three adolescents with ASD, intellectual disability and anxiety were included. Treatment acceptability along with adolescent anxiety symptoms was assessed via parent report measures. RESULTS: Of the 23 participants, 19 completed treatment and attended 94% of sessions. Parent acceptability was high. Significant reductions were noted on anxiety symptoms post-intervention. CONCLUSIONS: Results indicate that the CBT group was feasible and acceptable. Preliminary outcomes suggest that adolescent anxiety improved, although replication with a larger sample and comparison to a control group is needed.

A longitudinal intervention to improve young children's liking and consumption of new foods: findings from the Colorado LEAP study.

BACKGROUND: Many interventions have been conducted to improve young children's liking and consumption of new foods however their impacts on children's consumption have been limited. Consistent evidence supports the use of repeated exposure to improve liking for new foods however longitudinal effects lasting greater than 6 months often have not been demonstrated. Here we report the eating-related findings of the Colorado Longitudinal Eating And Physical Activity (LEAP) Study, a multi-component intervention, delivered primarily in the school setting, which aimed to improve children's liking and consumption of a target food via repeated exposure and positive experiential learning. METHODS: Four sites in rural Colorado, each housing Head Start preschool programs, matched on state vital statistics for childhood obesity rates, (2 intervention and 2 control sites) took part in a quasi-experimental study design which included 4 time points (baseline, post-intervention, one-year [Y1] and two- year [Y2] follow ups). A total of 250 children and families were enrolled (n = 143 intervention and n = 107 control; 41% Hispanic and 69% low-income). A 12-week intervention, Food Friends - Fun With New Foods®, delivered by trained preschool teachers and which focuses on positive and repeated experiences with new foods, and a 5-month (1 unit/month) social marketing "booster program" was delivered in kindergarten (one-year follow up) and 1st grade (two-year follow up). Main outcome measures included change in children's liking for new foods, analyzed by ordinal regression using generalized estimating equations, and change in weighed consumption of new foods over time, analyzed using a hierarchical mixed effects model. RESULTS: The intervention was delivered with good fidelity (87%). Both intervention and control groups demonstrated an increase in liking for the target food over time (p = 0.0001). The pattern of consumption of the target food was different, over time, for intervention and control groups (p < 0.005). In particular the change in intake between baseline and post-intervention was significantly greater in the intervention compared to the control group (p < 0.0001) though this pattern of change did not hold between baseline and Y2 follow up (p = 0.1144). Children in the intervention group who liked the target food consumed nearly double their baseline consumption at post-intervention (p < 0.0001;) and maintained this increase at Y2 follow up (p < 0.0001). CONCLUSIONS: The Food Friends intervention, which utilized positive, repeated experiences with new foods, and was delivered with good fidelity by trained preschool teachers, found that larger improvements were observed in children's eating behaviors than would be expected with developmentally-based changes in eating behaviors. TRIAL REGISTRATION NUMBER: This trial is registered at ClinicalTrials.gov : NCT01937481. Date registered: 09/09/2013; Retrospectively registered. Date first participant registered: 09/15/2010.

Home food availability and child intake among rural families identified to be at-risk for health disparities.

BACKGROUND: Home food environments (HFE) of children impact dietary intake, though relatively few studies have focused on young children from backgrounds with socioeconomic and racial-ethnic diversity. The objective of the present study was to examine the relationship between the HFE and child dietary intake of preschool-aged children from rural and low-income, culturally diverse families. METHODS: Children (aged 2-5 years) and their primary caregivers (n = 164 parent-child dyads) participated in this study using a cross-sectional design. HFE, including home food availability, accessibility and purchasing, was measured by the Home-IDEA, a checklist instrument completed by parents. Parents also reported child dietary intake using the Block Kids Food Screener (BKFS). RESULTS: Home food availability of both healthful and unhealthful foods, including fruits, vegetables, meats, and sugar-sweetened beverages significantly predicted reported child intake of these foods after controlling for demographic, location and weight status. Overall dietary intake recommendations were not met for vegetables, whole grains, protein, and dairy. The accessibility and purchasing frequency of foods was not associated with reported child dietary intake. CONCLUSIONS: The available HFE showed positive associations with dietary intake for a broad range of foods ranging from healthy and less healthy foods among preschool-aged children from a health disparate population. Recommendations to improve the quality of dietary intake for young children may be facilitated by modifying the HFE by focusing on increasing the availability of healthy foods and diminishing the presence of less healthful options.

