Edward O. Bixler, PhD: from the Apollo project and chimpanzees to sleep epidemiology.

What an honor to write about Dr. Edward O. Bixler's contributions to the sleep field. In 1967, Dr. Bixler published a case report on a chimpanzee with implanted brain electrodes while working at an Air Force base in New Mexico. A few years later, in 1971, he published on the sleep effects of flurazepam in individuals with insomnia together with Dr. Anthony Kales, data that he had collected when the Sleep Research & Treatment Center (SRTC) was housed at the University of California Los Angeles. Dr. Bixler, a meticulous scientist, learned from Dr. Kales, a devoted clinician, to study "the whole patient, and all aspects of sleep," a legacy that continued when the SRTC moved to Penn State in Hershey. Indeed, Dr. Bixler's tenure at Penn State from 1971 until 2019 kept the science of the SRTC focused on that premise and helped translate scientific evidence into clinical care. He not only contributed early to the pharmacology of sleep and the effects of hypnotics, but he was also a pioneer in "sleep epidemiology." His "Prevalence of sleep disorders in the Los Angeles metropolitan area" study of 1979 was the first rigorous epidemiological study on sleep disturbances. Starting in 1990, he established the Penn State Adult Cohort to estimate the prevalence and natural history of sleep-disordered breathing and other sleep disorders in adults. Inspired by life-course epidemiology, he established in 2001 the Penn State Child Cohort to estimate the same phenomena in children. This Living Legend paper captures and highlights Dr. Bixler's enduring legacy to sleep science.

Short-term stability and night-to-night variability of sleep parameters in nightmares comorbid with chronic insomnia Disorder across multiple nights of polysomnography.

STUDY OBJECTIVES: The purpose of this study was to examine the degree of short-term stability of polysomnographic (PSG) measured sleep parameters and the overall differences between individuals with comorbid nightmares and insomnia compared to those with chronic insomnia disorder alone or good sleeping controls across four nights in the sleep lab. METHODS: A total of 142 good sleeping controls, 126 chronic insomnia alone, and 24 comorbid insomnia/nightmare participants underwent four consecutive nights of 8-hour PSG recordings. Outcomes included sleep continuity, architecture, and REM-related parameters across nights one through four. Intraclass correlation coefficients with mixed-effect variances and repeated-measure analysis of covariance were used, respectively, to determine short-term stability as well as between-participants and time-by-group interaction effects. RESULTS: Wake after sleep onset and stage 1 showed "poor stability" in the comorbid insomnia/nightmare group compared to "moderate stability" in the good sleeping controls and chronic insomnia alone group. Significant between-group effects (all ps < .05) showed that the comorbid insomnia/nightmare group took longer to fall asleep and had a greater first-night-effect in stage 1 compared to good sleeping controls and chronic insomnia alone group; in addition, the comorbid insomnia/nightmare and insomnia alone groups slept shorter, with fewer awakenings and REM periods, compared to the good sleeping controls. CONCLUSIONS: Nightmares are associated with abnormal sleep above and beyond REM disruption, as sleep continuity was the primary aspect in which poor stability and group differences emerged. The greater inability to fall asleep and instability of sleep fragmentation in those with comorbid insomnia/nightmares compared to chronic insomnia alone may be attributed to the impact of presleep anticipatory anxiety and nightmare-related distress itself. CLINICAL TRIAL INFORMATION: The data analyzed in this study does not come from any current or previous clinical trials. Therefore, there is no clinical trial information to report.

Racial/ethnic disparities in the trajectories of insomnia symptoms from childhood to young adulthood.

