Developmental changes in obstructive sleep apnea and sleep architecture in Down syndrome.

BACKGROUND: Down syndrome (DS, also known as Trisomy 21) is a condition associated with abnormal neurodevelopment and a higher risk for sleep apnea. Our study sought to better understand and characterize the age-related developmental differences in sleep architecture and obstructive sleep apnea (OSA) severity in children with DS compared to euploid individuals. METHODS: Retrospective review of polysomnograms in over 4151 infants, children, and adolescents in the pediatric sleep center at Children's National Hospital in Washington D.C. (0-18 years) including 218 individuals with DS. RESULTS: The primary findings of our study are that: (1) severe OSA (obstructive apnea-hypopnea index ≥ 10/h) was more prevalent in the DS group (euploid 18% vs. DS 34%, p < 0.001) with the highest OSA severity being present in young children (<3 years old) and adolescents (>10 years old), (2) abnormalities in sleep architecture in children with DS were characterized by a prolonged rapid-eye movement (REM) sleep onset latency (SOL) (euploid 119 min vs. DS 144 min, p < 0.001) and greater arousal indexes (euploid 10.7/h vs. DS 12.2/h, p < 0.001), (3) developmental changes in the amount of REM sleep or slow wave sleep were not different in DS individuals relative to euploid children, (4) multivariate analyses showed that OSA and REM sleep latency differences between DS and euploid individuals were still present after adjusting by age, biological sex, and body mass index. CONCLUSION: Severe OSA is highly prevalent in children with DS and follows an age-dependent "U" distribution with peaks in newborns/infants and children >10 years of age. Children with DS also have disturbances in sleep architecture characterized by a longer REM SOL and elevated arousal indexes. As sleep cycle generation and continuity play crucial roles in neuroplasticity and cognitive development, these findings offer clinically relevant insights to guide anticipatory guidance for infants, children, and adolescents with DS.

Real-world data evaluation of PAP responsiveness in pediatric obstructive sleep apnea.

STUDY OBJECTIVES: The use of positive airway pressure (PAP) in children is a complex process determined by multiple factors. There are limited data on the response of the pediatric population to PAP therapy at home. The goal of the study was to examine real-world responses using PAP home monitoring in children with obstructive sleep apnea. METHODS: The study included PAP therapy data for 195 children aged between 1 month and 18 years with obstructive sleep apnea and polysomnogram baseline study. We collected demographics, clinical variables, and polysomnogram parameters in all study participants. The individual response to PAP therapy was calculated comparing the apnea-hypopnea index (AHI) in the initial polysomnogram with the mean AHI provided by the download of PAP devices. Multivariate models (logistic regression) were used to examine the predictors of positive PAP response defined as a reduction in AHI ≥ 75%. RESULTS: We found excellent responses to PAP therapy in children (median 85% AHI reduction). However, there was substantial heterogeneity in AHI reductions while on PAP therapy. The best PAP responses were linked to more severe obstructive sleep apnea and higher PAP levels. We also identified that the response to PAP was higher in obese children and lower in males. The best predictive model for individual PAP response was biological sex, obesity, and obstructive AHI ≥ 20 events/h (area under the receiver operating characteristic curve of 0.791). CONCLUSIONS: Real-world data show that PAP is overall an effective therapy in children but the response is heterogeneous. Obstructive sleep apnea parameters and individual factors can be used to predict individual AHI reductions while on PAP and optimize PAP responses at home. CITATION: Aguilar H, Kahanowitch R, Weiss M, et al. Real-world data evaluation of PAP responsiveness in pediatric obstructive sleep apnea. J Clin Sleep Med. 2023;19(7):1313-1319.

Defining Age-related OSA Features in Robin Sequence Using Polysomnographic-based Analyses of Respiratory Arousal Responses and Gas-exchange Parameters.