A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects.

Genetic leukoencephalopathies (gLEs) are a group of heterogeneous disorders with white matter abnormalities affecting the central nervous system (CNS). The causative mutation in ~50% of gLEs is unknown. Using whole exome sequencing (WES), we identified homozygosity for a missense variant, VPS11: c.2536T>G (p.C846G), as the genetic cause of a leukoencephalopathy syndrome in five individuals from three unrelated Ashkenazi Jewish (AJ) families. All five patients exhibited highly concordant disease progression characterized by infantile onset leukoencephalopathy with brain white matter abnormalities, severe motor impairment, cortical blindness, intellectual disability, and seizures. The carrier frequency of the VPS11: c.2536T>G variant is 1:250 in the AJ population (n = 2,026). VPS11 protein is a core component of HOPS (homotypic fusion and protein sorting) and CORVET (class C core vacuole/endosome tethering) protein complexes involved in membrane trafficking and fusion of the lysosomes and endosomes. The cysteine 846 resides in an evolutionarily conserved cysteine-rich RING-H2 domain in carboxyl terminal regions of VPS11 proteins. Our data shows that the C846G mutation causes aberrant ubiquitination and accelerated turnover of VPS11 protein as well as compromised VPS11-VPS18 complex assembly, suggesting a loss of function in the mutant protein. Reduced VPS11 expression leads to an impaired autophagic activity in human cells. Importantly, zebrafish harboring a vps11 mutation with truncated RING-H2 domain demonstrated a significant reduction in CNS myelination following extensive neuronal death in the hindbrain and midbrain. Thus, our study reveals a defect in VPS11 as the underlying etiology for an autosomal recessive leukoencephalopathy disorder associated with a dysfunctional autophagy-lysosome trafficking pathway.

Incorporating Appetite Awareness Training Within Family-Based Behavioral Treatment of Pediatric Obesity: A Randomized Controlled Pilot Study.

Objective: To assess additive effects of incorporating appetite awareness training (AAT), a strategy to encourage eating in response to hunger and satiety cues, within a family-based behavioral treatment (FBT) for childhood obesity. Methods: Total 84 families with a child with obesity in the age range of 8-12 years, Body Mass Index Standard Deviation Score (BMI-SDS) ≥ 2, and a participating parent were randomly allocated to two conditions; standard FBT was compared with FBT incorporating AAT strategies (FBT-AAT). Treatment consisted of group therapy sessions (held separately for children and parents) as well as single-family (parent-child dyad) sessions (24 sessions total) delivered over 18 weeks at a tertiary care outpatient clinic. One booster session was provided 1-year posttreatment and a final follow-up assessment was conducted at 2 years. The primary outcome was change in child standardized body mass index (BMI-SDS). Results: The two conditions did not differ significantly at posttest, but the FBT-AAT group was at a significantly lower weight compared with FBT at both the first-year, F(1, 82) = 4.150, p<.05, and the second-year follow-ups, F(1, 82) = 14.912, p <.001. It was notable that over the second-year of follow-up, the FBT-AAT group continued to show improvement, whereas the FBT group did not. Conclusions: Incorporating specific self-regulatory training in attending to hunger and fullness signals during a standardized family-based treatment may have enhanced the long-term maintenance of treatment effects. Findings are promising and warrant further study.

Beliefs About Child TV Viewing in Low-Income Mexican American Parents of Preschoolers: Development of the Beliefs About Child TV Viewing Scale (B-TV).