STUDY OBJECTIVES: To examine differences in the longitudinal prevalence of childhood insomnia symptoms across black/African American, Hispanic/Latinx, and non-Hispanic white groups. METHODS: Participants were 519 children from the Penn State Child Cohort (baseline [V1] from 2000-2005) who were followed up 8 years later as adolescents (V2) and 15 years later as young adults (S3). Mean age at S3 was 24.1 ±â€…2.7 years. Approximately, 76.5% identified as non-Hispanic white, 12.9% as black/African American, 7.1% as Hispanic/Latinx, and 3.5% as "other" race/ethnicity. Insomnia symptoms were defined as parent-reported (childhood) or self-reported (adolescence and young adulthood) moderate-to-severe difficulties initiating/maintaining sleep. Longitudinal trajectories of insomnia symptoms were identified across three-time points and the odds of each trajectory were compared between racial/ethnic groups, adjusting for sex, age, overweight, sleep apnea, periodic limb movements, psychiatric/behavioral disorders, and psychotropic medication use. RESULTS: Black/African Americans compared to non-Hispanic whites were at significantly higher odds of having a childhood-onset persistent trajectory through young adulthood (OR = 2.58, 95% CI [1.29, 5.14]), while Hispanics/Latinx were at nonsignificantly higher odds to have the same trajectory (OR = 1.81, 95% CI [0.77, 4.25]). No significant racial/ethnic differences were observed for remitted and waxing-and-waning trajectories since childhood or incident/new-onset trajectories in young adulthood. CONCLUSIONS: The results indicate that disparities in insomnia symptoms among black/African American and, to a lesser extent, Hispanic/Latinx groups start early in childhood and persist into young adulthood. Identifying and intervening upon upstream determinants of racial/ethnic insomnia disparities are warranted to directly address these disparities and to prevent their adverse health sequelae. CLINICAL TRIAL INFORMATION: N/A; Not a clinical trial.

Circadian misalignment impacts the association of visceral adiposity with metabolic syndrome in adolescents.

STUDY OBJECTIVES: Although insufficient sleep is a risk factor for metabolic syndrome (MetS), the circadian timing of sleep (CTS) is also involved in cardiac and metabolic regulation. We examined whether delays and deviations in the sleep midpoint (SM), a measure of CTS, modify the association between visceral adipose tissue (VAT) and MetS in adolescents. METHODS: We evaluated 277 adolescents (median 16 years) who had at least 5 nights of at-home actigraphy (ACT), in-lab polysomnography (PSG), dual-energy X-ray absorptiometry (DXA) scan, and MetS score data. Sleep midpoint (SM), sleep irregularity (SI), and social jetlag (SJL) were examined as effect modifiers of the association between VAT and MetS, including waist circumference, blood pressure, insulin resistance, triglycerides, and cholesterol. Linear regression models adjusted for demographics, ACT-sleep duration, ACT-sleep variability, and PSG-apnea-hypopnea index. RESULTS: The association between VAT and MetS was significantly stronger (p-values for interactions < 0.001) among adolescents with a schooldays SM later than 4:00 (2.66 [0.30] points increase in MetS score), a SI higher than 1 hour (2.49 [0.30]) or a SJL greater than 1.5 hours (2.15 [0.36]), than in those with an earlier SM (<3:00; 1.76 [0.28]), lower SI (<30 minutes; 0.98 [0.70]), or optimal SJL (<30 minutes; 1.08 [0.45]). CONCLUSIONS: A delayed sleep phase, an irregular sleep-wake cycle, and greater social jetlag on schooldays identified adolescents in whom VAT had a stronger association with MetS. Circadian misalignment is a risk factor that enhances the impact of visceral obesity on cardiometabolic morbidity and should be a target of preventative strategies in adolescents.

Cognitive Disengagement Syndrome (CDS) (Formerly Sluggish Cognitive Tempo), Autism, and Insomnia Symptoms in Childhood Predict CDS in Adolescence: A Longitudinal Population-Based Study.

Our study is the first using multiple variables to compare concurrent with longitudinal predictors of cognitive disengagement syndrome (CDS). The population-based sample comprised 376 youth (mean baseline age 8.7 and follow-up 16.4 years) rated by parents on the Pediatric Behavior Scale. The baseline CDS score was the strongest predictor of follow-up CDS. Baseline autism and insomnia symptoms also predicted follow-up CDS above and beyond baseline CDS. Autism, insomnia, inattention, somatic complaints, and excessive sleep were concurrently related to CDS at baseline and follow-up. Additionally, follow-up depression was associated with follow-up CDS, and baseline hyperactivity/impulsivity was negatively associated with baseline CDS. Oppositional defiant/conduct problems and anxiety were nonsignificant. Age, sex, race, and parent occupation were unrelated to CDS, and correlations between baseline CDS and 15 IQ, achievement, and neuropsychological test scores were nonsignificant. Results indicate childhood CDS is the strongest risk factor for adolescent CDS, followed by autism and insomnia symptoms.

Circadian Misalignment Impacts the Association of Visceral Adiposity With Elevated Blood Pressure in Adolescents.

