Airway transcriptome networks identify susceptibility to frequent asthma exacerbations in children.

BACKGROUND: Frequent asthma exacerbators, defined as those experiencing more than 1 hospitalization in a year for an asthma exacerbation, represent an important subgroup of individuals with asthma. However, this group remains poorly defined and understudied in children. OBJECTIVE: Our aim was to determine the molecular mechanisms underlying asthma pathogenesis and exacerbation frequency. METHODS: We performed RNA sequencing of upper airway cells from both frequent and nonfrequent exacerbators enrolled in the Ohio Pediatric Asthma Repository. RESULTS: Through molecular network analysis, we found that nonfrequent exacerbators display an increase in modules enriched for immune system processes, including type 2 inflammation and response to infection. In contrast, frequent exacerbators showed expression of modules enriched for nervous system processes, such as synaptic formation and axonal outgrowth. CONCLUSION: These data suggest that the upper airway of frequent exacerbators undergoes peripheral nervous system remodeling, representing a novel mechanism underlying pediatric asthma exacerbation.

Factors Associated With Residential Relocation and Effects on Early Childhood Development in a Low-Income Home Visitation Population.

Residential relocation (RR) is associated with behavior problems and cognitive delays in school-age children. Little is known regarding effects of RR on early childhood development. The data from this study were collected from 2011 to 2016 through the Cincinnati Home Injury Prevention and Literacy Promotion Trial. The purpose of the current study was to identify factors associated with RR and determine effects of RR on early childhood development in a cohort of mother/child dyads (n = 424). High RR was relocating ≥ 3 times over the 24-month study period. Differences in baseline characteristics and early childhood development, measured by the Ages and Stages Questionnaire (ASQ) and MacArthur Bates Communicative Development Inventory, according to relocations, were estimated by negative binomial regression and logistic regression, respectively. Participants moved on average 1.46 times over 24 months. Relocations decreased by 0.05 for each year of increasing maternal age. Mothers with college degrees moved 0.72 fewer times than those with a high school diploma or less. Mothers living alone moved 0.47 fewer times than their counterparts. Mothers who could not count on someone to loan them $1000 and those with food insecurity more (0.41) than their counterparts (0.50). Odds of scoring in the bottom-tertile for the communication domain of the ASQ was significantly higher in those relocating ≥ 3 times. High RR was associated with concern for delayed language development at 24-month follow-up in some, but not all models. Early intervention may be more successful if primary care physicians and community health professionals collaborate to link families at risk of high RR to relevant community based resources.

Paracrine signals regulate human liver organoid maturation from induced pluripotent stem cells.

A self-organizing organoid model provides a new approach to study the mechanism of human liver organogenesis. Previous animal models documented that simultaneous paracrine signaling and cell-to-cell surface contact regulate hepatocyte differentiation. To dissect the relative contributions of the paracrine effects, we first established a liver organoid using human induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs) and human umbilical vein endothelial cells (HUVECs) as previously reported. Time-lapse imaging showed that hepatic-specified endoderm iPSCs (HE-iPSCs) self-assembled into three-dimensional organoids, resulting in hepatic gene induction. Progressive differentiation was demonstrated by hepatic protein production after in vivo organoid transplantation. To assess the paracrine contributions, we employed a Transwell system in which HE-iPSCs were separately co-cultured with MSCs and/or HUVECs. Although the three-dimensional structure did not form, their soluble factors induced a hepatocyte-like phenotype in HE-iPSCs, resulting in the expression of bile salt export pump. In conclusion, the mesoderm-derived paracrine signals promote hepatocyte maturation in liver organoids, but organoid self-organization requires cell-to-cell surface contact. Our in vitro model demonstrates a novel approach to identify developmental paracrine signals regulating the differentiation of human hepatocytes.

Maternal depression is associated with altered functional connectivity between neural circuits related to visual, auditory, and cognitive processing during stories listening in preschoolers.