Objectives Parental beliefs about child television viewing may affect the way parents regulate child television viewing. Despite this, little research has focused on the development of measures of parental beliefs about child television viewing, particularly among ethnic minority parents and parents of young children. This study's objective was to develop and test a culturally-based measure of parental beliefs about television viewing in low-income Mexican American mothers of preschoolers. Methods Using a cross-sectional study design, 22 items reflecting parental beliefs about influences of TV on children were developed and assessed for psychometric properties in a sample of 312 low-income Mexican American mothers of preschoolers. Results Using exploratory factor analysis, we identified four factors reflecting four domains of parental beliefs: positive general beliefs, positive sleep-related beliefs, positive functional beliefs, and negative general beliefs. Internal reliabilities were acceptable (Cronbach's alpha = 0.70-0.89) for all factors except negative general beliefs (Cronbach's alpha = 0.61). Positive sleep-related beliefs and Positive Functional Beliefs were correlated with children's average daily hours of TV (r = 0.16, p < .01; r = 0.22, p < .001, respectively) and with mother's average daily hours of TV (r = 0.14, p < .05; r = 0.22, p < .001, respectively), providing initial support for construct validity. Conclusions for Practice The Beliefs about Child TV viewing scale measures four domains of parental beliefs regarding child TV viewing, and has good initial reliability and validity for three factors. Future use will allow investigators to conduct more in-depth evaluations on the influence of parental beliefs on the way parents shape their child's use of the TV.

Home Visitations for Delivering an Early Childhood Obesity Intervention in Denver: Parent and Patient Navigator Perspectives.

Objective This qualitative study explored parent and patient navigator perspectives of home visitation as part of a childhood obesity program in a low-income, largely Latino population. Methods Three patient navigators and 25 parents who participated in a home-based, childhood obesity program participated in focus groups or interviews. Emergent themes were identified through content analysis of qualitative data. Results Three overall themes were identified. Patient navigators and parents perceived: (1) enabling characteristics of home-based program delivery which facilitated family participation and/or behavior change (i.e., convenience, increased accountability, inclusion of household members, delivery in a familiar, intimate setting, and individualized pace and content); (2) logistic and cultural challenges to home-based delivery which reduced family participation and program reach (i.e., difficulties scheduling visits, discomfort with visitors in the home, and confusion about the patient navigator's role); and (3) remediable home-based delivery challenges which could be ameliorated by additional study staff (e.g., supervision of children, safety concerns) or through organized group sessions. Both patient navigators and participating parents discussed an interest in group classes with separate, supervised child-targeted programming and opportunities to engage with other families for social support. Conclusions for Practice A home visitation program delivering a pediatric obesity prevention curriculum in Denver was convenient and held families accountable, but posed scheduling difficulties and raised safety concerns. Conducting home visits in pairs, adding obesity prevention curriculum to existing home visiting programs, or pairing the convenience of home visits with group classes may be future strategies to explore.

Molecular and clinical spectra of FBXL4 deficiency.

F-box and leucine-rich repeat protein 4 (FBXL4) is a mitochondrial protein whose exact function is not yet known. However, cellular studies have suggested that it plays significant roles in mitochondrial bioenergetics, mitochondrial DNA (mtDNA) maintenance, and mitochondrial dynamics. Biallelic pathogenic variants in FBXL4 are associated with an encephalopathic mtDNA maintenance defect syndrome that is a multisystem disease characterized by lactic acidemia, developmental delay, and hypotonia. Other features are feeding difficulties, growth failure, microcephaly, hyperammonemia, seizures, hypertrophic cardiomyopathy, elevated liver transaminases, recurrent infections, variable distinctive facial features, white matter abnormalities and cerebral atrophy found in neuroimaging, combined deficiencies of multiple electron transport complexes, and mtDNA depletion. Since its initial description in 2013, 36 different pathogenic variants in FBXL4 were reported in 50 affected individuals. In this report, we present 37 additional affected individuals and 11 previously unreported pathogenic variants. We summarize the clinical features of all 87 individuals with FBXL4-related mtDNA maintenance defect, review FBXL4 structure and function, map the 47 pathogenic variants onto the gene structure to assess the variants distribution, and investigate the genotype-phenotype correlation. Finally, we provide future directions to understand the disease mechanism and identify treatment strategies.

Family Chaos and Child Functioning in Relation to Sleep Problems Among Children at Risk for Obesity.

