Desensitization and remission after peanut sublingual immunotherapy in 1- to 4-year-old peanut-allergic children: A randomized, placebo-controlled trial.

BACKGROUND: Prior studies of peanut sublingual immunotherapy (SLIT) have suggested a potential advantage with younger age at treatment initiation. OBJECTIVE: We studied the safety and efficacy of SLIT for peanut allergy in 1- to 4-year-old children. METHODS: Peanut-allergic 1- to 4-year-old children were randomized to receive 4 mg peanut SLIT versus placebo. Desensitization was assessed by double-blind, placebo-controlled food challenge (DBPCFC) after 36 months of treatment. Participants desensitized to at least 443 mg peanut protein discontinued therapy for 3 months and then underwent DBPCFC to assess for remission. Biomarkers were measured at baseline and longitudinally during treatment. RESULTS: Fifty participants (25 peanut SLIT, 25 placebo) with a median age of 2.4 years were enrolled across 2 sites. The primary end point of desensitization was met with actively treated versus placebo participants having a significantly greater median cumulative tolerated dose (4443 mg vs 143 mg), higher likelihood of passing the month 36 DBPCFC (60% vs 0), and higher likelihood of demonstrating remission (48% vs 0). The highest rate of desensitization and remission was seen in 1- to 2-year-olds, followed by 2- to 3-year-olds and 3- to 4-year-olds. Longitudinal changes in peanut skin prick testing, peanut-specific IgG4, and peanut-specific IgG4/IgE ratio were seen in peanut SLIT but not placebo participants. Oropharyngeal itching was more commonly reported by peanut SLIT than placebo participants. Skin, gastrointestinal, upper respiratory, lower respiratory, and multisystem adverse events were similar between treatment groups. CONCLUSION: Peanut SLIT safely induces desensitization and remission in 1- to 4-year-old children, with improved outcomes seen with younger age at initiation.

Kinetics of basophil hyporesponsiveness during short-course peanut oral immunotherapy.

BACKGROUND: Oral immunotherapy (OIT) leads to suppression of mast cell and basophil degranulation along with changes in the adaptive immune response. OBJECTIVES: This study aimed to determine how rapidly these effects occur during OIT and more broadly, the kinetics of basophil and mast cell suppression throughout the course of therapy. METHODS: Twenty participants, age 4 to 12 years, were enrolled in a peanut OIT trial and assessed for desensitization and sustained unresponsiveness after 9 months of therapy. Blood was collected 5 times in the first month and then intermittently throughout to quantify immunoglobulins and assess basophil activation by CD63, CD203c, and phosphorylated SYK (pSYK). RESULTS: Twelve of 16 participants that completed the trial were desensitized after OIT, with 9 achieving sustained unresponsiveness after discontinuing OIT for 4 weeks. Basophil hyporesponsiveness, defined by lower CD63 expression, was detected as early as day 90. pSYK was correlated with CD63 expression, and there was a significant decrease in pSYK by day 250. CD203c expression remained unchanged throughout therapy. Interestingly, although basophil activation was decreased across the cohort during OIT, basophil activation did not correlate with individual clinical outcomes. Serum peanut-specific IgG4 and IgA increased throughout therapy, whereas IgE remained unchanged. CONCLUSIONS: Suppression of basophil activation occurs within the first 90 days of peanut OIT, ultimately leading to suppression of signaling through pSYK.

Early Peanut Introduction in Infants: Improving Guideline Adherence With EMR Standardization.

OBJECTIVES: Peanut allergy in children is a population health problem. Evidence suggests early peanut introduction (EPI) for infants can reduce the development of peanut allergy. Primary care settings have not widely adopted guidelines recommending EPI. Peanut allergy prevention depends on primary care providers incorporating EPI guidelines into well-child check (WCC) encounters. We aimed to improve guideline adherence in a primary care setting by implementing a bundle of clinical decision support (CDS) tools. METHODS: Using quality improvement methodology, the team developed a standardized work protocol and CDS tools within an electronic medical record (EMR) at 4, 6, and 9-month WCC encounters. The team executed changes and modifications through plan-do-study-act cycles and analyzed results with statistical process control charts. RESULTS: We collected data from 445 WCC encounters from baseline through sustainability. EMR documentation of EPI guidance at 4, 6, and 9-month WCCs shifted from 13.9% to 83.5% over 12 months. Provider adoption of smart lists and templates increased from 2% to 73%, the distribution of home peanut introduction handouts increased from 5.2% to 54.1%, and caregiver-reported peanut ingestion increased from 0% to 34.6%. Diphtheria-tetanus-acellular pertussis vaccination rates remained at 100% for 6-month visits, and patient in-room time remained at 65 minutes. CONCLUSIONS: Quality improvement methodology improved documentation of EPI guidance and increased reported peanut ingestion at routine WCC encounters without impacting other measures. Broader use of bundled CDS tools and EMR standardization could further improve guideline adherence and increase early peanut introduction to prevent peanut allergy in infants.

The perception and identification of facial emotions in individuals with autism spectrum disorders using the Let's Face It! Emotion Skills Battery.

BACKGROUND: Although impaired social-emotional ability is a hallmark of autism spectrum disorder (ASD), the perceptual skills and mediating strategies contributing to the social deficits of autism are not well understood. A perceptual skill that is fundamental to effective social communication is the ability to accurately perceive and interpret facial emotions. To evaluate the expression processing of participants with ASD, we designed the Let's Face It! Emotion Skills Battery (LFI! Battery), a computer-based assessment composed of three subscales measuring verbal and perceptual skills implicated in the recognition of facial emotions. METHODS: We administered the LFI! Battery to groups of participants with ASD and typically developing control (TDC) participants that were matched for age and IQ. RESULTS: On the Name Game labeling task, participants with ASD (N = 68) performed on par with TDC individuals (N = 66) in their ability to name the facial emotions of happy, sad, disgust and surprise and were only impaired in their ability to identify the angry expression. On the Matchmaker Expression task that measures the recognition of facial emotions across different facial identities, the ASD participants (N = 66) performed reliably worse than TDC participants (N = 67) on the emotions of happy, sad, disgust, frighten and angry. In the Parts-Wholes test of perceptual strategies of expression, the TDC participants (N = 67) displayed more holistic encoding for the eyes than the mouths in expressive faces whereas ASD participants (N = 66) exhibited the reverse pattern of holistic recognition for the mouth and analytic recognition of the eyes. CONCLUSION: In summary, findings from the LFI! Battery show that participants with ASD were able to label the basic facial emotions (with the exception of angry expression) on par with age- and IQ-matched TDC participants. However, participants with ASD were impaired in their ability to generalize facial emotions across different identities and showed a tendency to recognize the mouth feature holistically and the eyes as isolated parts.

The Toddler Autism Symptom Inventory: Use in diagnostic evaluations of toddlers.

LAY ABSTRACT: Determining whether a young child has an autism spectrum disorder requires direct observation of the child and caregiver report of the child's everyday behaviors. There are few interviews for parents that are specifically designed for children under 3 years of age. The Toddler Autism Symptom Inventory is a new interview that asks caregivers of children age 12-36 months about symptoms of possible autism spectrum disorder. The Toddler Autism Symptom Inventory uses a cutoff score to indicate likelihood for autism spectrum disorder; this cutoff score appears to accurately identify most children who are diagnosed with autism spectrum disorder without identifying too many who do not have autism spectrum disorder. The Toddler Autism Symptom Inventory interview can help clinicians to determine whether a young child shows symptoms suggestive of an autism spectrum disorder.

Using computerized games to teach face recognition skills to children with autism spectrum disorder: the Let's Face It! program.

BACKGROUND: An emerging body of evidence indicates that relative to typically developing children, children with autism are selectively impaired in their ability to recognize facial identity. A critical question is whether face recognition skills can be enhanced through a direct training intervention. METHODS: In a randomized clinical trial, children diagnosed with autism spectrum disorder were pre-screened with a battery of subtests (the Let's Face It! Skills battery) examining face and object processing abilities. Participants who were significantly impaired in their face processing abilities were assigned to either a treatment or a waitlist group. Children in the treatment group (N = 42) received 20 hours of face training with the Let's Face It! (LFI!) computer-based intervention. The LFI! program is comprised of seven interactive computer games that target the specific face impairments associated with autism, including the recognition of identity across image changes in expression, viewpoint and features, analytic and holistic face processing strategies and attention to information in the eye region. Time 1 and Time 2 performance for the treatment and waitlist groups was assessed with the Let's Face It! Skills battery. RESULTS: The main finding was that relative to the control group (N = 37), children in the face training group demonstrated reliable improvements in their analytic recognition of mouth features and holistic recognition of a face based on its eyes features. CONCLUSION: These results indicate that a relatively short-term intervention program can produce measurable improvements in the face recognition skills of children with autism. As a treatment for face processing deficits, the Let's Face It! program has advantages of being cost-free, adaptable to the specific learning needs of the individual child and suitable for home and school applications.

Conditioned fear inhibits c-fos mRNA expression in the central extended amygdala.

We have shown previously that unconditioned stressors inhibit neurons of the lateral/capsular division of the central nucleus of the amygdala (CEAl/c) and oval division of the bed nucleus of the stria terminalis (BSTov), which form part of the central extended amygdala. The current study investigated whether conditioned fear inhibits c-fos mRNA expression in these regions. Male rats were trained either to associate a visual stimulus (light) with footshock or were exposed to the light alone. After training, animals were replaced in the apparatus, and 2 h later injected remotely, via a catheter, with amphetamine (2 mg/kg i.p.), to induce c-fos mRNA and allow inhibition of expression to be measured. The rats were then presented with 15 visual stimuli over a 30 minute period. As expected, fear conditioned animals that were not injected with amphetamine, had extremely low levels of c-fos mRNA in the central extended amygdala. In contrast, animals that were trained with the light alone (no fear conditioning) and were injected with amphetamine had high levels of c-fos mRNA in the CEAl/c and BSTov. Animals that underwent fear conditioning, and were re-exposed to the conditioned stimulus after amphetamine injection had significantly reduced levels of c-fos mRNA in both the BSTov and CEAl/c, compared to the non-conditioned animals. These data suggest that conditioned fear can inhibit neurons of the central extended amygdala. Because these neurons are GABAergic, and project to the medial CEA (an amygdaloid output region), this may be a novel mechanism whereby conditioned fear potentiates amygdaloid output.

Preschool predictors of school-age academic achievement in autism spectrum disorder.

OBJECTIVE: Characterization of academic functioning in children with autism spectrum disorder (ASD), particularly predictors of achievement, may have important implications for intervention. The current study aimed to characterize achievement profiles, confirm associations between academic ability and concurrent intellectual and social skills, and explore preschool predictors of school-age academic achievement in a sample of children with ASD. METHOD: Children with ASD (n = 26) were evaluated at the approximate ages of two, four, and ten. Multiple regression was used to predict school-age academic achievement in reading and mathematics from both concurrent (i.e. school-age) and preschool variables. RESULTS: Children with ASD demonstrated a weakness in reading comprehension relative to word reading. There was a smaller difference between mathematics skills; math reasoning was lower than numerical operations, but this did not quite reach trend level significance. Concurrent IQ and social skills were associated with school-age academic achievement across domains. Preschool verbal abilities significantly predicted school-age reading comprehension, above and beyond concurrent IQ, and early motor functioning predicted later math skills. CONCLUSIONS: Specific developmental features of early ASD predict specific aspects of school-age achievement. Early intervention targeting language and motor skills may improve later achievement in this population.

Restricted and Repetitive Behaviors as Predictors of Outcome in Autism Spectrum Disorders.

Questions have been raised about the significance of restricted and repetitive behaviors (RRBs) in predicting outcomes of children with Autism Spectrum Disorders (ASDs). Previous studies have yielded mixed findings, but some suggest that the presence of RRBs during preschool years is a negative prognostic indicator for later childhood. This study examined the effect of RRBs at ages 1-2 and 3-5 years on cognitive functioning, adaptive abilities, and ASD symptomatology at age 8-10 years in 40 children with ASDs. At 1-2 years, RRBs did not predict later functioning. However, at 3-5 years, more severe preoccupations with parts of objects, sensory interests, and stereotyped motor movements predicted less developed cognitive and adaptive skills, and greater ASD symptom severity at age 8-10 years.