BACKGROUND: Although insufficient sleep has been shown to contribute to obesity-related elevated blood pressure, the circadian timing of sleep has emerged as a novel risk factor. We hypothesized that deviations in sleep midpoint, a measure of circadian timing of sleep, modify the association between visceral adiposity and elevated blood pressure in adolescents. METHODS: We studied 303 subjects from the Penn State Child Cohort (16.2±2.2 years; 47.5% female; 21.5% racial/ethnic minority). Actigraphy-measured sleep duration, midpoint, variability, and regularity were calculated across a 7-night period. Visceral adipose tissue (VAT) was measured with dual-energy X-ray absorptiometry. Systolic blood pressure (SBP) and diastolic blood pressure levels were measured in the seated position. Multivariable linear regression models tested sleep midpoint and its regularity as effect modifiers of VAT on SBP/diastolic blood pressure levels, while adjusting for demographic and sleep covariables. These associations were also examined as a function of being in-school or on-break. RESULTS: Significant interactions were found between VAT and sleep irregularity, but not sleep midpoint, on SBP (P interaction=0.007) and diastolic blood pressure (P interaction=0.022). Additionally, significant interactions were found between VAT and schooldays sleep midpoint on SBP (P interaction=0.026) and diastolic blood pressure (P interaction=0.043), whereas significant interactions were found between VAT and on-break weekdays sleep irregularity on SBP (P interaction=0.034). CONCLUSIONS: A delayed and an irregular sleep midpoint during school and during free-days, respectively, increase the impact of VAT on elevated blood pressure in adolescents. These data suggest that deviations in the circadian timing of sleep contribute to the increased cardiovascular sequelae associated with obesity and that its distinct metrics require measurement under different entrainment conditions in adolescents.

Pediatric sleep: current knowledge, gaps, and opportunities for the future.

This White Paper addresses the current gaps in knowledge, as well as opportunities for future studies in pediatric sleep. The Sleep Research Society's Pipeline Development Committee assembled a panel of experts tasked to provide information to those interested in learning more about the field of pediatric sleep, including trainees. We cover the scope of pediatric sleep, including epidemiological studies and the development of sleep and circadian rhythms in early childhood and adolescence. Additionally, we discuss current knowledge of insufficient sleep and circadian disruption, addressing the neuropsychological impact (affective functioning) and cardiometabolic consequences. A significant portion of this White Paper explores pediatric sleep disorders (including circadian rhythm disorders, insomnia, restless leg and periodic limb movement disorder, narcolepsy, and sleep apnea), as well as sleep and neurodevelopment disorders (e.g. autism and attention deficit hyperactivity disorder). Finally, we end with a discussion on sleep and public health policy. Although we have made strides in our knowledge of pediatric sleep, it is imperative that we address the gaps to the best of our knowledge and the pitfalls of our methodologies. For example, more work needs to be done to assess pediatric sleep using objective methodologies (i.e. actigraphy and polysomnography), to explore sleep disparities, to improve accessibility to evidence-based treatments, and to identify potential risks and protective markers of disorders in children. Expanding trainee exposure to pediatric sleep and elucidating future directions for study will significantly improve the future of the field.

Agreement between mother, father, and teacher ratings of cognitive disengagement syndrome (sluggish cognitive tempo) in children with autism and children with ADHD.

No studies have analyzed differences between mother, father, and teacher ratings of cognitive disengagement syndrome (CDS; formerly sluggish cognitive tempo). The sample included 1,115 children with autism and/or attention-deficit/hyperactivity disorder (ADHD) 4-16 years of age who were rated by mothers on the Pediatric Behavior Scale. Subsets of these children were also rated by fathers and/or teachers, resulting in 896 mother/father, 964 mother/teacher, and 745 father/teacher dyads. The CDS factor comprised four items assessing the core features of CDS: cognitive disengagement (in a fog/confused and stares/preoccupied/in own world) and hypoactivity (sluggish/slow moving/low energy and drowsy/sleepy/not alert). Overall, 37% of teachers, 22% of mothers, and 16% of fathers rated the children as significantly elevated on CDS symptoms. Teacher scores were significantly higher than mother scores, whose scores exceeded those of fathers. Agreement on whether a child had CDS was fair-moderate for mothers and fathers but poor for parents and teachers. Findings of more severe CDS teacher than parent ratings are in marked contrast to the opposite pattern found in studies of anxiety, depression, ADHD, oppositional behavior, conduct problems, autism, bullying, and victimization. Children may display fewer behavior problems at school than at home, and parents may be more aware of their child's internal state than teachers. However, teachers may be more aware of the cognitive component of CDS that might interfere with functioning in the classroom more so than at home. Cognitive demands in school may reveal and intensify CDS symptoms. Findings highlight the importance of multi-informant ratings in research and clinical practice. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Sluggish cognitive tempo: Association with neuropsychological test scores, motor incoordination, and dysgraphia in elementary school children.