INTRODUCTION: Robin sequence (RS) is a leading cause of obstructive sleep apnea (OSA) in newborns. Most studies have focused on understanding anatomic factors leading to OSA and changes in apnea-hypopnea index (AHI) on polysomnography (PSG) beyond the neonatal period. This study aims to define age-related OSA features between patients with RS, without RS and healthy controls using PSG-based analyses of respiratory arousal responses and gas-exchange parameters. DESIGN: Retrospective comparison of PSG features in a total of 48 children encompassing three groups: (a) infants with RS (n = 24, <1-year old), (b) non-RS older children (1-2 years old) with severe OSA (obstructive AHI (OAHI) of ≥10 events; n = 12), and (c) control infants and children (0-2 years old) without sleep apnea (OAHI ≤1.5/h, n = 12). We examined OSA sleep-stage specific and position-specific indexes, and the relationship between OSA severity and respiratory arousal indexes (OAHI/respiratory arousal indexes). RESULTS: OSA sleep-stage specific indexes (rapid eye movement [REM] vs non-REM[NREM]) as well as position-specific indexes (supine vs nonsupine) were similar in individuals with and without RS. Relative to the non-RS groups, infants with RS have more sustained hypoxemia (time with SpO2 < 90%) and reduced arousal responses to OSA demonstrated by higher OAHI/respiratory arousal indexes. OAHI/respiratory arousal indexes significantly correlated with the severity of hypoxemia in infants with RS. CONCLUSION: Infants with RS and OSA show reduced arousal responses to apneic events, which correlates with higher hypoxemia severity. OAHI/respiratory arousal indexes in RS may identify high-risk individuals with upper airway obstruction and reduced arousal protective responses.

Increased incidence of pediatric narcolepsy following the 2009 H1N1 pandemic: a report from the pediatric working group of the sleep research network.

This study was aimed to evaluate the yearly incidence of pediatric narcolepsy prior to and following the 2009 H1N1 pandemic and to evaluate seasonal patterns of narcolepsy onset and associations with H1N1 influenza infection in the United States. This was a multicenter retrospective study with prospective follow-up. Participants were recruited from members of the Pediatric Working Group of the Sleep Research Network including 22 sites across the United States. The main outcomes were monthly and yearly incident cases of childhood narcolepsy in the United States, and its relationship to historical H1N1 influenza data. A total of 950 participants were included in the analysis; 487 participants were male (51.3%). The mean age at onset of excessive daytime sleepiness (EDS) was 9.6  ±â€… 3.9 years. Significant trend changes in pediatric narcolepsy incidence based on EDS onset (p  <  .0001) occurred over the 1998-2016 period, peaking in 2010, reflecting a 1.6-fold increase in narcolepsy incidence. In addition, there was significant seasonal variation in narcolepsy incident cases, with increased cases in spring (p  <  .05). Cross-correlation analysis demonstrated a significant correlation between monthly H1N1 infection and monthly narcolepsy incident cases (p  =  .397, p  <  .0001) with a lag time of 8 months. We conclude that there is a significant increase in pediatric narcolepsy incidence after the 2009 H1N1 pandemic in the United States. However, the magnitude of increase is lower than reported in European countries and in China. The temporal correlation between monthly H1N1 infection and monthly narcolepsy incidence, suggests that H1N1 infection may be a contributing factor to the increased pediatric narcolepsy incidence after the 2009 H1N1 pandemics.

Defining the patterns of PAP adherence in pediatric obstructive sleep apnea: a clustering analysis using real-world data.

STUDY OBJECTIVES: The implementation of positive airway pressure (PAP) therapy to treat obstructive sleep apnea in children is a complex process. PAP therapy data are highly heterogeneous in pediatrics, and the clinical management cannot be generalized. We hypothesize that pediatric PAP users can be subgrouped via clustering analysis to guide tailored interventions. METHODS: PAP therapy data for 250 children with obstructive sleep apnea were retrospectively examined using unsupervised hierarchical cluster analysis based on (1) PAP tolerance (average hours on days used) and (2) consistency of PAP use (percentage of days used). Clinical features in each cluster were defined, and a tree decision analysis was generated for clinical implementation. RESULTS: We were able to subclassify all 250 children (median age = 11.5 years) into five clusters: A (13.6%), B (29.6%), C (17.6%), D (16.4%), and E (22.8%). The clusters showed significant differences in PAP use patterns (Kruskal-Wallis P value < 1e-16). The most consistent PAP use patterns were seen in clusters A, B, and C. Major differences across clusters included the prevalence of obesity, PAP setting, developmental delay, and adenotonsillectomy. We also identified important differences in mask acceptance, OSA severity, and individual responses to PAP therapy based on objective apnea-hypopnea reductions in PAP downloads. CONCLUSIONS: A simple method to subset PAP use patterns in children can be implemented by analyzing cloud-based PAP therapy data. This novel approach may contribute to optimization of PAP therapy in children of all ages based on real-world evidence at the individual level.

Central breathing abnormalities in children with trisomy 21: Effect of age, sex, and concomitant OSA.