BACKGROUND: Maternal depression can influence the early activity of a mother reading stories to a young child, as depressed mothers are less likely to read to their children. Here, maternal depression association to neurobiological circuitry of narrative comprehension, visualization, and executive functions during stories listening was examined in 21 4-year-old girls and their mothers. Maternal depression scores were collected from the mothers, and functional MRI during stories listening was collected from the children. RESULTS: Increased maternal depression was related to decreased functional connectivity between visualization and auditory regions and increased connectivity between the right visual cortex and dorsolateral prefrontal cortex in the children. CONCLUSIONS: This study highlights the need to monitor maternal depression and provide interventions to ensure positive linguistic outcomes in children.

Maternal reading fluency is positively associated with greater functional connectivity between the child's future reading network and regions related to executive functions and language processing in preschool-age children.

The role of the parent or educator in a child's learning is a key feature in child development. Evidence supports the impact of early language exposure for future language and cognitive abilities and of home reading environment on neural circuits supporting language and reading. As shared parent-child reading is largely contingent on the reading ability of the parent, the aim of the current study was to explore association of parental reading ability on functional connectivity of brain networks involved with reading acquisition in their children. Twenty-two 4-year-old girls and their mothers participated in the current study. Maternal reading fluency was applied as predictors of functional connectivity analyses of a stories-listening functional MRI task. Results indicate a positive association between maternal fluency scores and greater functional connectivity between regions in the future reading network and brain regions supporting language and cognitive control in the children. Maternal reading fluency is important in facilitating development of a child's reading network. Implications regarding shared reading are discussed, and an extended ecological model for child language and literacy development is proposed.

Shared reading quality assessment by parental report: preliminary validation of the DialogPR.

BACKGROUND: The American Academy of Pediatrics (AAP) recommends shared reading beginning as soon as possible after birth to promote healthy development. Shared reading quality can strongly influence outcomes, especially in children from low-SES households. Dialogic reading is a method developed to enhance verbal interactivity and engagement through book sharing, advocated by the AAP and clinic-based programs such as Reach Out and Read. There is no brief, validated, caregiver report measure of dialogic reading or shared reading quality currently available. METHODS: This cross-sectional study involved 49 healthy mother-child dyads (mean child age 4.5 yrs., SD = 0.6 yrs.) from 2 separate MRI-based studies. The DialogPR was administered by trained research coordinators following MRI, along with the READ subscale of the validated StimQ-P measure of home cognitive environment. The DialogPR consists of eight items developed in consultation with experts in early literacy, based on the PEER/CROWD dialogic reading conceptual model. Estimated reading level is 6th grade. Descriptive statistics were computed at both the item and scale levels. Modern theory Rasch methods were used to analyze all eight DialogPR items along with preliminary estimates of reliability and validity. RESULTS: Our combined sample involved 15 boys and 34 girls, and was diverse in terms of age, household income, and maternal education. DialogPR administration time was less than 2 min, with no problems reported. The DialogPR demonstrated strong internal consistency and reliability (Cronbach's alpha = 0.82), and criterion-related validity with the StimQ-P READ (Spearman's rho coefficient = 0.53). Rasch analysis revealed strong psychometric properties in terms of reliability, variability in item difficulty, and inter-item and item-measure correlations. CONCLUSIONS: Preliminary evidence suggests that the DialogPR may be an efficient means to assess shared reading quality and dialogic reading via caregiver report for clinical and research purposes, warranting further investigation.

Shared Reading Quality and Brain Activation during Story Listening in Preschool-Age Children.

