Genetic and epigenetic signatures associated with plasma oxytocin levels in children and adolescents with autism spectrum disorder.

Oxytocin (OT), the brain's most abundant neuropeptide, plays an important role in social salience and motivation. Clinical trials of the efficacy of OT in autism spectrum disorder (ASD) have reported mixed results due in part to ASD's complex etiology. We investigated whether genetic and epigenetic variation contribute to variable endogenous OT levels that modulate sensitivity to OT therapy. To carry out this analysis, we integrated genome-wide profiles of DNA-methylation, transcriptional activity, and genetic variation with plasma OT levels in 290 participants with ASD enrolled in a randomized controlled trial of OT. Our analysis identified genetic variants with novel association with plasma OT, several of which reside in known ASD risk genes. We also show subtle but statistically significant association of plasma OT levels with peripheral transcriptional activity and DNA-methylation profiles across several annotated gene sets. These findings broaden our understanding of the effects of the peripheral oxytocin system and provide novel genetic candidates for future studies to decode the complex etiology of ASD and its interaction with OT signaling and OT-based interventions. LAY SUMMARY: Oxytocin (OT) is an abundant chemical produced by neurons that plays an important role in social interaction and motivation. We investigated whether genetic and epigenetic factors contribute to variable OT levels in the blood. To this, we integrated genetic, gene expression, and non-DNA regulated (epigenetic) signatures with blood OT levels in 290 participants with autism enrolled in an OT clinical trial. We identified genetic association with plasma OT, several of which reside in known autism risk genes. We also show statistically significant association of plasma OT levels with gene expression and epigenetic across several gene pathways. These findings broaden our understanding of the factors that influence OT levels in the blood for future studies to decode the complex presentation of autism and its interaction with OT and OT-based treatment.

Intranasal Oxytocin in Children and Adolescents with Autism Spectrum Disorder.

BACKGROUND: Experimental studies and small clinical trials have suggested that treatment with intranasal oxytocin may reduce social impairment in persons with autism spectrum disorder. Oxytocin has been administered in clinical practice to many children with autism spectrum disorder. METHODS: We conducted a 24-week, placebo-controlled phase 2 trial of intranasal oxytocin therapy in children and adolescents 3 to 17 years of age with autism spectrum disorder. Participants were randomly assigned in a 1:1 ratio, with stratification according to age and verbal fluency, to receive oxytocin or placebo, administered intranasally, with a total target dose of 48 international units daily. The primary outcome was the least-squares mean change from baseline on the Aberrant Behavior Checklist modified Social Withdrawal subscale (ABC-mSW), which includes 13 items (scores range from 0 to 39, with higher scores indicating less social interaction). Secondary outcomes included two additional measures of social function and an abbreviated measure of IQ. RESULTS: Of the 355 children and adolescents who underwent screening, 290 were enrolled. A total of 146 participants were assigned to the oxytocin group and 144 to the placebo group; 139 and 138 participants, respectively, completed both the baseline and at least one postbaseline ABC-mSW assessments and were included in the modified intention-to-treat analyses. The least-squares mean change from baseline in the ABC-mSW score (primary outcome) was -3.7 in the oxytocin group and -3.5 in the placebo group (least-squares mean difference, -0.2; 95% confidence interval, -1.5 to 1.0; P = 0.61). Secondary outcomes generally did not differ between the trial groups. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONS: This placebo-controlled trial of intranasal oxytocin therapy in children and adolescents with autism spectrum disorder showed no significant between-group differences in the least-squares mean change from baseline on measures of social or cognitive functioning over a period of 24 weeks. (Funded by the National Institute of Child Health and Human Development; SOARS-B ClinicalTrials.gov number, NCT01944046.).

Use of long-term antibiotic treatment in COPD patients in the UK: a retrospective cohort study.

BACKGROUND: Exacerbations of chronic obstructive pulmonary disease (COPD) are a burden to patients and impose a major cost on health services. Long-term antibiotic therapy may prevent exacerbations, but at present it is not recommended by management guidelines. AIMS: To identify the type and prevalence of long-term oral antibiotic treatments prescribed to patients with COPD and to assess the patient characteristics associated with long-term antibiotic use. METHODS: A retrospective cohort using all eligible practices in The Health Improvement Network (THIN) UK primary care database between 2000 and 2009 was studied. We identified patients with COPD and then those who received a course of long-term antibiotics. Long-term courses were defined as >6 months in duration with <50% concomitant oral corticosteroid treatment. RESULTS: We identified 92,576 patients with COPD, but only 567 patients (0.61%) who received 998 long-term antibiotic courses. Mean follow-up time was 3 years and 10 months. The median long-term antibiotic course length was 280 days (interquartile range 224, 394) and 58 patients (0.06%) were continuously prescribed antibiotics for >2 years. The most commonly used long-term antibiotics were oxytetracycline, doxycycline, and penicillin. Azithromycin, erythromycin, and clarithromycin were less frequently used. There was little evidence of the use of rotating courses of antibiotics. Men, people aged 50-79 years, non-smokers, and patients with poorer lung function were more likely to receive long-term antibiotic treatment. CONCLUSIONS: Relatively few COPD patients are currently prescribed long-term antibiotics. Further clinical trials are required to determine the efficacy of this therapy. If beneficial, the use of such treatments should be incorporated into clinical guidelines.