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Background Obesity is an established risk factor for severe COVID-19 outcomes. The mechanistic underpinnings of this association are not well-understood. Objective To evaluate the mediating role of systemic inflammation in obesity-associated COVID-19 outcomes. Methods This hospital-based, observational study included 3828 SARS-CoV-2-infected patients who were hospitalized February to May 2020 at Massachusetts General Hospital (MGH) or Columbia University Irving Medical Center/New York Presbyterian Hospital (CUIMC/NYP). We use mediation analysis to evaluate whether peak inflammatory biomarkers (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], D-dimer, ferritin, white blood cell count and interleukin-6) are in the causal pathway between obesity (BMI ≥ 30) and mechanical ventilation or death within 28 days of presentation to care. Results In the MGH cohort (n = 1202), obesity was associated with greater likelihood of ventilation or death (OR = 1.73; 95% CI = [1.25, 2.41]; P = 0.001) and higher peak CRP (P Conclusion Findings support systemic inflammatory pathways in obesity-associated severe COVID-19 disease, particularly in patients

We examined racial and ethnic differences in the prevalence of behavioral problems measured by the Child Behavioral Checklist (CBCL), sleep disturbances measured by the Child Sleep Habits Questionnaire (CSHQ), and medication use among children with Autism Spectrum Disorders (ASD). We analyzed data from the Autism Treatment Network (ATN) dataset for 2,576 children ages 6 to 18 years of age diagnosed with ASD. Multivariable logistic regression accounting for age, gender, Diagnostic and Statistical Manual of Mental Disorders (4th Edition – Text Revision), diagnosis (Autistic Disorder, PDD-NOS, Asperger's Disorder), and parents' education did not show any racial or ethnic differences in behavioral challenges, conduct problems, or sleep disturbances for any of the groups, but Black children had lower odds of Total Problem Behaviors and Asian children had lower odds of Hyperactivity compared to White children. As a group, children from racial and ethnic minorities had lower odds of Total Problem Behaviors and Conduct Problems compared to White children. Hispanic children had lower odds of medication use for Behavioral Challenges, Total Problem Behaviors, Hyperactivity, and Conduct Problems. Asian children had lower odds of medication use for Behavioral Challenges, Total Problem Behaviors, and Hyperactivity; and had close to lower odds in medication use for Conduct Problems. Black children had lower odds for medication use for Total Problem Behaviors only. As a group, children from racial and ethnic minorities had lower odds for medication use for Behavioral Challenges, Total Problem Behaviors, Hyperactivity, and Conduct problems, but not for Sleep Disturbances. While these results are consistent with previous studies showing that White children are significantly more likely to receive psychotropic medication compared to children from racial and ethnic minority groups, we found no such differences for sleep challenges, suggesting that they are more consistently identified and equitably treated than other behavioral problems associated with ASD. We draw upon Andersen's (1995) Behavioral Model of Healthcare Use to suggest predisposing, enabling, and needs factors that may contribute to this pattern of racial and ethnic differences in the use of medications among children ASD.

Introduction: The use of online platforms for pediatric healthcare research is timely, given the current pandemic. These platforms facilitate trial efficiency integration including electronic consent, randomization, collection of patient/family survey data, delivery of an intervention, and basic data analysis. Methods: We created an online digital platform for a multicenter study that delivered an intervention for sleep disorders to parents of children with autism spectrum disorder (ASD). An advisory parent group provided input. Participants were randomized to receive either a sleep education pamphlet only or the sleep education pamphlet plus three quick-tips sheets and two videos that reinforced the material in the pamphlet (multimedia materials). Three measures – Family Inventory of Sleep Habits (FISH), Children’s Sleep Habits Questionnaire modified for ASD (CSHQ-ASD), and Parenting Sense of Competence (PSOC) – were completed before and after 12 weeks of sleep education. Results: Enrollment exceeded recruitment goals. Trial efficiency was improved, especially in data entry and automatic notification of participants related to survey completion. Most families commented favorably on the study. While study measures did not improve with treatment in either group (pamphlet or multimedia materials), parents reporting an improvement of ≥3 points in the FISH score showed a significantly improved change in the total CSHQ (P = 0.038). Conclusion: Our study demonstrates the feasibility of using online research delivery platforms to support studies in ASD, and more broadly, pediatric clinical and translational research. Online platforms may increase participant inclusion in enrollment and increase convenience and safety for participants and study personnel.