OBJECTIVE: To explore the relationship between maternal shared reading quality (verbal interactivity and engagement) and brain function during story listening in at-risk, preschool-age children, in the context of behavioral evidence and American Academy of Pediatrics, recommendations. STUDY DESIGN: In this cross-sectional study, 22 healthy, 4-year-old girls from low socioeconomic status households completed functional magnetic resonance imaging using an established story listening task, followed by videotaped observation of uncoached mother-daughter reading of the same, age-appropriate picture book. Shared reading quality was independently scored applying dialogic reading and other evidence-based criteria reflecting interactivity and engagement, and applied as a predictor of neural activation during the functional magnetic resonance imaging task, controlling for income and maternal education. RESULTS: Shared reading quality scores were generally low and negatively correlated with maternal distraction by smartphones (P < .05). Scores were positively correlated with activation in left-sided brain areas supporting expressive and complex language, social-emotional integration, and working memory (P <.05, false discovery rate corrected). CONCLUSIONS: Maternal shared reading quality is positively correlated with brain activation supporting complex language, executive function, and social-emotional processing in at-risk, preschool-age children. These findings represent novel neural biomarkers of how this modifiable aspect of home reading environment may influence foundational emergent literacy skills, reinforce behavioral evidence and American Academy of Pediatrics, recommendations, and underscore the potential of dialogic reading interventions to promote healthy brain development, especially in at-risk households.

Cognitive and motor abilities of young children and risk of injuries in the home.

OBJECTIVE: Residential injury is a leading cause of morbidity and mortality in US children. Rates and types of injury vary by child age but little is known about injury risk based on child cognitive and motor abilities. The objective of this study was to determine whether cognitive or motor development in young children is associated with residential injury. METHODS: We employed data from Health Outcomes and Measures of the Environment (HOME) Study. Parent report of medically attended injury was obtained at regular intervals from 0 to 42 months. Child development was assessed at 12, 24 and 36 months using Bayley Scales of Infant and Toddler Development, 2nd edition, which generates both mental developmental index (MDI) and a psychomotor developmental index (PDI). Injury risk was modelled using multivariable logistic regression as function of child's MDI or PDI. Effects of MDI and PDI on injury risk were examined separately and jointly, adjusting for important covariates. RESULTS: Children with cognitive delay (MDI <77) were at significantly higher risk of injury than children without cognitive delay (OR=3.7, 95% CI 1.4 to 10.5, p=0.012). There was no significant association of PDI with injury. There was, however, significant interaction of MDI and PDI (p=0.02); children with cognitive delay but normal motor development were at significantly higher risk of injury than children with normal cognitive and motor development (OR=9.6, 95% CI 2.6 to 35.8, p=0.001). CONCLUSIONS: Children with cognitive delays, especially those with normal motor development, are at elevated risk for residential injuries. Injury prevention efforts should target children with developmental delays. CLINICAL TRIALS NUMBER: NCT00129324; post-results.

Maternal supervision of children during their first 3 years of life: the influence of maternal depression and child gender.

OBJECTIVE: The present study examined the effect of child gender and maternal depressive symptoms on routine supervisory practices of mothers longitudinally. METHOD: Self-report supervision practices were obtained at various time points from 3 months through 3 years of age. RESULTS: From 3 to 36 months, the quantity of time mothers reported supervising decreased from 7.1 to 6.3 hours, and the proportion of time spent in an intense style decreased from 63 to 46%, whereas that spent in a peripheral style increased from 14 to 32%. Mothers reported more time supervising girls and a greater proportion of this was in an intense style. Mothers with elevated depressive symptoms reported more time supervising but a lower proportion in an intense style. CONCLUSION: Over the first 36 months of life, routine patterns of supervision change and these vary as a function of maternal depression symptoms and child gender. Implications for child injury risk are discussed.

Filaggrin loss-of-function variants are associated with atopic dermatitis phenotypes in a diverse, early-life prospective cohort.

Loss-of-function (LoF) variants in the filaggrin (FLG) gene are the strongest known genetic risk factor for atopic dermatitis (AD), but the impact of these variants on AD outcomes is poorly understood. We comprehensively identified genetic variants through targeted region sequencing of FLG in children participating in the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children cohort. Twenty FLG LoF variants were identified, including 1 novel variant and 9 variants not previously associated with AD. FLG LoF variants were found in the cohort. Among these children, the presence of 1 or more FLG LoF variants was associated with moderate/severe AD compared with those with mild AD. Children with FLG LoF variants had a higher SCORing for Atopic Dermatitis (SCORAD) and higher likelihood of food allergy within the first 2.5 years of life. LoF variants were associated with higher transepidermal water loss (TEWL) in both lesional and nonlesional skin. Collectively, our study identifies established and potentially novel AD-associated FLG LoF variants and associates FLG LoF variants with higher TEWL in lesional and nonlesional skin.