This study evaluated the influence of child and family functioning on child sleep behaviors in low-income minority families who are at risk for obesity. A cross-sectional study was utilized to measure child and family functioning from 2013 to 2014. Participants were recruited from Head Start classrooms while data were collected during home visits. A convenience sample of 72 low-income Hispanic (65%) and African American (32%) families of preschool-aged children were recruited for this study. We assessed the association of child and family functioning with child sleep behaviors using a multivariate multiple linear regression model. Bootstrap mediation analyses examined the effects of family chaos between child functioning and child sleep problems. Poorer child emotional and behavioral functioning related to total sleep behavior problems. Chaos associated with bedtime resistance significantly mediated the relationship between Behavioral and Emotional Screening System (BESS) and Bedtime Resistance. Families at high risk for obesity showed children with poorer emotional and behavioral functioning were at higher risk for problematic sleep behaviors, although we found no link between obesity and child sleep. Family chaos appears to play a significant role in understanding part of these relationships. Future longitudinal studies are necessary to establish causal relationships between child and family functioning and sleep problems to further guide obesity interventions aimed at improving child sleep routines and increasing sleep duration.

Mitochondrial Disease Sequence Data Resource (MSeqDR): a global grass-roots consortium to facilitate deposition, curation, annotation, and integrated analysis of genomic data for the mitochondrial disease clinical and research communities.

Success rates for genomic analyses of highly heterogeneous disorders can be greatly improved if a large cohort of patient data is assembled to enhance collective capabilities for accurate sequence variant annotation, analysis, and interpretation. Indeed, molecular diagnostics requires the establishment of robust data resources to enable data sharing that informs accurate understanding of genes, variants, and phenotypes. The "Mitochondrial Disease Sequence Data Resource (MSeqDR) Consortium" is a grass-roots effort facilitated by the United Mitochondrial Disease Foundation to identify and prioritize specific genomic data analysis needs of the global mitochondrial disease clinical and research community. A central Web portal (https://mseqdr.org) facilitates the coherent compilation, organization, annotation, and analysis of sequence data from both nuclear and mitochondrial genomes of individuals and families with suspected mitochondrial disease. This Web portal provides users with a flexible and expandable suite of resources to enable variant-, gene-, and exome-level sequence analysis in a secure, Web-based, and user-friendly fashion. Users can also elect to share data with other MSeqDR Consortium members, or even the general public, either by custom annotation tracks or through the use of a convenient distributed annotation system (DAS) mechanism. A range of data visualization and analysis tools are provided to facilitate user interrogation and understanding of genomic, and ultimately phenotypic, data of relevance to mitochondrial biology and disease. Currently available tools for nuclear and mitochondrial gene analyses include an MSeqDR GBrowse instance that hosts optimized mitochondrial disease and mitochondrial DNA (mtDNA) specific annotation tracks, as well as an MSeqDR locus-specific database (LSDB) that curates variant data on more than 1300 genes that have been implicated in mitochondrial disease and/or encode mitochondria-localized proteins. MSeqDR is integrated with a diverse array of mtDNA data analysis tools that are both freestanding and incorporated into an online exome-level dataset curation and analysis resource (GEM.app) that is being optimized to support needs of the MSeqDR community. In addition, MSeqDR supports mitochondrial disease phenotyping and ontology tools, and provides variant pathogenicity assessment features that enable community review, feedback, and integration with the public ClinVar variant annotation resource. A centralized Web-based informed consent process is being developed, with implementation of a Global Unique Identifier (GUID) system to integrate data deposited on a given individual from different sources. Community-based data deposition into MSeqDR has already begun. Future efforts will enhance capabilities to incorporate phenotypic data that enhance genomic data analyses. MSeqDR will fill the existing void in bioinformatics tools and centralized knowledge that are necessary to enable efficient nuclear and mtDNA genomic data interpretation by a range of shareholders across both clinical diagnostic and research settings. Ultimately, MSeqDR is focused on empowering the global mitochondrial disease community to better define and explore mitochondrial diseases.

Young Children's Food Neophobia Characteristics and Sensory Behaviors Are Related to Their Food Intake.

