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Emotional reactivity (e.g. explosive outbursts, tantrums) is a common but understudied challenge for individuals with autism spectrum disorder. Prior research has relied primarily on questionnaire data or observations of very young children. The current study coded emotional reactivity and recovery during a series of standardized frustration tasks in a sample of psychiatrically hospitalized youth with autism spectrum disorder ( N = 150; mean age: 12.76) inclusive of the full spectrum of intellectual and functional abilities and explored relationships between emotional reactivity and participant characteristics. The amount, intensity, and duration of negative affect and total range of affect significantly increased from a baseline period to frustration tasks and significantly decreased during recovery. Younger children displayed more negative affect overall; however, age did not moderate change in affect from baseline to frustration tasks or recovery. Adaptive functioning and verbal ability both moderated change in affect, with individuals with lower adaptive functioning and minimally verbal individuals displaying greater reactivity and less recovery. Reactivity was unrelated to non-verbal IQ, overall autism symptom severity, and parent-reported psychiatric/behavioral problems. The results highlight the feasibility and importance of examining emotional reactivity in more severely affected individuals and suggest the need to develop more targeted interventions for emotional reactivity in this group. Lay Abstract Large emotional reactions (e.g. outbursts, tantrums) can be common and distressing in the lives of individuals with autism spectrum disorder and their families. Most previous research that has examined these types of emotional responses have used questionnaire data or focused only on young children. In addition, very little research has included individuals across a large range of intellectual and functional abilities or individuals with more severe emotional and/or behavioral difficulties. This study examined emotional reactions to frustrating tasks in 6–21-year-olds with autism spectrum disorder who were psychiatrically hospitalized due to emotional and/or behavioral difficulties. We describe change in the amount, intensity, duration, and range of emotional reactions that the participants displayed from a neutral activity to the frustrating tasks and then to a neutral recovery period. We also examined associations between characteristics of the participants and these emotional reactions. We found that younger children displayed more negative emotions across the neutral and frustrating tasks; however, age did not relate to how big their reactions to frustration were. Furthermore, we found that individuals with fewer adaptive skills (i.e. age-appropriate life skills) and minimally verbal individuals had bigger reactions and recovered less following the frustration tasks. The results highlight the importance of examining emotional reactions in individuals with lower verbal and adaptive abilities and for interventions to consider the connection between verbal and adaptive skills and emotional reactions.

Autoimmune Hepatitis (AIH) and Idiopathic Hypereosinophilia Syndrome (HES) are viewed as distinct diseases. Our patient presented with hepatic and serum IgG4+ plasma cell infiltration, in addition to a marked bone marrow and peripheral eosinophilia with colonic involvement, raising the diagnosis of IgG4-related disease (IgG4-RD) and HES. This is the first reported case of IgG4 - AIH presenting with HES, both of which resolved with immune suppressive therapy.

Evidence suggests increased rates of suicidality in autism spectrum disorder (ASD), but the research has rarely used comparison samples and the role of emotion dysregulation has not been considered. We compared the prevalence of parent-reported suicidality ideation and considered the role of emotion dysregulation in 330 psychiatric inpatient youth with ASD, 1169 community youth with ASD surveyed online, and 1000 youth representative of the US census. The prevalence of suicidal ideation was three and five times higher in the community and inpatient ASD samples, respectively, compared to the general US sample. In the ASD groups, greater emotion dysregulation was associated with suicidal ideation. Implications include consideration of emotion regulation as a potential mechanism and treatment target for suicidality in ASD.

Unpredictable and potentially dangerous aggressive behavior by youth with Autism Spectrum Disorder (ASD) can isolate them from foundational educational, social, and familial activities, thereby markedly exacerbating morbidity and costs associated with ASD. This study investigates whether preceding physiological and motion data measured by a wrist-worn biosensor can predict aggression to others by youth with ASD. We recorded peripheral physiological (cardiovascular and electrodermal activity) and motion (accelerometry) signals from a biosensor worn by 20 youth with ASD (ages 6-17 years, 75% male, 85% minimally verbal) during 69 independent naturalistic observation sessions with concurrent behavioral coding in a specialized inpatient psychiatry unit. We developed prediction models based on ridge-regularized logistic regression. Our results suggest that aggression to others can be predicted 1 min before it occurs using 3 min of prior biosensor data with an average area under the curve of 0.71 for a global model and 0.84 for person-dependent models. The biosensor was well tolerated, we obtained useable data in all cases, and no users withdrew from the study. Relatively high predictive accuracy was achieved using antecedent physiological and motion data. Larger trials are needed to further establish an ideal ratio of measurement density to predictive accuracy and reliability. These findings lay the groundwork for the future development of precursor behavior analysis and just-in-time adaptive intervention systems to prevent or mitigate the emergence, occurrence, and impact of aggression in ASD. Autism Res 2019, 12: 1286-1296. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Unpredictable aggression can create a barrier to accessing community, therapeutic, medical, and educational services. The present study evaluated whether data from a wearable biosensor can be used to predict aggression to others by youth with autism spectrum disorder (ASD). Results demonstrate that aggression to others can be predicted 1 min before it occurs with high accuracy, laying the groundwork for the future development of preemptive behavioral interventions and just-in-time adaptive intervention systems to prevent or mitigate the emergence, occurrence, and impact of aggression to others in ASD.