Research on the relationship between sluggish cognitive tempo (SCT) and scores on neuropsychological tests (such as those measuring processing speed and reaction time) is inconclusive, and the association between SCT and motor incoordination and dysgraphia has not been objectively investigated. Mothers of 413 elementary school children (6-12 years of age) rated their children on the Pediatric Behavior Scale (PBS), which yields psychological problem scores, including SCT. Children were administered an extensive battery of neuropsychological tests assessing processing and performance speed, working memory, immediate and delayed recall, sustained attention, response inhibition, cognitive flexibility, fine motor manipulative skill, verbal fluency and retrieval, set shifting, and interference control, as well as intelligence and reading and math achievement. Only three of the 19 correlations between SCT and neuropsychological scores were significant, and all involved graphomotor tests (two timed and one untimed). In regression analysis, the strongest independent predictor of SCT was the maternal PBS incoordination factor score, followed by ratings of autism, inattention, and depression. Neuropsychological test scores did not contribute significantly more to predicting SCT. Among the incoordination PBS factor items, clumsy and draws or writes poorly were significant SCT predictors. Our novel and unexpected findings showed that motor incoordination was a stronger correlate of SCT than other variables assessed in our study, including those previously linked with SCT. Future SCT research needs to include measures of incoordination and dysgraphia in order to replicate and expand upon the current findings. Our results suggest that SCT traits are not reliably measured by currently available neuropsychological tests.

Comparison of the Cognitive Disengagement and Hypoactivity Components of Sluggish Cognitive Tempo in Autism, ADHD, and Population-Based Samples of Children.

An international Sluggish Cognitive Tempo (SCT) Work Group proposed a new term for SCT, "cognitive disengagement syndrome," that more accurately describes the syndrome than does SCT. According to the Work Group, symptoms of SCT represent a cognitive dimension (cognitive disengagement) and a motor dimension (hypoactivity). Our study determined (1) if distinct factors representing cognitive disengagement and hypoactivity emerged when SCT items were factor analyzed and (2) the degree of differences in cognitive disengagement and hypoactivity within diagnostic groups. Mothers rated 1,177 children with autism, 725 with ADHD-Combined, and 307 with ADHD-Inattentive (4-17 years) and 665 elementary school children (6-12 years) on the Pediatric Behavior Scale (PBS). SCT prevalence rates were autism 32%, ADHD-Inattentive 27%, ADHD-Combined 18%, and elementary school students 7%. Factor analysis of the SCT items yielded two factors reflecting cognitive disengagement (in a fog/confused and stares/preoccupied/in own world) and hypoactivity (sluggish/slow moving/low energy, drowsy/sleepy/not alert, and tires easily) in all diagnostic groups. Cognitive disengagement prevalence rates and scores were significantly higher than hypoactivity in the autism and ADHD-C groups and in the autism and ADHD-C subgroups of children with SCT (but not in the ADHD-I and elementary school total groups and SCT subgroups). Our findings factor analyzing five SCT items support two SCT subfactors: cognitive disengagement and hypoactivity.

Association of insomnia phenotypes based on polysomnography-measured sleep duration with suicidal ideation and attempts.