What Have Mechanistic Studies Taught Us About Childhood Asthma?

Childhood asthma is a chronic heterogeneous syndrome consisting of different disease entities or phenotypes. The immunologic and cellular processes that occur during asthma development are still not fully understood but represent distinct endotypes. Mechanistic studies have examined the role of gene expression, protein levels, and cell types in early life development and the manifestation of asthma, many under the influence of environmental stimuli, which can be both protective and risk factors for asthma. Genetic variants can regulate gene expression, controlled partly by different epigenetic mechanisms. In addition, environmental factors, such as living space, nutrition, and smoking, can contribute to these mechanisms. All of these factors produce modifications in gene expression that can alter the development and function of immune and epithelial cells and subsequently different trajectories of childhood asthma. These early changes in a partially immature immune system can have dramatic effects (e.g., causing dysregulation), which in turn contribute to different disease endotypes and may help to explain differential responsiveness to asthma treatment. In this review, we summarize published studies that have aimed to uncover distinct mechanisms in childhood asthma, considering genetics, epigenetics, and environment. Moreover, a discussion of new, powerful tools for single-cell immunologic assays for phenotypic and functional analysis is included, which promise new mechanistic insights into childhood asthma development and therapeutic and preventive strategies.

Housing interventions and control of injury-related structural deficiencies: a review of the evidence.

Subject matter experts systematically reviewed evidence on the effectiveness of housing interventions that affect safety and injury outcomes, such as falls, fire-related injuries, burns, drowning, carbon monoxide poisoning, heat-related deaths, and noise-related harm, associated with structural housing deficiencies. Structural deficiencies were defined as those deficiencies for which a builder, landlord, or home-owner would take responsibility (ie, design, construction, installation, repair, monitoring). Three of the 17 interventions reviewed had sufficient evidence for implementation: installed, working smoke alarms; 4-sided isolation pool fencing; and preset safe hot water temperature. Five interventions needed more field evaluation, 8 needed formative research, and 1 was found to be ineffective. This evidence review shows that housing improvements are likely to help reduce burns and scalds, drowning in pools, and fire-related deaths and injuries.

Combinations of adverse childhood events and risk of postpartum depression among mothers enrolled in a home visiting program.

PURPOSE: The purpose of this study was to examine how combinations of adverse childhood events (ACEs) contribute to the risk of postpartum depression and the mediating role of prenatal social support. METHODS: The Adverse Childhood Experiences Scale Questionnaire and the Edinburgh Postnatal Depression Scale Questionnaire were used to measure the study's exposure and outcome. Among a cohort of 419 mothers enrolled in a home visiting (HV) program, latent class analyses were used to identify classes of ACEs exposure. General linear models assessed the risk of postpartum depression, and prenatal social support was examined as a mediator. RESULTS: Four distinct classes of ACE exposure were identified. On the Edinburgh Postnatal Depression scale, mothers who were classified in Classes 1-3 scored higher by 2.6-4.4 points compared with women in Class 0. ACE class was found to be indirectly associated with postpartum depression scores through prenatal social support. CONCLUSIONS: Identifying combinations of ACEs in an HV program has the potential to improve the characterization of ACEs among low-income perinatal women in the United States. Elucidating how these combinations contribute to the risk of postpartum depression has the potential to identify women at increased risk, which can help HV programs prioritize prevention efforts.

Comparing the frequency of unrecognized attention deficit hyperactivity disorder symptoms in injured versus noninjured patients presenting for care in the pediatric emergency department.