Emerging evidence suggests that emotion regulation (ER) impairment in those with ASD is associated with poor mental health. This study used the Emotion Dysregulation Inventory, a new norm-referenced ER measure with clinical cut-offs, developed and validated in ASD and non-ASD samples, to establish rates of ER impairment and understand its association with psychiatric service use in ASD. Parents of 6-17 year olds in three well-characterized samples (nationally representative US n = 1,000; community ASD n = 1,169; inpatient ASD n = 567) completed a battery of questionnaires about their child. The prevalence of ER impairment was significantly higher in the ASD groups compared to the nationally representative sample and highest in the psychiatric Inpatient ASD group. The community ASD and inpatient ASD samples were four and seven times more likely, respectively, to exceed clinical cutoffs for emotional reactivity than the general US sample. Similarly, history of psychiatric hospitalization, recent emergency services use (police contact, emergency room visits, or in-home crisis evaluations for emotional or behavioral concerns in the past 2 months), and psychotropic medication prescriptions were significantly higher in the ASD groups. ER impairment was significantly associated with all forms of psychiatric service use, after controlling for demographics (age, sex, race), co-occurring intellectual disability, and ADHD symptoms. This is the first large-scale study to document substantially higher rates of ER impairment in youth with ASD compared to the general population. The importance of ER impairment is underscored by its association with higher utilization of inpatient, emergency, and medication services in ASD, after accounting for demographics and ADHD-related symptoms.

Insomnia subtypes have not been characterized in severely affected youth with autism spectrum disorder. We examined indices of clinical impairment (i.e. length of hospital stay, autism severity, nonverbal intelligence quotient, and adaptive and maladaptive behaviors) across insomnia subtypes in 427 psychiatrically hospitalized children with autism spectrum disorder (mean age = 12.8 ± 3.4; 81.3% male). Multivariate analysis with Bonferroni adjustment tested for differences in clinical impairment across insomnia subtypes adjusting for age and sex. Per parent report, 60% (n = 257) of children had at least one form of insomnia. The distribution of subtypes was sleep onset (26.1%, n = 67), sleep maintenance (24.9%, n = 64), early morning waking (4.3%, n = 11), and combined (44.7%, n = 115). There was a significant multivariate effect of insomnia subtypes on clinical impairment (Pillai’s Trace = 0.25, F = 2.78, p < 0.001). Sleep maintenance and early morning waking were associated with longer hospital stays. Early morning waking was also associated with greater autism symptom severity. In general, children with sleep-maintenance or combined insomnias scored lower on adaptive behaviors and higher on maladaptive behaviors. Sleep-maintenance and combined insomnias appear to be more indicative of or consequential for impaired behavioral functioning. Lay abstract Insomnia subtypes are not well understood in the most severely affected children with autism spectrum disorder. We examined length of hospital stay, autism severity, nonverbal intelligence quotient, and behavioral functioning across insomnia subtypes in 427 psychiatrically hospitalized children with autism spectrum disorder (mean age = 12.8 ± 3.4; 81.3% male). Per parent report, 60% (n = 257) of children had at least one type of insomnia. The distribution of subtypes was difficulty falling asleep (26.1%, n = 67), difficulty staying asleep (24.9%, n = 64), early morning awakening (4.3%, n = 11), and multiple insomnia symptoms (44.7%, n = 115). Difficulty staying asleep and early morning awakenings were associated with longer hospital stays. Early morning awakening was also associated with higher autism symptom severity. In general, children with difficulty staying asleep or multiple insomnia symptoms scored lower on adaptive behaviors (e.g. communication, self-care, socialization) and higher on maladaptive behaviors (e.g. irritability, hyperactivity, emotional reactivity, and emotional dysphoria). Difficulty staying asleep or having multiple insomnia symptoms appears to be most strongly related to impaired behavioral functioning. Conversely, early morning awakenings may be more closely tied with autism spectrum disorder itself. Further research is needed regarding insomnia subtypes at the severe end of the autism spectrum.

Despite significant advances in autism research, experts have noted that children severely affected by autism spectrum disorder (ASD) appear to have been understudied. Rigorous analysis of this observation has been limited, and the representation of severity has not been well-described. We assessed three domains of severity (communication ability, cognitive functioning, and adaptive functioning) in 367 treatment studies of children with ASD published 1991-2013. We found that the proportion of studies that included the severely affected population decreased significantly over time, as well as wide variability in measurement and reporting. Inadequate representation of the full autism spectrum in the literature could lead to an unbalanced picture of ASD and leave behind those with arguably the greatest need.

Research on individuals severely affected by autism, including those who are minimally verbal, have intellectual disability or challenging behaviors, has become less common. The Autism Inpatient Collection (AIC) was initiated so data on this group is available to the research community. Ten studies utilizing phenotypic data from the first 350 AIC participants are presented. Greater autism severity, sleep disturbance, and psychiatric disorders are risks for hospitalization; fluently verbal youth experience more depression and oppositional symptoms; lower adaptive/coping skills are associated with increased problem behaviors; lower IQ is a risk for SIB; post-traumatic and suicidal symptoms are common; and challenging behaviors improve with specialized inpatient treatment. A new measure of emotion regulation and prescribing practices are described and future research discussed.

Youth with autism spectrum disorder (ASD) are psychiatrically hospitalized at high rates. Though specialized psychiatric units are effective, few specialized units exist. The ASD Care Pathway (ASD-CP) was developed as a scalable approach to improving care in general psychiatric units through staff training and a package of autism-specific intervention strategies. An evaluation of the effectiveness of the ASD-CP in a public hospital child psychiatric service compared 18 months (n = 17) versus 18 months (n = 20) post implementation. Average length of hospital stay decreased 40% (22.4-13.4 days) and use of crisis interventions decreased 77% (holds/restraints; 0.65/day to 0.15/day), though each result only approached statistical significance (p = 0.07; 0.057). This study provides preliminary evidence for improved outcomes after implementation of an ASD-CP.