OBJECTIVE: To assess the association of insomnia phenotypes, being insomnia with short sleep duration (ISSD) and insomnia with normal sleep duration (INSD), with suicidality in a randomly selected population-based sample. METHODS: Data were analyzed from the Penn State Adult Cohort. Participants (N = 1741, 52.5 years, 57.4% female) were randomly recruited from the general population between January 1990 through March 1999 and mortality data were available through December 2018. Insomnia symptoms were defined as self-reports of moderate-to-severe difficulties initiating or maintaining sleep, early morning awakening and non-restorative sleep, or having chronic insomnia (n = 719). Short sleep duration was defined as <6 hours of in-lab polysomnography-measured sleep duration (n = 879). Suicidality (SAI; n = 102) was ascertained by a lifetime history of suicidal ideation (SI; n = 84), suicide attempts (SA; n = 48) or death by suicide (DBS; n = 10). RESULTS: Compared to normal sleepers who slept ≥6 hours, participants with ISSD and INSD were associated with 1.72-fold and 2.22-fold increased odds of SAI, respectively; these associations were significant for SI, with 2.09-fold and 2.24-fold increased odds, respectively, but not for SA, after adjusting for physical and mental health comorbidities. ISSD and INSD differed in SAI age of onset and hospitalizations after SA. CONCLUSIONS: The results of this cohort study suggest that both INSD and ISSD phenotypes are associated with increased suicidal ideation, while the INSD phenotype has an earlier age of onset and is more likely to experience hospitalizations after attempting suicide. These results highlight the importance of targeting insomnia symptoms to help prevent suicide.

Trajectories of Insomnia Symptoms From Childhood Through Young Adulthood.

OBJECTIVES: Insomnia symptoms are transdiagnostic to physical and mental health disorders. Given the lack of population-based cohorts with objective sleep measures and long-term follow-ups, little is known about the chronicity of childhood insomnia symptoms. We determined the developmental trajectories of insomnia symptoms, their evolution into adult insomnia, and the role of objective sleep duration in the transition to adulthood. METHODS: A total of 502 children (median 9 years old, 71.7% response rate) were studied 7.4 years later as adolescents (median 16 years old) and 15 years later as adults (median 24 years old). Insomnia symptoms were ascertained as moderate-to-severe difficulties initiating and/or maintaining sleep via parent- or self reports at all 3 time points, adult insomnia via self-report in young adulthood, and objective short-sleep duration via polysomnography in childhood and adolescence. RESULTS: Among children with insomnia symptoms, the most frequent trajectory was persistence (43.3%), followed by remission (26.9% since childhood, 11.2% since adolescence) and a waxing-and-waning pattern (18.6%). Among children with normal sleep, the most frequent trajectory was persistence (48.1%), followed by developing insomnia symptoms (15.2% since adolescence, 20.7% in adulthood) and a waxing-and-waning pattern (16.0%). The odds of insomnia symptoms worsening into adult insomnia (22.0% of children, 20.8% of adolescents) were 2.6-fold and 5.5-fold among short-sleeping children and adolescents, respectively. CONCLUSIONS: Early sleep interventions are a health priority because pediatricians should not expect insomnia symptoms to developmentally remit in a high proportion of children. Objective sleep measures may be clinically useful in adolescence, a critical period for the adverse prognosis of the insomnia with short-sleep duration phenotype.

Evidence of a maturational disruption in non-rapid eye movement sleep slow wave activity in youth with attention-deficit/hyperactivity, learning and internalizing disorders.

BACKGROUND: Sleep slow wave activity (SWA) peaks during childhood and declines in the transition to adolescence during typical development (TD). It remains unknown whether this trajectory differs in youth with neuropsychiatric disorders. METHODS: We analyzed sleep EEGs of 664 subjects 6 to 21 y (449 TD, 123 unmedicated, 92 medicated) and 114 subjects 7-12 y (median 10.5 y) followed-up at 18-22 y (median 19 y). SWA (0.4-4 Hz) power was calculated during non-rapid eye movement sleep. RESULTS: TD and unmedicated youth showed cubic central and frontal SWA trajectories from 6 to 21 y (p-cubic<0.05), with TD youth showing peaks in central SWA at 6.8 y and frontal at 8.2 y. Unmedicated attention-deficit/hyperactivity (ADHD) and/or learning disorders (LD) showed peak central SWA 2 y later (at 9.6 y, coinciding with peak frontal SWA) than TD, followed by a 67% steeper slope by 19 y. Frontal SWA peak and slope in unmedicated ADHD/LD, and that of central and frontal in internalizing disorders (ID), were similar to TD. Unmedicated ADHD/LD did not differ in the longitudinal SWA percent change by 18-22 y; unmedicated ID showed a lower longitudinal change in frontal SWA than TD. Medicated youth showed a linear decline in central and frontal SWA from 6 to 21 y (p-linear<0.05). CONCLUSIONS: ADHD/LD youth show a maturational delay and potential topographical disruption in SWA during childhood and steeper decline throughout adolescence, suggesting faster synaptic pruning. Youth with ID experience less changes in frontal SWA by late adolescence. Psychotropic medications may impact the maturational trajectory of SWA, but not the magnitude of developmental decline by late adolescence.

