The role of psychiatric symptoms, sociodemographic factors, and baseline sleep variables on pediatric insomnia treatment outcomes in a clinically referred population.

STUDY OBJECTIVES: The current study aimed to examine clinically relevant psychiatric and sociodemographic predictors of insomnia treatment outcomes in pediatric patients clinically referred for insomnia. METHODS: Pediatric patients (N = 1428; ages 1.5 - 18 years), presenting for insomnia evaluation in a medical/sleep center-based behavioral sleep clinic were followed for treatment as clinically indicated. According to patient age, parent/patients completed validated measures of insomnia severity, psychiatric symptoms, and sociodemographic measures. Patients were also categorized by treatment outcome status (i.e., not recommended to follow-up after initial evaluation and treatment session, successful treatment completion, lost to follow-up after initial evaluation and treatment session, and early termination) according to the clinically indicated treatment recommended and dose of treatment received. RESULTS: Youth had elevated scores on psychiatric screening indexes with affective problems being highest for all age groups. Other co-morbid sleep disorders were present in nearly 25% of insomnia patients and use of sleep aids (melatonin; hypnotics) was commonplace. Baseline insomnia severity significantly predicted sleep treatment trajectories and post-treatment insomnia severity with large effects for all age groups. Other clinically relevant predictors of insomnia treatment outcomes included medication use and externalizing mental health concerns in younger patients and internalizing mental health concerns and chronological age in older patients. Lack of treatment follow-up and premature treatment termination was observed for patients with the worst insomnia symptoms at time of initial evaluation. CONCLUSIONS: Pediatric health providers delivering insomnia treatment should take a developmentally sensitive approach that is proactive with regards to managing treatment barriers that are likely influenced by severity of insomnia and co-morbid mental health concerns.

Advancing Patient-Centered Care: An International Survey of Adolescent Perspectives on Insomnia.

OBJECTIVE: The study objective was to inform patient-centered care for adolescent insomnia by describing adolescents' perspectives on insomnia. Specific constructs of interest included: 1) factors that contributed to insomnia development or maintenance, 2) impact of insomnia on day-to-day life, 3) recommended research priorities, and 4) overall experience living with insomnia. METHOD: A convenience sample of adolescents (ages 13-18 years) self-identifying with insomnia symptoms was recruited through social media. Respondents (n = 3,014) completed an online survey. Responses to an open-ended item assessing patient experience were coded using thematic analysis. RESULTS: Participants identified as 70.8% White non-Hispanic, 77.0% female, and lived in one of five English-speaking countries (United States, United Kingdom, Canada, Australia, or New Zealand). Most (87.5%) met DSM-V diagnostic criteria for insomnia. The most common contributory factors to insomnia endorsed were stress (72.1%) and depressed mood (63.6%), while common impact areas were mood (72.2%), focus (61.0%), and pain (49.7%). Patient-centered research priorities were identifying insomnia causes (66.4%) and early detection (66.1%). Common adolescent experiences included high distress levels, feelings of invalidation, and helplessness about their insomnia. CONCLUSIONS: Adolescents with insomnia offer a unique perspective that should inform patient-centered research and care. There is a need for heightened screening and awareness about insomnia as a condition that causes significant distress and impairment for adolescents. To provide validating care, providers should recognize the multifaceted causes of insomnia.

Factors affecting pediatric adherence to positive airway pressure: Patient- and caregiver-reported treatment barriers and sleep difficulties.

OBJECTIVE/BACKGROUND: Adherence to positive airway pressure (PAP) treatment among children and adolescents is often suboptimal. Little is understood about modifiable determinants of PAP adherence. We evaluated whether patient and caregiver-perceived treatment barriers (across behavioral, environmental, emotional, and physical domains), as well as insomnia severity, were associated with PAP adherence among youth with sleep disordered breathing (SDB). PATIENTS/METHODS: We conducted a retrospective review of 188 patients prescribed PAP, ages 2-19 years. At the clinical visit, PAP adherence was assessed via objective download/smartcard and patients and their caregivers completed validated standardized questionnaires on barriers to PAP adherence and sleep onset and maintenance difficulties. We tested predictors of PAP adherence using linear regression. RESULTS: On average, patients wore their PAP 2/3 of nights for 5.3 ± 3.4 h. Patients reported more barriers overall compared to caregivers, and specifically more behavioral and emotional barriers (e.g., over a third of patients reported they just want to forget about sleep apnea). After controlling for demographic/treatment characteristics, patient-reported barriers accounted for a significant proportion of the variance in percent nights used (51%) and average nightly use (42%). Greater difficulties with sleep maintenance predicted poorer PAP adherence (percent nights and nightly duration). CONCLUSIONS: Study findings suggest that assessment of both patient and caregiver-perceived barriers to PAP adherence, as well as evaluating for sleep maintenance concerns, may provide important treatment targets for promoting PAP adherence among youth. Results also support the potential benefit of a multi-disciplinary team-based approach to managing SDB and promoting PAP adherence.

Relationship of overweight and obesity to insomnia severity, sleep quality, and insomnia improvement in a clinically referred pediatric sample.