INTRODUCTION: Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common pediatric mental health problems but often goes unrecognized. Children with ADHD have an increased risk of injuries. Whether injured children presenting to the emergency department (ED) have an increased frequency of unrecognized ADHD symptoms compared to noninjured children is not known. PURPOSE: Examine the association of medically unrecognized ADHD symptoms in injured compared to noninjured children presenting to a pediatric ED. METHODS: A prospective age- and sex-matched cross-sectional comparison design of parent reported ADHD symptoms based on the Vanderbilt Assessment Scale in injured and noninjured children ages 5 to 18 years. Families were excluded if ADHD was listed in the medical history by nurses or physicians or if the child was currently taking medications for ADHD. Injured children were matched with noninjured children who presented with medical complaints. Univariate and bivariate analyses were performed. Proportions of children with ADHD symptoms in injured and noninjured children were compared with the chi statistic. RESULTS: One hundred sixty-four mothers of children were enrolled into the study: 82 in the injured and 82 noninjured group. The frequency of parent reported ADHD symptoms was the same in the 2 groups (9.8%). CONCLUSIONS: Children presenting with injuries are no more likely than a noninjured age- and sex-matched group to have unrecognized ADHD based on parental screen. Targeting injured children for ADHD screening is not supported by this study.

Story time turbocharger? Child engagement during shared reading and cerebellar activation and connectivity in preschool-age children listening to stories.

Expanding behavioral and neurobiological evidence affirms benefits of shared (especially parent-child) reading on cognitive development during early childhood. However, the majority of this evidence involves factors under caregiver control, the influence of those intrinsic to the child, such as interest or engagement in reading, largely indirect or unclear. The cerebellum is increasingly recognized as playing a "smoothing" role in higher-level cognitive processing and learning, via feedback loops with language, limbic and association cortices. We utilized functional MRI to explore the relationship between child engagement during a mother-child reading observation and neural activation and connectivity during a story listening task, in a sample of 4-year old girls. Children exhibiting greater interest and engagement in the narrative showed increased activation in right-sided cerebellar association areas during the task, and greater functional connectivity between this activation cluster and language and executive function areas. Our findings suggest a potential cerebellar "boost" mechanism responsive to child engagement level that may contribute to emergent literacy development during early childhood, and synergy between caregiver and child factors during story sharing.

Volunteer driven home safety intervention results in significant reduction in pediatric injuries: A model for community based injury reduction.

BACKGROUND: Home based injuries account for a significant number of injuries to children between 1 and 5years old. Evidence-based safety interventions delivered in the home with installation of safety equipment have been demonstrated to reduce injury rates. The aim of this study was to evaluate the impact of a community based volunteer implemented home safety intervention. METHODS: In partnership with a community with high injury rates for children between 1 and 5years old, a home safety bundle was developed and implemented by volunteers. The safety bundle included installing evidence based safety equipment. Monthly community emergency room attended injury rates as well as emergency room attended injuries occurring in intervention and nonintervention homes was tracked throughout the study. RESULTS: Between May 2012 and May 2014 a total of 207 homes with children 1-5years old received the home safety bundle. The baseline monthly emergency room attended injury rate for children aged 1-5years within our target community was 11.3/1000 and that within our county was 8.7/1000. Following the intervention current rates are now 10.3/1000 and 9.2/1000 respectively. Within intervention homes the injury rate decreased to 4.2/1000 while the rate in the homes not receiving the intervention experienced an increase in injury rate to 12/1000 (p<0.05). When observed vs. expected injuries were examined the intervention group demonstrated 59% fewer injuries while the nonintervention group demonstrated a 6% increase (p<0.05). CONCLUSION: Children in homes that received a volunteer-provided, free home safety bundle experienced 59% fewer injuries than would have been expected. By partnering with community leaders and organizing volunteers, proven home safety interventions were successfully provided to 207 homes during a two-year period, and a decline in community injury rates for children younger than 5years was observed compared to county wide injury rates.