Limited information about self-injurious behavior (SIB) is known for children and adolescents with Autism Spectrum Disorder (ASD) who require intensive behavioral health interventions. We examined risk-factors for SIB in 302 individuals with ASD (ages 4-20) admitted to six specialized psychiatric inpatient units. Seventy-four percent were reported by a caregiver to display SIB, however, only 25% were observed to engage in daily SIB during hospitalization. Those exhibiting SIB across environments had significantly higher ratings on caregiver questionnaires of SIB severity. Tree-structured classification was used to develop and validate two predictive models, one indicating which inpatient youth with ASD are likely to have SIB and a second indicating which individuals with SIB at home are likely to continue in an inpatient setting.

Summary We describe the development and characterization of a mouse and human epithelial cell monolayer platform of the small and large intestines, with a broad range of potential applications including the discovery and development of minimally systemic drug candidates. Culture conditions for each intestinal segment were optimized by correlating monolayer global gene expression with the corresponding tissue segment. The monolayers polarized, formed tight junctions, and contained a diversity of intestinal epithelial cell lineages. Ion transport phenotypes of monolayers from the proximal and distal colon and small intestine matched the known and unique physiology of these intestinal segments. The cultures secreted serotonin, GLP-1, and FGF19 and upregulated the epithelial sodium channel in response to known biologically active agents, suggesting intact secretory and absorptive functions. A screen of over 2,000 pharmacologically active compounds for inhibition of potassium ion transport in the mouse distal colon cultures led to the identification of a tool compound., Highlights • Epithelial cell monolayer growth conditions developed for all intestinal segments • Monolayer gene expression is consistent with tissue from each intestinal segment • Ion transport, secretory, and absorptive functions match intestinal physiology • Compound screen identified inhibitor of mouse distal colon potassium transport, Siegel and colleagues describe their development of a human and mouse intestinal epithelial cell monolayer platform that maintains the cellular, molecular, and functional characteristics of tissue for each intestinal segment. They demonstrate the platform's application to drug discovery by screening a library of over 2,000 compounds to identify an inhibitor of potassium ion transport in the mouse distal colon.

We examined the relationship between sleep duration and awakenings to Aberrant Behavior Checklist-Community (ABC-C) and Autism Diagnostic Observation Schedule (ADOS-2) scores in hospitalized youth with ASD and behavioral disturbance. Participants included 106 patients with a stay of at least 10 nights. Sleep in the hospital was recorded by staff observation. Higher scores on the ABC-C (irritability, stereotypy, and hyperactivity subscales) at admission were significantly associated with fewer minutes slept during the last five nights of hospitalization. There was no association between total awakenings and ABC-C scores or ADOS-2 comparison scores. Improved understanding of the relationship between sleep quality and maladaptive behavior in this challenging cohort of patients with ASD is vital to the definition and design of future effective interventions.

Little is known about suicidal ideation in youth with autism spectrum disorder (ASD), making it difficult to identify those at heightened risk. This study describes the prevalence of thoughts about death and suicide in 107 verbal youth with ASD with non-verbal IQ >55, assessed during inpatient psychiatric admission. Per parent report, 22% of youth with ASD had several day periods when they talked about death or suicide “often,” or “very often.” Clinical correlates included the presence of a comorbid mood (OR 2.71, 95% CI 1.12–6.55) or anxiety disorder (OR 2.32, 95% CI 1.10–4.93). The results suggest a need for developmentally appropriate suicide risk screening measures in ASD. Reliable detection of suicidal thoughts in this high-risk population will inform suicide prevention strategies.

Data from the Autism Inpatient Collection was used to examine the relationship between problem behaviors and verbal ability, which have generally, though not universally, been highly associated. In a comparison of 169 minimally-verbal and 177 fluently-verbal 4 to 20-year-old psychiatric inpatients with ASD, the severity of self-injurious behavior, stereotyped behavior, and irritability (including aggression and tantrums) did not significantly differ, when controlling for age and NVIQ. Verbal ability was not strongly related to the severity of problem behaviors. However, lower adapting/coping scores were significantly associated with increasing severity of each type of problem behavior, even when accounting for verbal ability. Interventions to develop adapting/coping mechanisms may be important for mitigation of problem behaviors across the spectrum of individuals with ASD.

Autism Spectrum Disorder (ASD) is associated with significant healthcare expenditures and a greater utilization of psychiatric health services. High utilization may not be evenly distributed across individuals with ASD. The objective of this study was to identify individual and family characteristics that increase the risk of psychiatric hospitalization. Naturalistic study of two age- and gender-matched ASD cohorts, inpatients enrolled in the Autism Inpatient Collection (AIC) and outpatients enrolled in the Rhode Island Consortium of Autism Research and Treatment (RI-CART), revealed a number of factors associated with hospitalization. Multiple logistic regression analyses revealed that adaptive functioning, ASD symptom severity, primary caregiver's marital status, the presence of mood disorders, and the presence of sleep problems independently increased the risk of psychiatric hospitalization.

Nearly 11% of youth with Autism Spectrum Disorder (ASD) undergo psychiatric hospitalization, and 65% are treated with psychotropic medication. Here we characterize psychotropic medication usage in subjects enrolled in the Autism Inpatient Collection. Participant psychotropic medication usage rates topped 90% at admission and discharge, though there was a decline at 2-month follow-up. Antipsychotics, ADHD medications, and sleep aids were the most commonly reported classes of medications. The impact of age, gender, and non-verbal IQ on medication usage rates was minimal, though age and IQ may play a role in prescribing practices. Future work is indicated to explore medication usage trends, the impact of clinical factors on medication use rates, and the safety of psychotropic medications in youth with ASD.