BACKGROUND AND OBJECTIVES: Children with autism spectrum disorder (ASD) have a higher prevalence of epilepsy compared with general populations. In this pilot study, we prospectively identified baseline risk factors for the development of seizures in individuals with ASD and also identified characteristics sensitive to seizure onset up to 6 years after enrollment in the Autism Speaks Autism Treatment Network. METHODS: Children with ASD and no history of seizures at baseline who either experienced onset of seizures after enrollment in the Autism Treatment Network or remained seizure free were included in the analysis. RESULTS: Among 472 qualifying children, 22 (4.7%) experienced onset of seizures after enrollment. Individuals who developed seizures after enrollment exhibited lower scores at baseline on all domains of the Vineland Adaptive Behavior Scales, greater hyperactivity on the Aberrant Behavior Checklist (25.4 ± 11.8 vs 19.2 ± 11.1; P = .018), and lower physical quality of life scores on the Pediatric Quality of Life Inventory (60.1 ± 24.2 vs 76.0 ± 18.2; P < .001). Comparing change in scores from entry to call-back, adjusting for age, sex, length of follow-up, and baseline Vineland II composite score, individuals who developed seizures experienced declines in daily living skills (−8.38; 95% confidence interval −14.50 to −2.50; P = .005). Adjusting for baseline age, sex, and length of follow-up, baseline Vineland II composite score was predictive of seizure development (risk ratio = 0.95 per unit Vineland II composite score, 95% confidence interval 0.92 to 0.99; P = .007). CONCLUSIONS: Individuals with ASD at risk for seizures exhibited changes in adaptive functioning and behavior.

The newest edition of the Diagnostic and Statistical Manual of Mental Disorders (5th ed., DSM-5) introduced substantial changes to the diagnostic criteria for autism spectrum disorder, including new severity level ratings for social communication and restricted and repetitive behavior domains. The purpose of this study was to evaluate the use of these new severity ratings and to examine their relation to other measures of severity and clinical features. Participants included 248 children with autism spectrum disorder who received diagnostic evaluations at one of six Autism Treatment Network sites. Higher severity ratings in both domains were associated with younger age, lower intelligence quotient, and greater Autism Diagnostic Observation Schedule–Second Edition domain-specific symptom severity. Greater restricted and repetitive behavior severity was associated with higher parent-reported stereotyped behaviors. Severity ratings were not associated with emotional or behavioral problems. The new DSM-5 severity ratings in both domains were significantly associated with behavioral observations of autism severity but not with measures of other behavioral or emotional symptoms. However, the strong associations between intelligence quotient and DSM-5 severity ratings in both domains suggest that clinicians may be including cognitive functioning in their overall determination of severity. Further research is needed to examine clinician decision-making and interpretation of these specifiers.

The transition from DSM-IV to DSM-5 criteria for autism spectrum disorder (ASD) sparked considerable concern about the potential implications of these changes. This study was designed to address limitations of prior studies by prospectively examining the concordance of DSM-IV and final DSM-5 criteria on a consecutive sample of 439 children referred for autism diagnostic evaluations. Concordance and discordance were assessed using a consistent diagnostic battery. DSM-5 criteria demonstrated excellent overall specificity and good sensitivity relative to DSM-IV criteria. Sensitivity and specificity were strongest for children meeting DSM-IV criteria for autistic disorder, but poor for those meeting criteria for Asperger's disorder and pervasive developmental disorder. Higher IQ, older age, female sex, and less pronounced ASD symptoms were associated with greater discordance.

In children with autism spectrum disorder, there have been equivocal results regarding primary caregiver education level and its influence on sleep. Thus, we assessed if lower primary caregiver education level is associated with more sleep problems. We evaluated 4,636 children with autism spectrum disorder in the Autism Speaks Autism Treatment Network's United States and Canadian registry, whose caregivers completed the Children's Sleep Habits Questionnaire. Using regression analysis, there was an association between lower primary caregiver education level and more sleep problems. Secondary analyses demonstrated that younger age, Hispanic ethnicity, higher IQ, autism diagnosis and lower adaptive function were also associated with more sleep problems. The finding that lower primary caregiver education level was associated with increased sleep problems in a large sample of children with autism spectrum disorder highlights the importance of screening for risk factors affecting sleep to help moderate sleep problems.

Objective: A randomized pilot trial of gastrointestinal (GI) symptoms targeting probiotic for quality of life in autism spectrum disorder (ASD). Methods: Thirteen children, 3–12 years of age with ASD, anxiety, and GI symptoms, were randomized into a probiotic crossover trial of 8 weeks each on VISBIOME and placebo separated by a 3-week washout. VISBIOME contains eight probiotic species, mostly Lactobacillus and Bifidobacterium. Primary outcome was the Pediatric Quality of Life Inventory (PedsQL) GI module. Secondary outcomes included gut microbiota analysis, the Parent-Rated Anxiety Scale for ASD (PRAS-ASD), and parent-selected target symptoms. A mixed analysis model was applied. Results: Thirteen children were randomized, with 10 completing the study (77% retention): 6 in probiotic/placebo sequence, 4 in placebo/probiotic sequence. Adherence to study treatment was 96%. There were no serious adverse events (AEs), and more nonserious AEs occurred with placebo than with probiotic, including those attributable to treatment. Only 6 of the 10 guessed the correct treatment at the end of week 8. Over the 19-week trial, each outcome improved from baseline and PedsQL correlated significantly with abundance of Lactobacillus without discernable changes to microbiota composition/diversity. Although probiotic showed more improvement than placebo, PedsQL and PRAS-ASD were not statistically significant, as expected at this sample size. PedsQL effect size was d = 0.49 by the general model and d = 0.79 by simple comparison of week 8 changes. A parent-selected target symptom showed significant improvement in GI complaints on probiotic compared with placebo (p = 0.02, d = 0.79). Probiotic effects carried over through the 3-week washout. Conclusion: The VISBIOME formulation was safe and suggested a health benefit in children with ASD and GI symptoms who retained Lactobacillus. The moderate effect size compared with placebo warrants a larger trial using a parallel-group design.

