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Intellectual disability (intellectual developmental disorder) (ID/IDD) is both a psychiatric disorder and a risk factor for co-occurring psychiatric disorders in children and adolescents. DSM-5 introduced important changes in the conceptualization and diagnosis of ID/IDD, and current research studies clarify assessment and treatment of co-occurring psychiatric disorders in this population. Optimal assessment and treatment of psychiatric illness in children and adolescents with ID/IDD includes modifications in diagnostic and treatment techniques, appreciation of variations in the clinical presentation of psychiatric disorders, an understanding of the spectrum of etiologies of behavioral disturbance, and knowledge of psychosocial and medical interventions.

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.

Takeda G protein-coupled receptor 5 (TGR5) agonists induce systemic release of glucagon-like peptides (GLPs) from intestinal L cells, a potentially therapeutic action against metabolic diseases such as nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and Type 2 diabetes. Historically, TGR5 agonist use has been hindered by side effects, including inhibition of gallbladder emptying. Here, we characterize RDX8940, a novel, orally administered TGR5 agonist designed to have minimal systemic effects and investigate its activity in mice fed a Western diet, a model of NAFLD and mild insulin resistance. Agonist activity, binding selectivity, toxicity, solubility, and permeability of RDX8940 were characterized in standard in vitro models. RDX8940 pharmacokinetics and effects on GLP secretion, insulin sensitivity, and liver steatosis were assessed in C57BL/6 mice fed normal or Western diet chow and given single or repeated doses of RDX8940 or vehicle, with or without dipeptidyl peptidase-4 (DPP4) inhibitors. Gallbladder effects were assessed in CD-1 mice fed normal chow and given RDX8940 or a systemic TGR5 agonist or vehicle. Our results showed that RDX8940 is minimally systemic, potent, and selective, and induces incretin (GLP-1, GLP-2, and peptide YY) secretion. RDX8940-induced increases in plasma active GLP-1 (aGLP-1) levels were enhanced by repeated dosing and by coadministration of DPP4 inhibitors. RDX8940 increased hepatic exposure to aGLP-1 without requiring coadministration of a DPP4 inhibitor. In mice fed a Western diet, RDX8940 improved liver steatosis and insulin sensitivity. Unlike systemic TGR5 agonists, RDX8940 did not inhibit gallbladder emptying. These results indicate that RDX8940 may have therapeutic potential in patients with NAFLD/NASH.NEW & NOTEWORTHY Takeda G protein-coupled receptor 5 (TGR5) agonists have potential as a treatment for nonalcoholic steatohepatitis and nonalcoholic fatty liver disease (NAFLD) but have until now been associated with undesirable side effects associated with systemic TGR5 agonism, including blockade of gallbladder emptying. We demonstrate that RDX8940, a potent, selective, minimally systemic oral TGR5 agonist, improves liver steatosis and insulin sensitivity in a mouse model of NAFLD and does not inhibit gallbladder emptying in mice.

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.

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.

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.

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.

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.

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 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.

Background and Purpose— Emerging data suggest that the molecular cell death pathways triggered by ischemic insults differ in the male and female brain. Cell death in males is initiated by poly(ADP-ribose) polymerase-1 (PARP-1) activation; however, manipulation of this pathway paradoxically increases ischemic damage in females. In contrast, females are exquisitely sensitive to caspase-mediated cell death. The effect of caspase inhibition in PARP-1 knockout mice was evaluated to determine if the detrimental effects of PARP deletion in females were secondary to increased caspase activation. Methods— -Focal stroke was induced by transient or permanent middle cerebral artery occlusion (MCAO) in wild-type (WT) and PARP-1 −/− mice of both sexes. The pan-caspase inhibitor, quinoline-Val-Asp(Ome)-CH2-O-phenoxy (Q-VD-OPh), was administered 90 minutes after middle cerebral artery occlusion. Infarct size and neurological sores were assessed. Separate cohorts were used for protein analysis for PAR, Apoptosis inducing factor (AIF), caspase-9, and caspase-3. Results— WT mice of both sexes had increased nuclear AIF after stroke compared to PARP-1 −/− mice. PARP-1 −/− females had higher mitochondrial cytochrome C and activated caspase-9 and -3 levels than WT female mice. PARP-1 −/− females also had an increase in stroke-induced cytosolic cytochrome C release compared with WT females, which was not seen in males. Q-VD-OPh decreased caspase-9 in both males and females but only led to reduction of infarct in females. PARP-1 −/− males had smaller infarcts, whereas PARP-1 −/− females had larger strokes compared with WT. Q-VD-OPh significantly decreased infarct in both WT and PARP-1 −/− females in both transient and permanent MCAO models, but had no effect in males. Conclusions— Deletion of PARP-1 reduces infarct in males but exacerbates injury in females. PARP-1 −/− females have enhanced caspase activation. The detrimental effects of PARP loss in females can be reversed with caspase inhibition.