Relationship between sluggish cognitive tempo, IQ and academic achievement test scores, and academic impairment in autism, ADHD, and elementary school samples.

Sluggish cognitive tempo (SCT) is of renewed interest. The relationship between SCT, IQ and achievement scores, and academic impairment ratings was investigated in 218 students with autism and 676 with ADHD (6-16 years) and 549 elementary school students (IQ ≥ 80). Mothers rated their children on the Pediatric Behavior Scale. Children in the autism/ADHD sample were also rated by teachers. Correlations between SCT and IQ and achievement scores (Verbal Comprehension, Perceptual Reasoning, Working Memory, Processing Speed, reading, math, and written expression) were all negative and were nonsignificant in the total autism/ADHD and elementary school samples, except for small correlations with Processing Speed and a timed math test. In contrast, mother and teacher SCT ratings were significantly related to mother and teacher academic and cognitive impairment ratings. SCT was not a significant predictor of achievement scores or academic impairment ratings in regression analysis. The strongest predictor of achievement test scores was IQ, and the strongest predictors of academic impairment were mother and teacher cognitive impairment ratings. Teacher inattention ratings predicted teacher academic impairment ratings in autism/ADHD and mother inattention ratings predicted mother academic impairment ratings in elementary school children. Therefore, inattention was more predictive of academic functioning than was SCT. Research shows a weak link between SCT and processing speed (contrary to what is implied by the term sluggish cognitive tempo), and other neuropsychological test scores are not consistently associated with SCT. It remains to be determined if neuropsychological tests can be developed to measure and further our understanding of SCT.

Behavioral, neurocognitive, polysomnographic and cardiometabolic profiles associated with obstructive sleep apnea in adolescents with ADHD.

BACKGROUND: A high comorbidity between attention-deficit/hyperactivity disorder (ADHD) and obstructive sleep apnea (OSA) as well as similar impairments across neurobehavioral outcomes has been described in children. However, there is a paucity of research examining the comorbidity of these two disorders in adolescents. This study examined the association of OSA with sleep, neurobehavioral, and cardiometabolic outcomes in adolescents with ADHD from the general population. METHODS: 421 adolescents (16.9 ± 2.3 years, 53.9% male) underwent 9-hr polysomnography, neurobehavioral, and physical evaluation. ADHD was ascertained by a parent-or-self-report of a lifetime diagnosis/treatment of ADHD. OSA was defined as an apnea hypopnea index of ≥2 events/hour. Groups of controls (n = 208), OSA-alone (n = 115), ADHD-alone (n = 54), and ADHD+OSA (n = 44) were studied. Multivariable-adjusted general linear models tested group differences in PSG parameters, neurobehavioral, and cardiometabolic outcomes after controlling for sex, race/ethnicity, age, and/or body mass index percentile. RESULTS: The ADHD+OSA group had significantly longer sleep onset latency, shorter total sleep time, lower sleep efficiency, and higher percent of stage 1 sleep, as compared with all other groups, however, these differences were diminished by excluding adolescents on psychoactive medication. The ADHD-alone group showed significantly higher periodic limb movements than controls. The ADHD+OSA and ADHD-alone groups did not significantly differ on any measure of neurocognitive or behavioral functioning. The ADHD+OSA and OSA-alone groups showed significantly worse cardiometabolic and inflammatory biomarkers when compared to controls or the ADHD-alone, but did not significantly differ between each other. CONCLUSIONS: Adolescents with a diagnosis ADHD+OSA showed phenotypic risk factors for OSA (i.e., overweight/obesity, visceral adiposity, metabolic syndrome, and inflammation) but not worse neurobehavioral outcomes when compared with ADHD-alone. While comorbidity is possible, these data support that adolescents with a suspicion of ADHD should be screened for OSA, before a diagnosis is reached and psychoactive medication initiated.

Cross-Sectional Age Analysis of Sleep Problems in 2 to 17 Year Olds with ADHD Combined, ADHD Inattentive, or Autism.

