A transcriptomics-based drug repositioning approach to identify drugs with similar activities for the treatment of muscle pathologies in spinal muscular atrophy (SMA) models.

Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder caused by the reduction of survival of motor neuron (SMN) protein levels. Although three SMN-augmentation therapies are clinically approved that significantly slow down disease progression, they are unfortunately not cures. Thus, complementary SMN-independent therapies that can target key SMA pathologies and that can support the clinically approved SMN-dependent drugs are the forefront of therapeutic development. We have previously demonstrated that prednisolone, a synthetic glucocorticoid (GC) improved muscle health and survival in severe Smn-/-;SMN2 and intermediate Smn2B/- SMA mice. However, long-term administration of prednisolone can promote myopathy. We thus wanted to identify genes and pathways targeted by prednisolone in skeletal muscle to discover clinically approved drugs that are predicted to emulate prednisolone's activities. Using an RNA-sequencing, bioinformatics, and drug repositioning pipeline on skeletal muscle from symptomatic prednisolone-treated and untreated Smn-/-; SMN2 SMA and Smn+/-; SMN2 healthy mice, we identified molecular targets linked to prednisolone's ameliorative effects and a list of 580 drug candidates with similar predicted activities. Two of these candidates, metformin and oxandrolone, were further investigated in SMA cellular and animal models, which highlighted that these compounds do not have the same ameliorative effects on SMA phenotypes as prednisolone; however, a number of other important drug targets remain. Overall, our work further supports the usefulness of prednisolone's potential as a second-generation therapy for SMA, identifies a list of potential SMA drug treatments and highlights improvements for future transcriptomic-based drug repositioning studies in SMA.

Follow-up of children with Down syndrome and sleep disordered breathing and the effects of treatment on actigraphically recorded sleep, quality of life, behaviour, and daytime functioning.

Children with Down syndrome are at increased risk of obstructive sleep disordered breathing, which has deleterious effects on daytime functioning. We aimed to examine the effects of treatment of sleep disordered breathing on sleep quality and daytime functioning in children with Down syndrome, and hypothesised that these would be improved. Thirty-four children completed a baseline study and a follow-up 2 years later. Measures at both time points included 7 days of actigraphy and parents completed a number of questionnaires assessing sleep, behaviour, daytime functioning, and quality of life. All children had overnight polysomnography at baseline; 15 children (44%) were treated. At baseline the treated group had more severe sleep disordered breathing compared with the untreated group: obstructive apneoa-hypopnoea index 29.3 ± 38.2 events/h versus 3.3 ± 5.2 events/h (p < 0.01). Actigraphy showed no significant differences in total sleep time, sleep efficiency, sleep schedules from baseline to follow up in either group. The sleep disturbance (p < 0.01) and total problems (p < 0.05) scales on the OSA-18 and the sleep disordered breathing subscale on the Paediatric Sleep Problem Survey Instrument (p < 0.01) improved in the treated children. There were no changes in any measure in the untreated children. Treatment of sleep disordered breathing improves symptoms, sleep disturbance and quality of life in children with Down syndrome, but has no demonstrable impact on actigraphic sleep measures or daytime behaviour or function. In contrast, children who were not treated, despite having less severe disease at baseline, had increased sleep disruption and no change in quality of life.

Preterm infants experience a nadir in cerebral oxygenation during sleep three months after hospital discharge.

AIM: Preterm infants are at increased risk of Sudden Infant Death Syndrome (SIDS) and frequently experience short central apnoeas which can occur in isolation or a repetitive pattern (periodic breathing). We investigated the relationship between central apnoeas experienced before and over the 6 months after hospital discharge and cerebral oxygenation. METHODS: Preterm infants born between 28 and 32 weeks gestational age (GA) were studied during supine daytime sleep at 32-36 weeks post menstrual age (PMA) (n = 40), 36-40 weeks PMA (n = 27), 3-months corrected age (CA) (n = 20) and 6-months CA (n = 26). Cerebral tissue oxygenation (TOI), peripheral oxygenation (SpO2) and heart rate were recorded continuously. The percentage total sleep time (%TST) spent having central apnoeas at each study and cerebral fractional oxygen extraction (SpO2-TOI/SpO2) were calculated. RESULTS: %TST spent with central apnoeas decreased with increasing age in both active sleep (AS) and quiet sleep (QS). TOI tended to be lower and cerebral fractional oxygen extraction higher at 3 months compared to the other studies and this reached statistical significance compared to 32-36 weeks in QS. CONCLUSION: The nadir in cerebral tissue oxygenation at 3 months of age coincides with the peak risk period for SIDS and this may contribute to increased risk in these infants.

Duration and Consequences of Periodic Breathing in Infants Born Preterm Before and After Hospital Discharge.