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.

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.

Background & Aims: We sought to determine whether prolyl endopeptidase (PEP) treatment of food gluten would obviate the intestinal dysfunction produced by small amounts of dietary gluten supplement in patients with celiac sprue. Methods: Twenty asymptomatic patients with histologically proven celiac sprue completed a randomized, double-blind, cross-over study involving two 14-day stages. Each patient consumed a low dose of a gluten supplement daily (5 g; equivalent to 1 slice of bread) in 1 stage and gluten pretreated with PEP in the other stage. Patients completed a daily symptom questionnaire and a D-xylose urine excretion and a 72-hour quantitative fecal fat were monitored before and after each stage. Results: Despite clinical remission at baseline, 40% of patients had at least 1 abnormal celiac antibody, 20% had an abnormal urine xylose, and 63% had an abnormal fecal fat test result. There was no difference in symptoms as a function of the type of gluten consumed. In response to gluten not treated with PEP, an appreciable proportion of patients developed malabsorption of fat (7 of 17, 41%) or xylose (8 of 14, 57%). When the gluten was pretreated with PEP, fat malabsorption was avoided in 5 of 7 and xylose malabsorption in 4 of 8 of these same patients. Conclusions: A significant proportion of asymptomatic patients with celiac sprue have abnormal celiac antibodies and fat or carbohydrate malabsorption. Pretreatment of gluten with PEP avoided the development of fat or carbohydrate malabsorption in the majority of those patients who developed fat or carbohydrate malabsorption after a 2-week gluten challenge.

In the regulated environment, valuation of power plants was simpler. Investor-owned utilities were able to pass costs of generation projects on to end users. Today, at least two power plant valuation methodologies exist: discounted cash flow (DCF) analyses and option approaches. While the approaches or modeling techniques are rather straightforward, the inputs or assumptions put into the model are not. Valuation in the current, quasi-deregulated market depends on numerous factors between the wellhead and the wall socket including fuel prices; environmental compliance costs; the changing structure of the generation, transmission, and distribution sectors; the role of energy marketers; the direction of electricity deregulation and national energy policy; and the plant owner9s business strategy (stand-alone or portfolio of plants; baseload, mid-merit, or peaker; etc.).

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.

Individuals severely affected by autism spectrum disorder (ASD), including those with intellectual disability, expressive language impairment, and/or self-injurious behavior (SIB), are underrepresented in the ASD literature and extant collections of phenotypic and biological data. An understanding of ASD’s etiology and subtypes can only be as complete as the studied samples are representative. The Autism Inpatient Collection (AIC) is a multi-site study enrolling children and adolescents with ASD aged 4–20 years admitted to six specialized inpatient psychiatry units. Enrollment began March, 2014, and continues at a rate of over 400 children annually. Measures characterizing adaptive and cognitive functioning, communication, externalizing behaviors, emotion regulation, psychiatric co-morbidity, self-injurious behavior, parent stress, and parent self-efficacy are collected. ASD diagnosis is confirmed by the Autism Diagnostic Observation Schedule – 2 (ADOS-2) and extensive inpatient observation. Biological samples from probands and their biological parents are banked and processed for DNA extraction and creation of lymphoblastoid cell lines. Sixty-one percent of eligible subjects were enrolled. The first 147 subjects were an average of 12.6 years old (SD 3.42, range 4–20); 26.5 % female; 74.8 % Caucasian, and 81.6 % non-Hispanic/non-Latino. Mean non-verbal intelligence quotient IQ = 70.9 (SD 29.16, range 30–137) and mean adaptive behavior composite score = 55.6 (SD 12.9, range 27–96). A majority of subjects (52.4 %) were non- or minimally verbal. The average Aberrant Behavior Checklist - Irritability Subscale score was 28.6, well above the typical threshold for clinically concerning externalizing behaviors, and 26.5 % of the sample engaged in SIB. Females had more frequent and severe SIB than males. Preliminary data indicate that the AIC has a rich representation of the portion of the autism spectrum that is understudied and underrepresented in extant data collections. More than half of the sample is non- or minimally verbal, over 40 % have intellectual disability, and over one quarter exhibit SIB. The AIC is a substantial new resource for study of the full autism spectrum, which will augment existing data on higher-functioning cohorts and facilitate the identification of genetic subtypes and novel treatment targets. The AIC investigators welcome collaborations with other investigators, and access to the AIC phenotypic data and biosamples may be requested through the Simons Foundation ( www.sfari.org ).