Sleep problems are common in autism and ADHD. No study has compared sleep problems by age in 2 to 17 year olds with autism versus ADHD-Combined versus ADHD-Inattentive type. Mothers rated 1415 youth with autism and 1041 with ADHD on 10 Pediatric Behavior Scale sleep items. Nighttime sleep problems were most severe in autism, followed by ADHD-Combined, and then ADHD-Inattentive. Difficulty falling asleep, restless during sleep, and waking during the night were the most common problems. Adolescents slept more at night than other age groups, and youth who slept more at night were sleepier during the day. Sleep problems declined with age, but correlations were small. In adolescence, 63% with autism, 53% with ADHD-Combined, and 57% with ADHD-Inattentive had difficulty falling asleep. Given that the majority of children in all age groups had one or more sleep problem, developmentally appropriate interventions are needed to address sleep difficulties and limit their adverse effects.

Association of a novel EEG metric of sleep depth/intensity with attention-deficit/hyperactivity, learning, and internalizing disorders and their pharmacotherapy in adolescence.

STUDY OBJECTIVES: Psychiatric/learning disorders are associated with sleep disturbances, including those arising from abnormal cortical activity. The odds ratio product (ORP) is a standardized electroencephalogram metric of sleep depth/intensity validated in adults, while ORP data in youth are lacking. We tested ORP as a measure of sleep depth/intensity in adolescents with and without psychiatric/learning disorders. METHODS: Four hundred eighteen adolescents (median 16 years) underwent a 9-hour, in-lab polysomnography. Of them, 263 were typically developing (TD), 89 were unmedicated, and 66 were medicated for disorders including attention-deficit/hyperactivity (ADHD), learning (LD), and internalizing (ID). Central ORP during non-rapid eye movement (NREM) sleep was the primary outcome. Secondary/exploratory outcomes included central and frontal ORP during NREM stages, in the 9-seconds following arousals (ORP-9), in the first and second halves of the night, during REM sleep and wakefulness. RESULTS: Unmedicated youth with ADHD/LD had greater central ORP than TD during stage 3 and in central and frontal regions during stage 2 and the second half of the sleep period, while ORP in youth with ADHD/LD on stimulants did not significantly differ from TD. Unmedicated youth with ID did not significantly differ from TD in ORP, while youth with ID on antidepressants had greater central and frontal ORP than TD during NREM and REM sleep, and higher ORP-9. CONCLUSIONS: The greater ORP in unmedicated youth with ADHD/LD, and normalized levels in those on stimulants, suggests ORP is a useful metric of decreased NREM sleep depth/intensity in ADHD/LD. Antidepressants are associated with greater ORP/ORP-9, suggesting these medications induce cortical arousability.

Multimeric Anti-DR5 IgM Agonist Antibody IGM-8444 Is a Potent Inducer of Cancer Cell Apoptosis and Synergizes with Chemotherapy and BCL-2 Inhibitor ABT-199.

Death receptor 5 (DR5) is an attractive target for cancer therapy due to its broad upregulated expression in multiple cancers and ability to directly induce apoptosis. Though anti-DR5 IgG antibodies have been evaluated in clinical trials, limited efficacy has been attributed to insufficient receptor crosslinking. IGM-8444 is an engineered, multivalent agonistic IgM antibody with 10 binding sites to DR5 that induces cancer cell apoptosis through efficient DR5 multimerization. IGM-8444 bound to DR5 with high avidity and was substantially more potent than an IgG with the same binding domains. IGM-8444 induced cytotoxicity in a broad panel of solid and hematologic cancer cell lines but did not kill primary human hepatocytes in vitro, a potential toxicity of DR5 agonists. In multiple xenograft tumor models, IGM-8444 monotherapy inhibited tumor growth, with strong and sustained tumor regression observed in a gastric PDX model. When combined with chemotherapy or the BCL-2 inhibitor ABT-199, IGM-8444 exhibited synergistic in vitro tumor cytotoxicity and enhanced in vivo efficacy, without augmenting in vitro hepatotoxicity. These results support the clinical development of IGM-8444 in solid and hematologic malignancies as a monotherapy and in combination with chemotherapy or BCL-2 inhibition.

Association of Pediatric Obstructive Sleep Apnea With Elevated Blood Pressure and Orthostatic Hypertension in Adolescence.