Residential injuries in U.S. children and adolescents.

OBJECTIVES: Injuries are the leading cause of death and disability for U.S. children, but little research exists on injury in the home environment. The purpose of this study was to estimate the rate and severity of and trends in unintentional residential injury for U.S. children <20 years for 1993-1999. METHODS: Data on emergency department (ED) visits were obtained from the National Hospital Ambulatory Medical Care Survey (NHAMCS). Rates and 95% confidence intervals (CIs) were calculated using SUDAAN. Chi-square analysis was used to test for differences among proportions. Time trends were analyzed using linear regression. RESULTS: Residential injuries accounted for an average of 4.01 million (95% CI 3.50 million, 4.56 million) ED visits each year for U.S. children, representing 39% of unintentional injury ED visits. There were an average of 531,000 (95% CI 456,000, 606,000) visits with moderate-to-severe injuries, resulting in 73,680 (95% CI 59,715, 87,645) hospital admissions annually. The rate of residential injury visits (excluding unknown locations) was 5.6 per 100 (95% CI 4.9 per 100, 6.4 per 100). The visit rates for children <5 years of age were higher than those for children >9 years (p<0.0001). Males had a higher rate of visits than females (p=0.01). Falls were the leading mechanisms, resulting in 1.5 million ED visits per year (95% CI 1.3 million, 1.8 million). Residential injury rates decreased by 28% over time (p<0.02), from 6.3 per 100 (95% CI 3.4, 9.2) in 1993 to 4.5 per 100 (95% CI 2.3, 6.7) in 1999. CONCLUSIONS: The predominant location of injury for U.S. children is the home, accounting for 4.01 million ED visits and more than 70,000 hospitalizations each year. Efforts targeted to the home environment are needed to reduce morbidity and mortality from unintentional injury in U.S. children.

Promoting the uptake and use of evidence: an overview of the problem.

Application of evidence-based practice principles in neonatology requires that the use of proved therapies is monitored and evaluated. Although studies of neonatal center practice variation are appearing in the literature, careful, population-based assessments of the use of proved therapies are lacking. Few center comparison studies focus on proved therapies or explore the patient-independent reasons for practice variation. For a specific proved neonatal therapy, the ideal studies would carefully determine the number of eligible patients and the proportion who receive the therapy and then evaluate the characteristics of hospitals, clinicians, parents, and other decision makers among users and non-users. This information may allow for targeted interventions to disseminate evidence to both clinicians and parents, train clinicians critically to appraise the evidence, address identified barriers, and train clinicians to recognize and deal with the inevitable uncertainties associated with changing practice. The authors suggest that studies designed to evaluate the net benefit of proposed new therapies include a plan for evaluating the extent of incorporation of the therapy into practice if and when the therapy is shown to be beneficial. Studies should also rigorously evaluate alternative methods of disseminating the primary study's findings and identify the characteristics of clinicians, patients, and parents associated with practice change.

The effects of housing interventions on child health.

Housing hazards contribute to considerable morbidity and mortality among millions of children each year in the US, but few interventions are proven to control asthma and lead poisoning. Moreover, there is little evidence that many of the current recommendations to control residential hazards are safe and efficacious. The only interventions that have been found to work consistently are home visitation programs and home modification, such as installment of window guards and carpet removal. Altering the environment to protect the health of children requires pediatrician intervention. New models of cooperation between pediatricians and public health agencies must deal with residential hazards in an integrated manner and cannot be focused on one disease process or one method at a time. With research in more effective environmental interventions and pediatric-public-health partnerships, primary and secondary prevention of diseases from residential hazards may become a reality in the future.

Clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis.

This guideline is a revision of the clinical practice guideline, "Diagnosis and Management of Bronchiolitis," published by the American Academy of Pediatrics in 2006. The guideline applies to children from 1 through 23 months of age. Other exclusions are noted. Each key action statement indicates level of evidence, benefit-harm relationship, and level of recommendation. Key action statements are as follows: