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Itch (pruritis) and pain represent two distinct sensory modalities; yet both have evolved to alert us to potentially harmful external stimuli. Compared with pain, our understanding of itch is still nascent. Here, we report a new clinical case of debilitating itch and altered pain perception resulting from the heterozygous de novo p.L811P gain-of-function mutation in NaV1.9, a voltage-gated sodium (NaV) channel subtype that relays sensory information from the periphery to the spine. To investigate the role of NaV1.9 in itch, we developed a mouse line in which the channel is N-terminally tagged with a fluorescent protein, thereby enabling the reliable identification and biophysical characterization of NaV1.9-expressing neurons. We also assessed NaV1.9 involvement in itch by using a newly created NaV1.9-/- and NaV1.9L799P/WT mouse model. We found that NaV1.9 is expressed in a subset of nonmyelinated, nonpeptidergic small-diameter dorsal root ganglia (DRGs). In WT DRGs, but not those of NaV1.9-/- mice, pruritogens altered action potential parameters and NaV channel gating properties. Additionally, NaV1.9-/- mice exhibited a strong reduction in acute scratching behavior in response to pruritogens, whereas NaV1.9L799P/WT mice displayed increased spontaneous scratching. Altogether, our data suggest an important contribution of NaV1.9 to itch signaling.

We explored patterns of concomitant psychiatric disorders in a large sample of treatment-seeking children and adolescents with autism spectrum disorder (ASD). Participants were 658 children with ASD (age 3–17 years; mean = 7.2 years) in one of six federally-funded multisite randomized clinical trials (RCT) between 1999 and 2014. All children were referred for hyperactivity or irritability. Study designs varied, but all used the Child and Adolescent Symptom Inventory or Early Childhood Inventory to assess Attention Deficit Hyperactivity Disorder (ADHD), Oppositional-Defiant Disorder (ODD), Conduct Disorder (CD), Anxiety Disorders, and Mood Disorders. In addition, several measures in common were used to assess demographic and clinical characteristics. Of the 658 children, 73% were Caucasian and 59% had an IQ >70. The rates of concomitant disorders across studies were: ADHD 81%, ODD 46%, CD 12%, any anxiety disorder 42%, and any mood disorder 8%. Two or more psychiatric disorders were identified in 66% of the sample. Of those who met criteria for ADHD, 50% also met criteria for ODD and 46% for any anxiety disorder. Associations between types of concomitant disorders and a number of demographic and clinical characteristics are presented. In this well-characterized sample of treatment-seeking children with ASD, rates of concomitant psychiatric disorders were high and the presence of two or more co-occurring disorders was common. Findings highlight the importance of improving diagnostic practice in ASD and understanding possible mechanisms of comorbidity. •We observed a high frequency of multiple concomitant DSM-defined disorders.•50% of children who met criteria for ADHD also met criteria for ODD.•46% of children who met criteria for ADHD also met criteria for an anxiety disorder.•Findings highlight the importance of improving diagnostic practices in ASD.

PurposeThis study investigates receptive and expressive language abilities in individuals with Smith-Lemli-Opitz syndrome (SLOS) and examines how these are associated with intellectual functioning, sex, autism spectrum disorder (ASD) diagnosis, and biochemical markers of cholesterol metabolism.MethodsParticipants (ages 4–18) with mild to classic SLOS were enrolled from a double-blind, placebo-controlled simvastatin trial. Receptive and expressive language scores were assessed using the Peabody Picture Vocabulary Test, Third Edition (PPVT-3), the Expressive One-Word Picture Vocabulary Test, 2000 Edition (EOWPVT-2000), and the MacArthur Communicative Developmental Inventories (MCDI). Intellectual ability and adaptive functioning were measured using the Stanford-Binet Intelligence Scales, Fifth Edition (SB-5) and Vineland Adaptive Behavior Scales, Third Edition (VABS-3). The SLOS Severity Scale (SSS) quantified disease severity. Associations with plasma and CSF sterol biomarkers (cholesterol, 7-dehydrocholesterol [7-DHC], 8-dehydrocholesterol [8-DHC]) were examined using nonparametric statistics with correction for multiple comparisons.ResultsTwenty-one participants (mean age 7.85 years) had complete data; 71.4% had a diagnosis of ASD. Receptive and expressive language scores correlated with IQ and adaptive functioning. Receptive vocabulary scores were significantly negatively associated with disease severity, plasma 7-DHC and 8-DHC, and CSF 7-DHC. Expressive vocabulary scores also declined with increasing disease severity, but associations with sterol biomarkers were not significant. ASD was linked to higher rates of non-scorable assessments, though did not fully explain floor effects. No sex differences were found.ConclusionsLanguage impairment in SLOS reflects contributions from disease severity, disrupted cholesterol metabolism, and ASD. Receptive language showed stronger biomarker associations, while expressive impairments were more pervasive. Integrating clinical, biochemical, and caregiver-report tools is critical for comprehensive assessment of individuals with SLOS.

Coaching has been identified as a best practice for early intervention (EI) services provided through the Individuals with Disabilities Education Act (IDEA) Part C. The current study describes the establishment and progress of a research-relationship partnership to deliver coaching via telehealth during the COVID-19 pandemic. Community-based EI providers implemented 9-weeks of telehealth coaching and evaluated the extent to which child and caregiver outcomes differed between families that had previously received in-person services versus telehealth only. Four EI providers completed the intervention with n=17 families of children aged 6-34 months during the pandemic (April-August 2020). We used the Canadian Occupational Performance Measure (COPM) and Goal Attainment Scaling (GAS) to collect outcomes on caregiver identified goals; we used Wilcoxon Signed Rank Tests to examine pre- to post-intervention data. Results showed significant improvements in parent satisfaction, child performance, and goal attainment (all p<.01). Findings suggest that telehealth coaching procedures implemented by community-based EI providers resulted in improvements in caregiver identified goals for young children.

An improved understanding of sterol and lipid abnormalities in individuals with autism spectrum disorder (ASD) could lead to personalized treatment approaches. Toward this end, in blood, we identified reduced synthesis of cholesterol in families with ≥2 children with ASD participating with the Autism Genetic Resource Exchange (AGRE), as well as reduced amounts of high-density lipoprotein cholesterol (HDL), apolipoprotein A1 (ApoA1) and apolipoprotein B (ApoB), with 19.9% of the subjects presenting with apolipoprotein patterns similar to hypolipidemic clinical syndromes and 30% with either or both ApoA1 and ApoB less than the fifth centile. Subjects with levels less than the fifth centile of HDL or ApoA1 or ApoA1 + ApoB had lower adaptive functioning than other individuals with ASD, and hypocholesterolemic subjects had apolipoprotein deficits significantly divergent from either typically developing individuals participating in National Institutes of Health or the National Health and Nutrition Examination Survey III.

There is growing interest in measuring social disability as a core element of autism spectrum disorders in medication trials. We conducted a secondary analysis on the Aberrant Behavior Checklist Social Withdrawal subscale using data from two federally-funded, multi-site, randomized trials with risperidone. Study 1 included 52 subjects assigned to placebo and 49 subjects to risperidone under double-blind conditions. Study 2 included 49 subjects assigned to risperidone only and 75 subjects assigned to risperidone plus parent training. After 8 weeks of treatment, all active treatments were superior to placebo (effect sizes ranging from 0.42 to 0.65). The findings suggest that the Social Withdrawal subscale may be a useful measure of social disability in acute treatment trials.

This study uses sheds to interrogate the gap between early modern London's built environment, as it appears in most secondary literature, and the much broader spectrum of structures present in the historical record. In doing so, it shows that attention to less durable aspects of the early modern built environment can help recalibrate our understanding of London's modernity at a crucial moment in the city's history.

This study explores the manifestation and measurement of anxiety symptoms in 415 children with ASDs on a 20-item, parent-rated, DSM-IV referenced anxiety scale. In both high and low-functioning children (IQ above vs. below 70), commonly endorsed items assessed restlessness, tension and sleep difficulties. Items requiring verbal expression of worry by the child were rarely endorsed. Higher anxiety was associated with functional language, IQ above 70 and higher scores on several other behavioral measures. Four underlying factors emerged: Generalized Anxiety, Separation Anxiety, Social Anxiety and Over-arousal. Our findings extend our understanding of anxiety across IQ in ASD and provide guidance for improving anxiety outcome measurement.

Itch (pruritis) and pain represent two distinct sensory modalities; yet both have evolved to alert us to potentially harmful external stimuli. Compared with pain, our understanding of itch is still nascent. Here, we report a new clinical case of debilitating itch and altered pain perception resulting from the heterozygous de novo p.L811P gain-of-function mutation in [Na.sub.V]1.9, a voltage-gated sodium ([Na.sub.V]) channel subtype that relays sensory information from the periphery to the spine.

Smith-Lemli-Opitz syndrome (SLOS) is a multiple malformation/cognitive impairment syndrome characterized by the accumulation of 7-dehydrocholesterol, a precursor sterol of cholesterol. Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor that crosses the blood–brain barrier, has been proposed for the treatment of SLOS based on in vitro and in vivo studies suggesting that simvastatin increases the expression of hypomorphic DHCR7 alleles. Safety and efficacy of simvastatin therapy in 23 patients with mild to typical SLOS were evaluated in a randomized, double-blind, placebo-controlled trial. The crossover trial consisted of two 12-month treatment phases separated by a 2-month washout period. No safety issues were identified in this study. Plasma dehydrocholesterol concentrations decreased significantly: 8.9 ± 8.4% on placebo to 6.1 ± 5.5% on simvastatin (P < 0.005); we observed a trend toward decreased cerebrospinal fluid dehydrocholesterol concentrations. A significant improvement (P = 0.017, paired t-test) was observed on the irritability subscale of the Aberrant Behavior Checklist–C when subjects were taking simvastatin. This article reports what is, to our knowledge, the first randomized, placebo-controlled trial designed to test the safety and efficacy of simvastatin therapy in SLOS. Simvastatin seems to be relatively safe in patients with SLOS, improves the serum dehydrocholesterol–to–total sterol ratio, and significantly improves irritability symptoms in patients with mild to classic SLOS. Genet Med19 3, 297–305.