STUDY OBJECTIVES: Children with overweight or obesity are more likely to experience sleep disorders, although the role of weight in pediatric insomnia treatment has not been examined. The current study examined the relationships of high body mass with pretreatment insomnia severity and global sleep problems and the potential moderating impact of weight on changes in insomnia severity following insomnia treatment. METHODS: Participants included 1,133 youth ages 2-18 years clinically referred for insomnia treatment. The Pediatric Insomnia Severity Index was collected at the initial assessment and throughout treatment as part of routine clinical care. Treatment status was coded as no treatment, early termination, and completed treatment. Secondary measures of global sleep problems at the initial assessment included the Adolescent Sleep Wake Scale, Adolescent Sleep Hygiene Scale, and Children's Sleep Habits Questionnaire. Medical chart review of visits within ± 3 months of baseline was used to obtain age-adjusted and sex-adjusted body mass index Z-score. RESULTS: Among adolescents, regression analyses found that higher body mass index Z-score modestly predicted baseline insomnia severity (P = .021) and worse sleep hygiene (P < .001). For children, higher body mass index Z-score was modestly associated with baseline total sleep problems (P = .006) but not insomnia severity (P = .792). Across ages, body mass index Z-score predicted neither treatment status nor insomnia improvement (P > .05). Findings were similar in categorical analyses comparing patients with overweight/obesity to healthy weight. CONCLUSIONS: Although there is evidence that children of higher body mass present for insomnia treatment with greater sleep concerns, body mass does not predict treatment completion or insomnia improvement. Data suggest insomnia treatment is effective irrespective of weight status. CITATION: Duraccio KM, Simmons DM, Beebe DW, Byars KC. Relationship of overweight and obesity to insomnia severity, sleep quality, and insomnia improvement in a clinically referred pediatric sample. J Clin Sleep Med. 2022;18(4):1083-1091.

Structural basis of fatty acid substrate binding to cyclooxygenase-2.

The cyclooxygenases (COX-1 and COX-2) are membrane-associated heme-containing homodimers that generate prostaglandin H(2) from arachidonic acid (AA). Although AA is the preferred substrate, other fatty acids are oxygenated by these enzymes with varying efficiencies. We determined the crystal structures of AA, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) bound to Co(3+)-protoporphyrin IX-reconstituted murine COX-2 to 2.1, 2.4, and 2.65 A, respectively. AA, EPA, and docosahexaenoic acid bind in different conformations in each monomer constituting the homodimer in their respective structures such that one monomer exhibits nonproductive binding and the other productive binding of the substrate in the cyclooxygenase channel. The interactions identified between protein and substrate when bound to COX-1 are conserved in our COX-2 structures, with the only notable difference being the lack of interaction of the carboxylate of AA and EPA with the side chain of Arg-120. Leu-531 exhibits a different side chain conformation when the nonproductive and productive binding modes of AA are compared. Unlike COX-1, mutating this residue to Ala, Phe, Pro, or Thr did not result in a significant loss of activity or substrate binding affinity. Determination of the L531F:AA crystal structure resulted in AA binding in the same global conformation in each monomer. We speculate that the mobility of the Leu-531 side chain increases the volume available at the opening of the cyclooxygenase channel and contributes to the observed ability of COX-2 to oxygenate a broad spectrum of fatty acid and fatty ester substrates.

His-311 and Arg-559 are key residues involved in fatty acid oxygenation in pathogen-inducible oxygenase.

Pathogen-inducible oxygenase (PIOX) oxygenates fatty acids into 2R-hydroperoxides. PIOX belongs to the fatty acid alpha-dioxygenase family, which exhibits homology to cyclooxygenase enzymes (COX-1 and COX-2). Although these enzymes share common catalytic features, including the use of a tyrosine radical during catalysis, little is known about other residues involved in the dioxygenase reaction of PIOX. We generated a model of linoleic acid (LA) bound to PIOX based on computational sequence alignment and secondary structure predictions with COX-1 and experimental observations that governed the placement of carbon-2 of LA below the catalytic Tyr-379. Examination of the model identified His-311, Arg-558, and Arg-559 as potential molecular determinants of the dioxygenase reaction. Substitutions at His-311 and Arg-559 resulted in mutant constructs that retained virtually no oxygenase activity, whereas substitutions of Arg-558 caused only moderate decreases in activity. Arg-559 mutant constructs exhibited increases of greater than 140-fold in Km, whereas no substantial change in Km was observed for His-311 or Arg-558 mutant constructs. Thermal shift assays used to measure ligand binding affinity show that the binding of LA is significantly reduced in a Y379F/R559A mutant construct compared with that observed for Y379F/R558A construct. Although Oryza sativa PIOX exhibited oxygenase activity against a variety of 14-20-carbon fatty acids, the enzyme did not oxygenate substrates containing modifications at the carboxylate, carbon-1, or carbon-2. Taken together, these data suggest that Arg-559 is required for high affinity binding of substrates to PIOX, whereas His-311 is involved in optimally aligning carbon-2 below Tyr-379 for catalysis.