Islet autotransplantation (IAT) is increasingly being performed to mitigate against the diabetic complications of pancreatic resection in patients with benign inflammatory pancreatic disorders; however, the glycemic benefit of IAT in patients undergoing partial pancreatic resection is not known. We aimed to determine whether IAT improved glycemic outcomes in patients undergoing distal pancreatectomy for benign inflammatory disease. We performed a multicenter, retrospective case-control study of patients who underwent distal pancreatic resection with IAT at two U S tertiary care centers. The primary outcome was the mean change in pre- vs post-operative HgA1c following transplant as well as the development of new post-operative diabetes. Nine patients requiring distal pancreatectomy for benign disease underwent IAT and were compared to 13 historical controls without IAT. Baseline characteristics were similar between groups. With a median follow-up of 22 months, those who received an IAT had a smaller increase in their pre- vs post-operative HgA1c (0.42 vs 2.83, P = .004), and one case patient (14.3%) vs three control patients (23.1%) developed new post-operative diabetes (P = .581). We conclude that patients undergoing distal pancreatic resection for benign inflammatory disease should be considered for IAT, as long-term glycemic outcomes appear to be improved in those undergoing transplant.

Background Fear of autism has led to a decline in childhood-immunization uptake and to a resurgence of preventable infectious diseases. Identifying characteristics of parents who believe in a causal role of vaccines for autism spectrum disorder (ASD) in their child may help targeting educational activities and improve adherence to the immunization schedule. Objectives To compare caregivers of children with ASD who agree or disagree that vaccines play an etiological role in autism for 1) socio-demographics characteristics and 2) developmental and clinical profiles of their children. Methods Data from 16,525 participants with ASD under age 18 were obtained from SPARK, a national research cohort started in 2016. Caregivers completed questionnaires at registration that included questions on beliefs about the etiologic role of childhood immunizations and other factors in ASD. Data were available about family socio-demographic characteristics, first symptoms of autism, developmental regression, co-occurring psychiatric disorders, seizures, and current levels of functioning. Results Participants with ASD were 80.4% male with a mean age of 8.1 years (SD = 4.1). Overall, 16.5% of caregivers endorsed immunizations as perceived causes of autism. Compared to caregivers who disagreed with vaccines as a cause for ASD, those who believed in vaccine causation came disproportionately from ethnic minority, less educated, and less wealthy backgrounds. More often their children had experienced developmental regression involving language and other skills, were diagnosed earlier, had lost skills during the second year of life, and had worse language, adaptive, and cognitive outcomes. Conclusion One in six caregivers who participate in a national research cohort believe that child immunizations could be a cause of autism in their child. Parent social background (non-White, less educated) and child developmental features (regression in second year, poorer language skills, and worse adaptive outcomes) index caregivers who are more likely to harbor these beliefs and could benefit from targeted educational activities.

This Practice Parameter is a revision of a previous Parameter addressing reactive attachment disorder that was published in 2005. It reviews the current status of reactive attachment disorder (RAD) and disinhibited social engagement disorder (DESD) with regard to assessment and treatment. Attachment is a central component of social and emotional development in early childhood, and disordered attachment is defined by specific patterns of abnormal social behavior in the context of "insufficient care" or social neglect. Assessment requires direct observation of the child in the context of his or her relationships with primary caregivers. Treatment requires establishing an attachment relationship for the child when none exists and ameliorating disturbed social relatedness with non-caregivers when evident.

Psychiatric hospitalization of children with autism spectrum disorder (ASD) is common, but there is little comparative information available on different psychiatric hospital treatment models. Children with ASD ages 4–20 were enrolled upon admission to either a specialized (N = 53) or a general child psychiatric unit (N = 27). Caregivers completed the Aberrant Behavioral Checklist-Irritability Sub-scale (ABC-I) at admission, discharge, and 2 months post-discharge and reported information on crisis service utilization 2 months post-discharge. Children treated in the specialized unit had lower ABC-I scores at discharge and 2 months post-discharge (F = 8.98, p = 0.003) and were significantly less likely to experience an ER visit within 2 months post-discharge (X2 = 5.51, p = 0.019). Specialized inpatient units may be more effective for children with ASD in need of psychiatric hospitalization.

The lack of sensitive measures suitable for use across the range of functioning in autism spectrum disorder (ASD) is a barrier to treatment development and monitoring. The Emotion Dysregulation Inventory (EDI) is a caregiver-report questionnaire designed to capture emotional distress and problems with emotion regulation without requiring verbal information. The first two phases of the EDI's development are described, including: 1) utilizing methods from the Patient-Reported Outcomes Measurement Information System (PROMIS(®)) project to develop the item pool and response options; and 2) assessment of the EDI in a sample of psychiatric inpatients with ASD. The results suggest that the EDI captures a wide range of emotion dysregulation, is sensitive to change, and is not biased by verbal or intellectual ability.

Children with Autism Spectrum Disorder (ASD) are admitted to inpatient psychiatric units at markedly high rates. As health insurance companies and government healthcare systems and regulators seek more evidence for healthcare outcomes, it is important to learn more about the effectiveness of psychiatric inpatient admissions for children with ASD to best inform decisions on provision and access to this level of care. Evidence for models of inpatient treatment for youth with ASD is presented, and key characteristics and consensus recommendations for care are discussed.

BACKGROUND AND OBJECTIVES: There has been an increasing focus on the relationship between pediatric prescribers and the biomedical industry. There is a lack of research, however, on the biomedical industry’s relationship with the professional medical associations (PMAs) of pediatric prescribers. We developed a systematic method to assess this relationship by evaluating PMA transparency and compliance with a set of 2009 best practice guidelines (BPGs). METHODS: Nine PMAs rated as having the greatest influence on pediatric prescribers were examined. Two researchers independently coded publicly accessible information from the PMAs’ Web sites for transparency and compliance with 36 BPG recommendations. Using the coded data, an industry relationship index (IRI) score was developed to systematize comparisons across PMAs. RESULTS: The PMAs demonstrated transparency and compliance with less than one-half of the 2009 BPGs (mean ± SD: 30.2 ± 15.6; range: 8–51 on the 66-point IRI scale). Two PMAs clustered in the high IRI (more transparent and compliant) group, 3 in the medium group, and 4 in the low group. There was no significant association of IRI group status and the PMAs’ number of members or age. PMAs were least compliant with recommendations that prohibit or limit financial relationships with industry. CONCLUSIONS: PMAs with influence on pediatric prescribers have achieved only limited transparency and compliance with a set of 2009 BPGs, particularly with respect to financial separation from industry. Use of quantifiable standards of conduct facilitates comparisons between organizations and may enhance public trust in PMAs, preserving their ability to achieve organizational goals.

The increasing prevalence of autism spectrum disorder (ASD), the severity of impairment, and its impact on systems are a source of ever-growing concern. This article (1) describes briefly the spectrum of ASD and its treatments; (2) discusses the impact that ASD has on the individual, family, and external environment; and (3) discusses the application of family therapy principles in order to meet the needs of children and families affected by ASD. Illustrative case examples are presented.

It has been suggested that changes in physiological arousal precede potentially dangerous aggressive behavior in youth with autism spectrum disorder (ASD) who are minimally verbal (MV-ASD). The current work tests this hypothesis through time-series analyses on biosignals acquired prior to proximal aggression onset. We implement ridge-regularized logistic regression models on physiological biosensor data wirelessly recorded from 15 MV-ASD youth over 64 independent naturalistic observations in a hospital inpatient unit. Our results demonstrate proof-of-concept, feasibility, and incipient validity predicting aggression onset 1 minute before it occurs using global, person-dependent, and hybrid classifier models., Comment: 40th International Engineering in Medicine and Biology Conference (EMBC 2018)

Psychiatric hospitalization of children with autism spectrum disorder (ASD) is relatively common and occurs at a higher rate than in non-ASD youth. This study compared changes in the severity of serious problem behaviors in 350 youth with ASD enrolled in the autism inpatient collection during and after hospitalization in six specialized child psychiatry units. There was a significant reduction in serious problem behaviors from admission (aberrant behavior checklist—irritability subscale M = 29.7, SD 9.6) to discharge (M = 15.0, SD 10.3) and 2-month follow-up (M = 19.3, SD 10.3). Between discharge and 2-month follow-up, tantrum-like behaviors but not self-injurious behaviors increased slightly. Improvement in the severity of problem behaviors was not uniform across sites, even after controlling for measured site differences.

Youth with autism spectrum disorder (ASD) experience high rates of psychiatric symptoms, but the relation of verbal ability with psychiatric symptoms is unknown. This study utilized a large sample of clinically referred inpatient and outpatient youth with ASD to compare psychiatric comorbidity between verbal and minimally-verbal (MV) youth, adjusting for nonverbal IQ, age, and ASD symptom severity. Results indicated that verbal youth were more likely to present with and meet clinical cutoffs for depression and oppositional defiant disorder symptoms, with greater impairment associated with depression. Youth in inpatient settings had greater symptom severity and impairment across almost all psychiatric comorbidities. These results present the most direct estimate to date of the association between verbal ability and psychiatric comorbidity in ASD.

Children with autism spectrum disorder (ASD) have higher rates of comorbid psychiatric disorders, including mood disorders, than the general child population. Although children with ASD may experience irritability (aggression, self-injury, and tantrums), a portion also experience symptoms that are typical of a mood disorder, such as euphoria/elevated mood, mania, hypersexuality, paranoia, or decreased need for sleep. Despite lithium's established efficacy in controlling mood disorder symptoms in the neurotypical population, lithium has been rarely studied in children with ASD.We performed a retrospective chart review of 30 children and adolescents diagnosed with ASD by the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) criteria who were prescribed lithium in order to assess target symptoms, safety, and tolerability. Clinical Global Impressions - Improvement (CGI-I) ratings were performed by two board-certified child psychiatrists with expertise in ASD. CGI-I scores were dichotomized into "improved" (CGI-I score of 1 or 2) or "not improved" (CGI-I score ≥3).Forty-three percent of patients who received lithium were rated as "improved" on the CGI-I. Seventy-one percent of patients who had two or more pretreatment mood disorder symptoms were rated as "improved." The presence of mania (p=0.033) or euphoria/elevated mood (p=0.041) were the pretreatment symptoms significantly associated with an "improved" rating. The mean lithium blood level was 0.70 mEq/L (SD=0.26), and the average length of lithium treatment was 29.7 days (SD=23.9). Forty-seven percent of patients were reported to have at least one side effect, most commonly vomiting (13%), tremor (10%), fatigue (10%), irritability (7%), and enuresis (7%).This preliminary assessment of lithium in children and adolescents with ASD suggests that lithium may be a medication of interest for those who exhibit two or more mood disorder symptoms, particularly mania or euphoria/elevated mood. A relatively high side effect rate merits caution, and these results are limited by the retrospective, uncontrolled study design. Future study of lithium in a prospective trial with treatment-sensitive outcome measures may be indicated.

Psychiatric hospitalization of children with autism spectrum disorder and/or intellectual disability is common, however, the effectiveness of this intervention is largely unknown. Thirty-eight clinically-referred children 8–19 years old admitted to a specialized inpatient psychiatry unit were assessed by a consistent caregiver on the Aberrant Behavior Checklist-Irritability (ABC-I) subscale at admission, discharge and 2 months post discharge. There was a decrease in the mean ABC-I score from admission (27.3, SD 7.4) to discharge (11.9, SD 8.8), which was sustained at 2 months post discharge (14.8, SD 9.3) (p

Children with autism spectrum disorder are psychiatrically hospitalized much more frequently than children in the general population. Hospitalization occurs primarily because of externalizing behaviors and is associated with behavioral disturbance, impaired emotion regulation, and psychiatric comorbidity. Additionally, a lack of practitioner and/or administrator training and experience with this population poses risks for denial of care by third-party payers or treatment facilities, inadequate treatment, extended lengths of stay, and poor outcomes. Evidence and best practices for the inpatient psychiatric care of this population are presented. Specialized treatment programs universally rely on multidisciplinary approaches, including behaviorally informed interventions.

To advance clinical care and research in children with intellectual disability and autism there is a growing need for efficient means to measure behavioral severity and response to treatment. The objective of this study was to assess the feasibility of telephone administration of the Aberrant Behavior Checklist–Irritability Subscale (ABC-I). The ABC-I was administered by telephone to the primary caregivers of 39 subjects with intellectual disability and/or autism. The same primary caregiver of each subject was also mailed a written copy of the ABC-I with a self-addressed, stamped envelope. Scores obtained by telephone and written administration were highly correlated ( r = 0.827, p < 0.001). Telephone administration of the ABC-I may be a feasible and efficient means of determining response to treatment in children with intellectual disability and/or autism, though these pilot findings need to be replicated in a larger sample.

Objective Autism spectrum disorder (ASD) is associated with amplified emotional responses and poor emotional control, but little is known about the underlying mechanisms. This article provides a conceptual and methodologic framework for understanding compromised emotion regulation (ER) in ASD. Method After defining ER and related constructs, methods to study ER were reviewed with special consideration on how to apply these approaches to ASD. Against the backdrop of cognitive characteristics in ASD and existing ER theories, available research was examined to identify likely contributors to emotional dysregulation in ASD. Results Little is currently known about ER in youth with ASD. Some mechanisms that contribute to poor ER in ASD may be shared with other clinical populations (e.g., physiologic arousal, degree of negative and positive affect, alterations in the amygdala and prefrontal cortex), whereas other mechanisms may be more unique to ASD (e.g., differences in information processing/perception, cognitive factors [e.g., rigidity], less goal-directed behavior and more disorganized emotion in ASD). Conclusions Although assignment of concomitant psychiatric diagnoses is warranted in some cases, poor ER may be inherent in ASD and may provide a more parsimonious conceptualization for the many associated socioemotional and behavioral problems in this population. Further study of ER in youth with ASD may identify meaningful subgroups of patients and lead to more effective individualized treatments.

A cross sectional survey was performed to obtain the characteristics of specialized inpatient psychiatry units exclusively serving children with autism and other developmental disorders in the United States. Identified units were surveyed on basic demographic characteristics, clinical challenges and therapeutic modalities. Average length of stay was 42.3 days, children with autism spectrum disorders constituted the majority of the inpatient population (62.5-87.5%), and obtaining adequate post-discharge services was identified as the greatest challenge. Health policy implications and future research directions are suggested.

This Parameter addresses the key concepts that differentiate the forensic evaluation of children and adolescents from a clinical assessment. There are ethical issues unique to the forensic evaluation, because the forensic evaluator's duty is to the person, court, or agency requesting the evaluation, rather than to the patient. The forensic evaluator clarifies the legal questions to be answered and structures the evaluation to address those issues. The forensic examination may include a review of collateral information, interviews and other assessments of the child or adolescent, and interviews with other relevant informants. The principles in this Parameter suggest the general approach to the forensic evaluation of children and adolescents and are relevant to delinquency, child custody, child maltreatment, personal injury, and other court-ordered and noncourt-ordered evaluations.

This paper presents a systematic review, rating and synthesis of the empirical evidence for the use of psychotropic medications in children with autism spectrum disorders (ASD). Thirty-three randomized controlled trials (RCTs) published in peer-reviewed journals qualified for inclusion and were coded and analyzed using a systematic evaluative method specific to autism research (Reichow et al. in Journal of Autism and Developmental Disorders 38:1311-1319, 2008). Results are presented by agent and primary target symptom(s). The findings suggest established evidence for relatively few agents, with preliminary and promising evidence for a larger group. Challenges and opportunities in the developing field of ASD psychopharmacology are identified, and recommendations for further research are provided.

Effective treatment of celiac disease is an unmet medical need. A glutenase that destroys immunogenic gluten peptides may be clinically valuable. Twenty patients with celiac disease were randomly assigned to ingest a large gluten meal (16 g daily for 3 days) pre-treated with ALV003, a mixture of highly specific glutenases (n=10), or pre-treated with placebo (n=10). Peripheral blood T-cell IFN-gamma ELISpot responses to gliadin and an immunogenic 33mer and symptoms were assessed. While baseline IFN-gamma ELISpot responses to gliadin and the 33mer were negative in all patients, a significant ELISpot response to gliadin or the 33mer was observed in 6 of 10 patients consuming placebo-treated gluten and 0 of 10 consuming ALV003 pre-treated gluten (p=0.011). Symptoms typically associated with gluten ingestion occurred in both groups and were not significantly reduced by ALV003 pre-treatment. ALV003 pre-treatment can abolish immune responses induced by gluten in patients with celiac disease.

Meningiomas are common intracranial tumors that occur in extra-axial locations, most often over the cerebral convexities or along the skull-base. Although often histologically benign these tumors frequently present challenging clinical problems. Primary clinical management of patients with symptomatic tumors is surgical resection. Radiation treatment may arrest growth or delay recurrence of these tumors, however, meningioma cells are generally resistant to apoptosis after treatment with radiation. Tumor cells are known to alter their expression of proteins that interact in the ECM to provide signals important in tumor progression. One such protein, fibronectin, is expressed in elevated levels in the ECM in a number of tumors including meningiomas. We recently reported that levels of both extracellular fibronectin and tissue transglutaminase 2 (TG2) were increased in glioblastomas. We examined the expression of fibronectin and its association TG2 in meningiomas. Both fibronectin and TG2 were strongly expressed in all meningiomas studied. TG2 activity was markedly elevated in meningiomas, and TG2 was found to co-localize with fibronectin. Treatment of meningiomas with the small molecule TG2 inhibitor, KCC009, inhibited the binding of TG2 to fibronectin and blocked disposition of linear strands of fibronectin in the ECM. KCC009 treatment promoted apoptosis and enhanced radiation sensitivity both in cultured IOMM-Lee meningioma cells and in meningioma tumor explants. These findings support a potential protective role for TG2 in meningiomas.

Complete, life-long exclusion of gluten containing foods from the diet is the only available treatment for celiac sprue, a widespread immune disease of the small intestine. Investigations into the molecular pathogenesis of celiac sprue have identified the major histocompatibility complex protein HLA-DQ2 and the multi-functional enzyme transglutaminase 2 as potential pharmacological targets. Based upon the crystal structure of HLA-DQ2, we rationally designed an aldehyde-functionalized, gluten peptide analogue as a tight-binding HLA-DQ2 ligand. Analogous aldehyde-bearing gluten peptide analogues were designed as high-affinity, reversible inhibitors of transglutaminase 2. By varying the side-chain length of the aldehyde-functionalized amino acid, we found that the optimal transglutaminase 2 inhibitor was 5 methylene units in length, 2 carbon atoms longer than its natural glutamine substrate.

Psychiatric hospitalization of children with Autism Spectrum Disorder (ASD) and/or Intellectual Disability (ID), is both common and challenging. Children with ASD are six times more likely to be psychiatrically hospitalized than children without ASD.1 Due to the limited number of specialized psychiatric units for children and adolescents with ASD or ID in the United States, most admissions are to general child and adolescent psychiatric units. Staff may have limited experience with this population, and the treatment approach and therapeutic milieu may not be well adapted to children with ASD or ID. General units typically use verbal interventions (e.g., individual, family and group therapies), programming with high social demands, and general reinforcements (e.g., level systems). These interventions can be less effective in children with ASD or ID, who have impairments in social communication and cognitive abilities and may have rigid routines and preferences. Specialized units have shown improvement in the behavioral functioning of children with ASD or ID two months after discharge2, as well as decreased readmissions,3 in two uncontrolled studies with an average length of stay of 26–42 days. To identify best practices for psychiatric inpatient care of children with ASD or ID a panel of expert clinicians (child and adolescent psychiatrists, psychologists and pediatricians) from six United States specialized units convened. Due to the limited amount of research in this area, evidence-based recommendations were not feasible, and the panel undertook a consensus process based on existing literature and expert opinion gathered from a survey, a semi-structured telephone interview with the participants and regular conference calls. Although inpatient facilities can have significant resource constraints, the following consensus statements encompass trends in practices currently utilized by specialized units, and offer a vision of how to best serve this population. As such, the panel sought to strike a balance between identifying best practices and providing recommendations that may be attainable on general units.

Transglutaminase 2 (TG2, a.k.a. tissue transglutaminase) belongs to a family of transglutaminase enzymes that stabilize proteins by affecting covalent crosslinking via formation of amide bonds. Cell surface TG2 is directly involved as an adhesive receptor in cell-extracellular matrix (ECM) interactions. Here, we show that TG2 activity is elevated in glioblastomas compared with non-neoplastic brain. Immunofluorescent studies showed increased staining of fibronectin colocalized with TG2 in the ECM in glioblastomas. In addition, small clusters of invading human glioblastoma cells present in non-neoplastic brain parenchyma secrete high levels of TG2 and fibronectin that distinguish them from normal brain stroma. Downregulation of TG2 in U87MG glioblastoma cells with RNAi demonstrated decreased assembly of fibronectin in the ECM. Treatment with KCC009 blocked the remodeling of fibronectin in the ECM in glioblastomas in both in vitro and in vivo studies. KCC009 treatment in mice harboring orthotopic glioblastomas (DBT-FG) sensitized the tumors to N,N'-bis(2-chloroethyl)-N-nitrosourea chemotherapy, as measured by reduced bioluminescence, increased apoptosis and prolonged survival. The ability of KCC009 to interfere with the permissive remodeling of fibronectin in the ECM in glioblastomas suggests a novel target to enhance sensitivity to chemotherapy directed not only at the tumor mass, but also invading glioblastoma cells.

Human transglutaminase 2 (TG2) is believed to play an important role in the pathogenesis of various human disorders including celiac sprue, certain neurological diseases, as well as some types of cancer. Selective inhibition of TG2 should therefore enable further investigation of its role in physiology and disease, and may lead to effective clinical treatment. Recently we showed that certain 3-halo-4-,5-dihydroisoxazole containing compounds are selective inhibitors of human TG2 with promising pharmacological activities. Here we present definitive evidence that this class of compounds targets the active site of human TG2. Structure-activity relationship studies have provided insights into the structural prerequisites for selectivity, and have led to the discovery of an inhibitor with ca. fifty-fold higher activity than a prototypical dihydroisoxazole inhibitor with good in vivo activity. A method for preparing enantiomerically enriched analogues was also developed. Our studies show that the 5-(S-) dihydroisoxazole is a markedly better inhibitor of human TG2 than its 5-(R-) stereoisomer.

SummaryCeliac sprue (also known as celiac disease) is an inheritable, gluten-induced enteropathy of the upper small intestine with an estimated prevalence of 0.5%–1% in most parts of the world. The ubiquitous nature of food gluten, coupled with inadequate labeling regulations in most countries, constantly poses a threat of disease exacerbation and relapse for patients. Here, we demonstrate that a two-enzyme cocktail comprised of a glutamine-specific cysteine protease (EP-B2) that functions under gastric conditions and a PEP, which acts in concert with pancreatic proteases under duodenal conditions, is a particularly potent candidate for celiac sprue therapy. At a gluten:EP-B2:PEP weight ratio of 75:3:1, grocery store gluten is fully detoxified within 10 min of simulated duodenal conditions, as judged by chromatographic analysis, biopsy-derived T cell proliferation assays, and a commercial antigluten antibody test.