Importance: Although pediatric guidelines have delineated updated thresholds for elevated blood pressure (eBP) in youth and adult guidelines have recognized obstructive sleep apnea (OSA) as an established risk factor for eBP, the relative association of pediatric OSA with adolescent eBP remains unexplored. Objective: To assess the association of pediatric OSA with eBP and its orthostatic reactivity in adolescence. Design, Setting, and Participants: At baseline of this population-based cohort study (Penn State Child Cohort) in 2000-2005, a random sample of 700 children aged 5 to 12 years from the general population was studied. A total of 421 participants (60.1%) were followed up in 2010-2013 after 7.4 years as adolescents (ages, 12-23 years). Data analyses were conducted from July 6 to October 29, 2020. Main Outcomes and Measures: Outcomes were the apnea-hypopnea index (AHI) score, ascertained via polysomnography conducted in a laboratory; eBP measured in the seated position identified using guideline-recommended pediatric criteria; orthostatic hyperreactivity identified with BP assessed in the supine and standing positions; and visceral adipose tissue assessed via dual-energy x-ray absorptiometry. Results: Among the 421 participants (mean [SD] age at follow-up, 16.5 [2.3] years), 227 (53.9%) were male and 92 (21.9%) were racial/ethnic minorities. A persistent AHI of 2 or more since childhood was longitudinally associated with adolescent eBP (odds ratio [OR], 2.9; 95% CI 1.1-7.5), while a remitted AHI of 2 or more was not (OR, 0.9; 95% CI 0.3-2.6). Adolescent OSA was associated with eBP in a dose-response manner; however, the association of an AHI of 2 to less than 5 among adolescents was nonsignificant (OR, 1.5; 95% CI, 0.9-2.6) and that of an AHI of 5 or more was approximately 2-fold (OR, 2.3; 95% CI, 1.1-4.9) after adjusting for visceral adipose tissue. An AHI of 5 or more (OR, 3.1; 95% CI, 1.2-8.5), but not between 2 and less than 5 (OR, 1.3; 95% CI, 0.6-3.0), was associated with orthostatic hyperreactivity among adolescents even after adjusting for visceral adipose tissue. Childhood OSA was not associated with adolescent eBP in female participants, while the risk of OSA and eBP was greater in male participants. Conclusions and Relevance: The results of this cohort study suggest that childhood OSA is associated with adolescent hypertension only if it persists during this developmental period. Visceral adiposity explains a large extent of, but not all, the risk of hypertension associated with adolescent OSA, which is greater in male individuals.

Sex and Pubertal Differences in the Maturational Trajectories of Sleep Spindles in the Transition from Childhood to Adolescence: A Population-Based Study.

Sleep spindles, bursts of electroencephalogram (EEG) activity in the σ-frequency (11-16 Hz) range, may be biomarkers of cortical development. Studies capturing the transition to adolescence are needed to delineate age-related, sex-related, and pubertal-related changes in sleep spindles at the population-level. We analyzed the sleep EEG of 572 subjects 6-21 years (48% female) and 332 subjects 5-12 years (46% female) followed-up at 12-22 years. From 6 to 21 years, spindle density (p quadratic = 0.019) and fast (12-16 Hz) spindle percent (p quadratic = 0.016) showed inverted U-shaped trajectories, with plateaus after 15 and 19 years, respectively. Spindle frequency increased (p linear < 0.001), while spindle power decreased (p linear < 0.001) from 6 to 21 years. The trajectories of spindle density, frequency, and fast spindle percent diverged between females and males, in whom density plateaued by 14 years, fast spindle percent by 16 years, and frequency by 18 years, while fast spindle percent and spindle frequency continued to increase until 21 years in females. Males experienced a longitudinal increase in spindle density 31% greater than females by 12-14 years (p = 0.006). Females experienced an increase in spindle frequency and fast spindle percent 2% and 41% greater, respectively, than males by 18-22 years (both p = 0.004), while males experienced a 14% greater decline in spindle power by 18-22 years (p = 0.018). Less mature adolescents (86% male) experienced a longitudinal increase in spindle density 36% greater than mature adolescents by 12-14 years (p = 0.002). Overall, males experience greater maturational changes in spindle density in the transition to adolescence, driven by later pubertal development, and sex differences become prominent in early adulthood when females have greater spindle power, frequency, and fast spindle percent.