BACKGROUND: Food neophobia in children has been associated with poor dietary variety and nutrient intakes. Underlying characteristics that may predispose a child to neophobia have not been widely studied. OBJECTIVE: We investigated the associations between children's food neophobia, sensory sensitivity, and dietary intake in a diverse sample of typically developing preschoolers. METHODS: Caregiver reports of children's food neophobia and sensory behaviors (SBs) as measured by the Food Neophobia Scale and the Sensory Profile, children's observed weight outcome [body mass index z score (BMIz)], and children's food intake as estimated from the Block Kids Food Screener were collected at baseline in the Colorado LEAP (Longitudinal Eating and Physical Activity Study) study of childhood obesity. Preschool-aged children (n = 249; 136 girls, 113 boys; aged 55.6 ± 4.7 mo; BMIz = 0.54 ± 1.14) and caregivers [n = 180; 57 Hispanic, 119 non-Hispanic white (NHW), 4 unknown] participated. Data were analyzed by Pearson correlations and multivariate hierarchical linear regression analyses. RESULTS: Lower scores for children's oral sensory characteristics (i.e., more atypical) were related to higher neophobia ratings (r = -0.53, P < 0.001), and neophobia was negatively associated with reported vegetable intake (r = -0.31, P = 0.001) and dietary variety (r = -0.22, P < 0.001). Hispanic caregivers reported more atypical child SB scores (46.2 ± 8.8) than did NHW caregivers (50.5 ± 7.6; P = 0.006); however, no differences were noted for neophobia and SB scores by parent income and education or child sex. Neophobia was negatively associated with vegetable intake and dietary variety (P < 0.001 for both). SBs were associated with children's energy intake from sugar-sweetened beverages in bivariate analyses (r = -0.18, P < 0.05); however, in regression models, only ethnicity was significantly associated with energy from sugar-sweetened beverages (P < 0.001). Hispanic ethnicity was positively associated with sugar-sweetened beverage consumption (P < 0.001). CONCLUSIONS: Children's neophobia and sensory sensitivity may be important in understanding underlying issues related to limited food acceptance in typically developing young children and for helping caregivers facilitate healthy dietary intake patterns for their children. This trial was registered at clinicaltrials.gov as NCT01937481.

Hepatoblastoma in a patient with methylmalonic aciduria.

Childhood malignant tumors and their treatment are not well described in the natural history of methylmalonic aciduria (MMA). Here we present a case of hepatoblastoma occurring in the native liver of a 19-month-old male with MMA. His tumor was unresectable at diagnosis and he received neoadjuvant chemotherapy with cisplatin, 5-fluorouracil and vincristine. He developed metabolic acidosis and hyperglycemia during chemotherapy. In addition, he developed anemia, thrombocytopenia and febrile neutropenia. He underwent a combined liver-kidney transplant for local control of his tumor and to treat MMA. He remains in remission more than five years after his transplant. In addition, his transplant has cured his MMA and he is able to tolerate a regular diet without developing metabolic crises.

A randomized, home-based, childhood obesity intervention delivered by patient navigators.

BACKGROUND: Although Colorado is perceived as a healthy state, in 2010, 14.1 % of children aged 2-5 were overweight and 9.1 % were obese. Despite the high prevalence of obesity in this population, evidence to support particular strategies to treat obese preschoolers is lacking. The efficacy of home-based, childhood obesity interventions to reduce a child's body mass index is inconclusive. However, this model uniquely provides an opportunity to observe and intervene with the home food and activity environment and engage the entire family in promoting changes that fit each family's unique dynamics. METHODS/DESIGN: Eligible participants are children aged 2-5 years who attended a well-child care visit at a Denver Health Community Health Service clinic within 12 months prior to recruitment and on that visit had a body mass index (BMI) >85th percentile-for-age. Participants are randomly recruited at study inception and allocated to the intervention in one of five defined 6-month stepped wedge engagements; the delayed intervention groups serves as control groups until the start of the intervention. The program is delivered by a patient navigator at the family' home and consists of a 16-session curriculum focused on 1) parenting styles, 2) nutrition, and 3) physical activity. At each visit, a portion of curriculum is delivered to guide parents and children in selecting one goal for behavior change in each of three work areas to work on during the following week. The primary study outcome measure is change in BMI z-score from baseline to post-intervention period. DISCUSSION: This childhood obesity study, innovative for its home-based intervention venue, provides rich data characterizing barriers and facilitators to healthy behavior change within the home. The study population is innovative as it is focused on preschool-aged, Latino children from low-income families; this population has not typically been targeted in obesity management assessments. The home-based intervention is linked to clinical care through update letters and assessment of the program's impact to the child's medical providers. Informing primary care providers about a child's accomplishments and challenges, allows the clinician to support the health weight effort when seeing families during subsequent clinical visits. TRIAL REGISTRATION: ClinicalTrials.gov NCT02024360 Registered December 21, 2013.