BACKGROUND: Trisomy 21 (TS21) is a condition with a high risk for sleep apnea. In the pediatric population, the risk also includes central breathing disorders. The aim of this study was to define the clinical and polysomnographic characteristics of central apnea in infants, children, and adolescents with TS21. METHODS: Retrospective review of baseline polysomnograms (PSGs) in children with TS21 in the sleep center at Children's National Medical Center in Washington DC. RESULTS: We included a total of 158 infants, children, and adolescents (0-18 years) with TS21 in this study. The median age was 4.82 years and 62% were male. The primary findings of the study are that (1) 12% of all pediatric subjects with TS21 included had a central apnea index (CAI) > 2/h; (2) the proportion of TS21 individuals with central breathing abnormalities progressively decreased with age being common in young individuals (≤2 years of age) but rare after 10 years of age; (3) additional sleep breathing disturbances (e.g., OSA and/or hypoxemia) are often present in children with TS21 and central apnea; and (4) the prevalence of central breathing abnormalities in TS21 is influenced by sex, being more likely to persist beyond early childhood (>2 years of age) in females than in males. CONCLUSION: Central breathing abnormalities are common in TS21 among young children (≤2 years of age) and in females older than 2 years of age. Central apnea is often associated with concomitant obstructive sleep apnea and/or hypoxemia in children with TS21.

Sleep interruption associated with house staff work schedules alters circadian gene expression.

BACKGROUND: Epidemiological studies indicate that disruption of circadian rhythm by shift work increases the risk of breast and prostate cancer. Our studies demonstrated that carcinogens disrupt the circadian expression of circadian genes (CGs) and circadian-controlled genes (CCGs) during the early stages of rat mammary carcinogenesis. A chemopreventive regimen of methylselenocysteine (MSC) restored the circadian expression of CGs and CCGs, including PERIOD 2 (PER2) and estrogen receptor ß (ERS2), to normal. The present study evaluated whether changes in CG and CCG expression in whole blood can serve as indicators of circadian disruption in shift workers. METHODS: Fifteen shift workers were recruited to a crossover study. Blood samples were drawn before (6 PM) and after (8 AM) completing a night shift after at least seven days on floating night-shift rotation, and before (8 AM), during (1 PM), and after (6 PM) completing seven days on day shift. The plasma melatonin level and messenger RNA (mRNA) expression of PER2, nuclear receptor subfamily 1, group d, member 1 (NR1D1), and ERS2 were measured, and the changes in levels of melatonin and gene expression were evaluated with statistical analyses. RESULTS: The mRNA expression of PER2 was affected by shift (p = 0.0079); the levels were higher in the evening for the night shift, but higher in the morning for the day shift. Increased PER2 expression (p = 0.034) was observed in the evening on the night versus day shifts. The melatonin level was higher in the morning for both day shifts (p = 0.013) and night shifts (p <0.0001). CONCLUSION: Changes in the level of PER2 gene expression can serve as a biomarker of disrupted circadian rhythm in blood cells. Therefore, they can be a useful intermediate indicator of efficacy in future MSC-mediated chemoprevention studies.

Mapping of Mcs30, a new mammary carcinoma susceptibility quantitative trait locus (QTL30) on rat chromosome 12: identification of fry as a candidate Mcs gene.

Rat strains differ dramatically in their susceptibility to mammary carcinogenesis. On the assumption that susceptibility genes are conserved across mammalian species and hence inform human carcinogenesis, numerous investigators have used genetic linkage studies in rats to identify genes responsible for differential susceptibility to carcinogenesis. Using a genetic backcross between the resistant Copenhagen (Cop) and susceptible Fischer 344 (F344) strains, we mapped a novel mammary carcinoma susceptibility (Mcs30) locus to the centromeric region on chromosome 12 (LOD score of ∼8.6 at the D12Rat59 marker). The Mcs30 locus comprises approximately 12 Mbp on the long arm of rat RNO12 whose synteny is conserved on human chromosome 13q12 to 13q13. After analyzing numerous genes comprising this locus, we identified Fry, the rat ortholog of the furry gene of Drosophila melanogaster, as a candidate Mcs gene. We cloned and determined the complete nucleotide sequence of the 13 kbp Fry mRNA. Sequence analysis indicated that the Fry gene was highly conserved across evolution, with 90% similarity of the predicted amino acid sequence among eutherian mammals. Comparison of the Fry sequence in the Cop and F344 strains identified two non-synonymous single nucleotide polymorphisms (SNPs), one of which creates a putative, de novo phosphorylation site. Further analysis showed that the expression of the Fry gene is reduced in a majority of rat mammary tumors. Our results also suggested that FRY activity was reduced in human breast carcinoma cell lines as a result of reduced levels or mutation. This study is the first to identify the Fry gene as a candidate Mcs gene. Our data suggest that the SNPs within the Fry gene contribute to the genetic susceptibility of the F344 rat strain to mammary carcinogenesis. These results provide the foundation for analyzing the role of the human FRY gene in cancer susceptibility and progression.