To quantify awareness of altitude sickness in a sample of trekkers in Nepal and identify strategies for increasing knowledge in that population.Sixty-five high-altitude trekkers were surveyed. Demographic data were gathered. Respondents were asked about their experience in high-altitude environments, and they answered clinical-vignette questions designed to test their abilities to recognize and identify treatments for common symptoms of altitude sickness. An altitude-awareness score was generated by tabulating correct answers to questions. Scores were correlated with demographic data.Respondents who scored highest (n = 8) had significantly more experience in high-altitude environments, averaging 5 to 10 years (P.05), and achieved higher average altitudes on their treks of 5171 m (P.05) than did low scorers. Respondents with low scores (n = 17) trekked to an average altitude of 4138 m. Seventy-three percent wanted to learn more about altitude sickness, 30% said they would prefer to learn from the Internet, and 27% said they would ask a doctor.This study suggests that a large population of at-risk high-altitude travelers may be relatively naive to the dangers of altitude sickness. Overall, respondents were interested in learning more about altitude sickness. Physicians and the Internet are the most attractive sources of information for this population.

Children with autism spectrum and related disorders and intellectual disability are not protected from the experience of psychiatric illnesses. Many factors can contribute to exacerbation of existing behavioral symptoms or to the emergence of new psychiatric problems. The psychiatric assessment must thus take into account a range of possible etiologic or contributory factors. The approach outlined in this article highlights the value of assessing 4 broad domains, including diagnostic (genetic) factors, medical considerations, developmental influences, and environmental factors. Examples of how the consideration of each of these domains may inform the diagnostic formulation are highlighted.

Children with autism spectrum disorder present with a high rate of maladaptive behaviors and comorbid psychopathology. Psychopharmacologic treatment is frequently used in this population and is particularly associated with comorbid mental illness and increasing age. Successful treatment of presenting problems, however, is most likely achieved through consideration of multiple potential etiologic factors, only some of which may respond to pharmacologic intervention. The evidence base for targeting specific symptoms and disorders with psychopharmacology in children with autism spectrum disorder is expanding rapidly and offers guidance for practicing clinicians. The current evidence for symptom-specific treatment is presented.

Objectives We report a positive response to electroconvulsive therapy in a severely functionally impaired adolescent with autistic disorder and classic bipolar I disorder, including an episodic pattern of decreased need for sleep, hypersexuality, expansive and agitated affect, aggression, self-injury, and property destruction. Methods After ineffective trials of mood stabilizers and antipsychotics as well as inability to sustain a positive response to lithium due to medication noncompliance, a course of acute and maintenance electroconvulsive therapy was attempted. Results A marked and sustained improvement across all symptom categories, as measured by directly observed frequency counts of target behaviors in an inpatient setting, was obtained. Conclusions Electroconvulsive therapy should be considered a potentially useful intervention in cases of children with autistic disorder and a severe comorbid affective disorder.

Celiac disease is the most common hereditary autoimmune disease in humans. The only treatment option for non-refractory celiac disease patients is adherence to a strict life-long gluten-free diet, which often fails to normalize small bowel histology. ALV003 is a mixture of two proteases that degrades gluten and is in clinical development as an oral therapy for patients with celiac disease. The safety, tolerability, and activity of ALV003 were assessed in two phase 1 clinical trials. In study 1 (N = 28) the study drug was administered in the fasted state; in study 2 (N = 53) the study drug was administered together with a gluten-containing meal. Both studies were single-dose, single-blind, placebo-controlled, cross-over trials. ALV003 was dosed at escalating dose levels by cohort (100, 300, 900, and 1,800 mg) and gastric samples were aspirated using a nasogastric tube. Adverse events, serum drug levels, and anti-drug antibody titers were measured. Gastric samples were assessed for ALV003 enzymatic activity over time (gastric pharmacokinetics) and gluten degradation (gastric pharmacodynamics). All doses were well tolerated, and no serious adverse events or allergic reactions were observed. Gastric aspirates collected 30 min following a meal showed that 100 and 300 mg ALV003 degraded 75 ± 10% (N = 8) and 88 ± 5% (N = 8), respectively, of one gram of wheat bread gluten. ALV003 is an orally active protease that appears to be stable in the fed stomach and degrades dietary gluten in this compartment. Single doses of oral ALV003 were not associated with serious adverse reactions.

Neurodevelopmental disorders with identified genetic etiologies present a unique opportunity to study gene-brain-behavior connections in child psychiatry. Parsing complex human behavior into dissociable components is facilitated by examining a relatively homogenous genetic population. As children with developmental delay carry a greater burden of mental illness than the general population, familiarity with the most common genetic disorders will serve practitioners seeing a general child population. In this article, basic genetic testing and 11 of the most common genetic disorders are reviewed, including the evidence base for treatment. Based on their training in child development, family systems, and multimodal treatment, child psychiatrists are well positioned to integrate cognitive, behavioral, social, psychiatric, and physical phenotypes, with a focus on functional impairment.

This Practice Parameter reviews the evidence from research and clinical experience and highlights significant advances in the assessment and treatment of posttraumatic stress disorder since the previous Parameter was published in 1998. It highlights the importance of early identification of posttraumatic stress disorder, the importance of gathering information from parents and children, and the assessment and treatment of comorbid disorders. It presents evidence to support trauma-focused psychotherapy, medications, and a combination of interventions in a multimodal approach.