Predictors of caregiver feeding practices differentiating persistently obese from persistently non-overweight adolescents.

Understanding the contribution of caregiver feeding practices to adolescent diet and weight is important to refining caregiver roles within the context of adolescent obesity prevention and treatment. This secondary data analysis examined whether feeding practices of female caregivers differentiated persistently non-overweight (n = 29) from persistently obese (n = 47) adolescents. Families who previously participated in a cross-sectional study on correlates of obesity were recruited for this follow-up study. At the time of the follow-up study, anthropometric measures were taken for all female caregivers and adolescents, and caregivers completed the Child Feeding Questionnaire-Adolescent version. Socioeconomic, demographic, female caregiver anthropometric, and psychological (caregiver perceived self-weight and concern for adolescent overweight) variables were examined as predictors of feeding practices found to differentiate the two groups. Female caregivers of persistently obese adolescents reported significantly greater use of restriction and monitoring compared to female caregivers of persistently non-overweight adolescents. Restriction was predicted by female caregiver age and concern for adolescent overweight whereas monitoring was predicted by concern for adolescent overweight only. Caregiver feeding strategies may be an important target for adolescent obesity prevention and intervention efforts particularly among those with heightened concern about their teen's weight status.

Mutation in the nuclear-encoded mitochondrial isoleucyl-tRNA synthetase IARS2 in patients with cataracts, growth hormone deficiency with short stature, partial sensorineural deafness, and peripheral neuropathy or with Leigh syndrome.

Mutations in the nuclear-encoded mitochondrial aminoacyl-tRNA synthetases are associated with a range of clinical phenotypes. Here, we report a novel disorder in three adult patients with a phenotype including cataracts, short-stature secondary to growth hormone deficiency, sensorineural hearing deficit, peripheral sensory neuropathy, and skeletal dysplasia. Using SNP genotyping and whole-exome sequencing, we identified a single likely causal variant, a missense mutation in a conserved residue of the nuclear gene IARS2, encoding mitochondrial isoleucyl-tRNA synthetase. The mutation is homozygous in the affected patients, heterozygous in carriers, and absent in control chromosomes. IARS2 protein level was reduced in skin cells cultured from one of the patients, consistent with a pathogenic effect of the mutation. Compound heterozygous mutations in IARS2 were independently identified in a previously unreported patient with a more severe mitochondrial phenotype diagnosed as Leigh syndrome. This is the first report of clinical findings associated with IARS2 mutations.

Quantitative pedigree analysis and mitochondrial DNA sequence variants in adults with cyclic vomiting syndrome.

BACKGROUND: Children with cyclic vomiting syndrome (CVS) have a high degree of maternal inheritance of functional gastrointestinal and neurological disorders. CVS in children is also associated with an increased prevalence of mitochondrial DNA single-nucleotide polymorphisms (mtDNA SNPs) 16519 T and 3010A. Preliminary data suggests that age of onset of symptoms (pediatric vs. adult) may be a determinant of the presence of such mtDNA SNP's. We sought to examine the degree of maternal inheritance pattern of functional disorders and the prevalence of mtDNA SNP's16519T and 3010A in adults with CVS and correlate this with age of onset of disease. METHODS: A Quantitative Pedigree Analysis (QPA) was performed in 195 of a total of 216 patients and all were genotyped using Restriction Fragment Length Polymorphism (RFLP) or sequencing. RESULTS: Adults with CVS had a higher degree of probable maternal inheritance (PMI) of functional disorders than controls (12% vs. 1%, p < 0.001). However, the prevalence of mitochondrial SNP's 16519 T, 3010A and the AT genotype were similar in Haplogroup H CVS patients compared to historical controls. There was no correlation between age of onset of disease and prevalence of these mtDNA SNP's. CONCLUSIONS: A subset of adults with CVS has a significantly higher degree of maternal inheritance pattern of functional disorders than controls. There was no association with mtDNA SNP's 16519 T and 3010A as seen in children and future studies sequencing the entire mitochondrial and nuclear genome to identify potential causes for this maternal inheritance pattern in adults are warranted.