Parents' first concerns about toddlers with autism spectrum disorder: effect of sibling status.

Symptoms of autism spectrum disorders may appear as early as 6 months, but parent concern, which can precipitate evaluation, often lags significantly. The presence of typical or atypical older siblings can change parents' sensitivity to departures from typical development. This study investigated type and age of parent's first concerns in toddlers with autism spectrum disorder, prior to diagnosis. Participants had (1) at least one older sibling with autism spectrum disorder (Sibs-ASD); (2) only typically developing older siblings (Sibs-TD), or (3) were only/oldest (No-Sibs). Specific autism spectrum disorder diagnoses and symptom severity were similar among groups. Developmentally, No-Sibs showed the largest delays, followed by Sibs-TD, followed by Sibs-ASD. Mean age of first concern was 16 months for No-Sibs, 14 months for Sibs-TD, and 10 months for Sibs-ASD. Age of first concern differed significantly by group, even after controlling for mother's age and education. Concern about language was prevalent in all groups. Thus, the presence of an older child with typical or, especially, atypical development was associated with earlier concerns for the affected child, despite milder developmental delays. These findings underscore the importance of encouraging parents to report concerns to pediatricians, routine standardized screening for autism spectrum disorder, and the need for pediatrician vigilance, especially for only or oldest children.

Standardized screening facilitates timely diagnosis of autism spectrum disorders in a diverse sample of low-risk toddlers.

OBJECTIVE: Routine, standardized screening for autism spectrum disorder (ASD) has been hypothesized to reduce known racial/ethnic and socioeconomic status (SES) disparities in age of first diagnosis. This study explored demographic differences in toddlers' age and performance on developmental measures at the time of ASD assessment. METHOD: Toddlers (16-39 months at evaluation) who screened at-risk for developmental delay on the Modified Checklist for Autism in Toddlers (M-CHAT) or M-CHAT-Revised (M-CHAT-R) and follow-up interview participated in a diagnostic assessment. Of these, 44.7% were racial/ethnic minorities and 53.5% were non-minorities. Child race/ethnicity, years of maternal education (MEd), and household yearly income (YI) were parent-reported. RESULTS: Small but significant correlations were observed between MEd or YI and evaluation age and adaptive communication, socialization, and motor scores. Controlling for MEd and YI, minority racial/ethnic group did not predict child's performance on most measures and did not predict likelihood of ASD diagnosis. Differences in age at evaluation and receptive language skills were small effects. CONCLUSION: Significant but small effects emerged for SES and minority status on toddlers' age at evaluation and parent-reported adaptive skills, but these did not predict ASD diagnosis. The small magnitude of these effects suggests that routine, standardized screening for ASD in toddlers and timely access to diagnostic evaluation can reduce disparities in age at diagnosis and possibly reduce racial/ethnic disparities in access to services for ASD and other developmental delays.

Specific impairment of face-processing abilities in children with autism spectrum disorder using the Let's Face It! skills battery.

Although it has been well established that individuals with autism exhibit difficulties in their face recognition abilities, it has been debated whether this deficit reflects a category-specific impairment of faces or a general perceptual bias toward the local-level information in a stimulus. In this study, the Let's Face It! Skills Battery [Tanaka & Schultz, 2008] of developmental face- and object-processing measures was administered to a large sample of children diagnosed with autism spectrum disorder (ASD) and typically developing children. The main finding was that when matched for age and IQ, individuals with ASD were selectively impaired in their ability to recognize faces across changes in orientation, expression and featural information. In a face discrimination task, ASD participants showed a preserved ability to discriminate featural and configural information in the mouth region of a face, but were compromised in their ability to discriminate featural and configural information in the eyes. On object-processing tasks, ASD participants demonstrated a normal ability to recognize automobiles across changes in orientation and a superior ability to discriminate featural and configural information in houses. These findings indicate that the face-processing deficits in ASD are not due to a local-processing bias, but reflect a category-specific impairment of faces characterized by a failure to form view-invariant face representations and discriminate information in the eye region of the face.