As clinicians we would all agree that the goal for our patients is to induce remission, which is usually defined as symptom resolution. Restoring continence and absence of rectal bleeding would be signs that the mucosa is at most minimally inflamed if not healed. However, there have not been any data to confirm that symptomatic improvement alters the natural history of the disease, nor decreases the lifetime risk for surgery. Because we understand the potential complications of this disease, it should not be enough that we “settle” for symptom resolution, but aim instead to decrease the risk of complications and alter the natural history of the disease. Until recently, mucosal healing endpoints have not been included in clinical trials. Clinical endpoints lead to high placebo responses, potentially diluting the effect of the therapy, even in large multinational trials. The hard endpoint of endoscopic mucosal healing reduces the number needed to power a study for treatment effect. The relevant questions during this discussion are: 1) What is endoscopic healing? 2) How often can we achieve this in ulcerative colitis (UC)? 3) Does mucosal healing change disease outcomes? and 4) Does mucosal healing lower the rate of complications? The history of mucosal healing starts in 2001 when Bitton et al1 reported on clinical, biological, and histologic parameters that would predict time to clinical relapse. One of the only factors that was statistically significant was basal plasmacytosis on rectal biopsy. The hazard ratio (HR) for predicting clinical relapse was 4.5 and the authors concluded that this factor may help identify patients with inactive UC who will require optimal maintenance therapy. An accepted definition of endoscopic healing has yet to be developed and validated. Everyone would agree that return to normal vascular pattern, the absence of friability, or ulcerations fits the bill, but what about some mild erythema or granularity? If there is no friability (however you want to measure it), should that suffice? Mucosal healing was defined as either completely normal (score of 0) or mild (score of 1) in the ASCEND and ACT trials but 1 in the MMX (mesalamine) trials. Using the ASCEND criteria, mucosal healing was achieved in up to 80% of those patients on 4.8 g/mesalamine/day at week 6.2,3 Using the stricter subscore of 0, then this percentage fell to 30%. In the MMX trials, 77.6% of patients had a score of 1 on 4.8 g/day at the end of the trial at 12 weeks.4,5 In the infliximab trial, healing was achieved by 62% of the 5 mg/kg dose at week 8, and was sustained in 45.5% of patients at week 54.6 If a score of 0 or 1 is acceptable, then certainly mucosal healing as an endpoint is an achievable and reasonable goal. Just because the majority of patients may achieve mucosal healing, does it make any difference? In the ACT trial, those patients with documented mucosal healing at week 8 and 30 were more likely to be in remission than those who did not (P 0.009).6 We do not have such data from the mesalamine trials, as endoscopy at the end of the trial was not part of the protocol. It would, however, make intuitive sense that those patients without any symptoms at the end of the trial would most likely have scores of 1 or 0. In a currently ongoing prospective study, preliminary results from patients with active UC were presented.7 Patients with mild to moderate UC were treated with 6 weeks of 4 g/day oral and 2 g enemas. In 78 patients, 59 achieved clinical remission. Endoscopic activity was still present in only 5. After a mean follow-up of 8.7 months, 15 (26%) relapsed. The cumulative rate of relapse at 1 year was 23% in patients with clinical and endoscopic remission and 80% in patients with only clinical remission. The conclusion of the authors was that persistence of endoscopic activity is a rare event, with active UC achieving clinical remission after 6 weeks, but a very strong predictor of early relapse. Data from the IBSEN study in Norway followed incident cases of UC over a period of 5 years.8 In all, 354 patients were endoscoped at 6 months to 2 years after their diagnosis, 328 Received for publication September 25, 2008; Accepted December 15, 2008. From the *Mayo Clinic, Rochester, Minnesota, Mount Sinai Hospital, New York, New York, University of Michigan Hospital, Ann Arbor, Michigan. Reprints: Dr. Peter Higgins, Box 0682, 1150 West Medical Center Dr., Ann Arbor, MI 48109 (e-mail: phiggins@umich.edu). Copyright © 2009 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1002/ibd.20875 Published online 11 February 2009 in Wiley InterScience (www. interscience.wiley.com).