OBJECTIVE: To investigate the amount of time spent in periodic breathing and its consequences in infants born preterm before and after hospital discharge. METHODS: Infants born preterm between 28-32 weeks of gestational age were studied during daytime sleep in the supine position at 32-36 weeks of postmenstrual age (PMA), 36-40 weeks of PMA, and 3 months and 6 months of corrected age. The percentage of total sleep time spent in periodic breathing (% total sleep time periodic breathing) was calculated and infants were grouped into below and above the median (8.5% total sleep time periodic breathing) at 32-36 weeks and compared with 36-40 weeks, 3 and 6 months. RESULTS: Percent total sleep time periodic breathing was not different between 32-36 weeks of PMA (8.5%; 1.5, 15.0) (median, IQR) and 36-40 weeks of PMA (6.6%; 0.9, 15.1) but decreased at 3 (0.4%; 0.0, 2.0) and 6 months of corrected age 0% (0.0, 1.1). Infants who spent above the median % total sleep time periodic breathing at 32-36 weeks of PMA spent more % total sleep time periodic breathing at 36-40 weeks of PMA (18.1%; 7.7, 23.9 vs 2.1%; 0.6, 6.4) and 6 months of corrected age 0.9% (0.0, 3.3) vs 0.0% (0.0, 0.0). CONCLUSIONS: Percentage sleep time spent in periodic breathing did not decrease as infants born preterm approached term corrected age, when they were to be discharged home. High amounts of periodic breathing at 32-36 weeks of PMA was associated with high amounts of periodic breathing at term corrected age (36-40 weeks of PMA), and persistence of periodic breathing at 6 months of corrected age.

Sleep spindles are reduced in children with Down syndrome and sleep-disordered breathing.

BACKGROUND: Children with Down syndrome (DS) are at increased risk of sleep-disordered breathing (SDB). We investigated sleep spindle activity, as a marker of sleep quality, and its relationship with daytime functioning in children with DS compared to typically developing (TD) children. METHODS: Children with DS and SDB (n = 44) and TD children matched for age, sex and SDB severity underwent overnight polysomnography. Fast or Slow sleep spindles were identified manually during N2/N3 sleep. Spindle activity was characterized as spindle number, density (number of spindles/h) and intensity (density × average duration) on central (C) and frontal (F) electrodes. Parents completed the Child Behavior Check List and OSA-18 questionnaires. RESULTS: In children with DS, spindle activity was lower compared to TD children for F Slow and F Slow&Fast spindles combined (p < 0.001 for all). Furthermore, there were no correlations between spindle activity and CBCL subscales; however, spindle activity for C Fast and C Slow&Fast was negatively correlated with OSA-18 emotional symptoms and caregiver concerns and C Fast activity was also negatively correlated with daytime function and total problems. CONCLUSIONS: Reduced spindle activity in children with DS may underpin the increased sleep disruption and negative effects of SDB on quality of life and behavior. IMPACT: Children with Down syndrome (DS) are at increased risk of sleep-disordered breathing (SDB), which is associated with sleep disruption affecting daytime functioning. Sleep spindles are a sensitive marker of sleep quality. We identified for the first time that children with DS had reduced sleep spindle activity compared to typically developing children matched for SDB severity. The reduced spindle activity likely underpins the more disrupted sleep and may be associated with reduced daytime functioning and quality of life and may also be an early biomarker for an increased risk of developing dementia later in life in children with DS.

Autonomic cardiovascular control is altered by intermittent hypoxia in preterm infants.

AIM: Preterm infants frequently experience short apnoeas and periodic breathing. Animal studies have shown that repetitive hypoxia associated with periodic breathing can alter autonomic control. We aimed to elucidate if apnoea and periodic breathing were associated with changes in autonomic control assessed using heart rate variability, thus exacerbating the consequences of respiratory disturbance. METHODS: Forty very preterm infants (15 M/25 F) were studied at 34.3 weeks post-menstrual age with daytime polysomnography. Total power, low frequency (LF, sympathetic+parasympathetic activity) high frequency (HF, parasympathetic activity) and LF/HF (sympathovagal balance) were calculated. RESULTS: Infants were divided into those with above and below the median total sleep time spent with respiratory events: Active sleep (AS) 13%, Quiet sleep (QS) 10%. In AS, including respiratory events, Total power (p < 0.05) and HF power (p < 0.05) were higher in the above median group. During AS excluding respiratory events, Total power (p < 0.05) and HF power (p = 0.061) were higher and LF power (p < 0.01) and LF/HF (p < 0.05) were lower in the above median group. There were no differences in HRV parameters in QS. CONCLUSION: This study provides new evidence that short apnoeas, particularly periodic breathing, which is currently not detected or treated in the neonatal unit can affect autonomic cardiovascular control.

Altered bone development with impaired cartilage formation precedes neuromuscular symptoms in spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a fatal neurodegenerative disease of newborns and children caused by mutations or deletions of the survival of motoneuron gene 1 resulting in low levels of the SMN protein. While neuromuscular degeneration is the cardinal symptom of the disease, the reduction of the ubiquitously expressed SMN additionally elicits non-motoneuron symptoms. Impaired bone development is a key feature of SMA, but it is yet unknown whether this is an indirect functional consequence of muscle weakness or caused by bone-intrinsic mechanisms. Therefore, we radiologically examined SMA patients in a prospective, non-randomized cohort study characterizing bone size and bone mineral density (BMD) and performed equivalent measurements in pre-symptomatic SMA mice. BMD as well as lumbar vertebral body size were significantly reduced in SMA patients. This growth defect but not BMD reduction was confirmed in SMA mice by µCT before the onset of neuromuscular symptoms indicating that it is at least partially independent of neuromuscular degeneration. Interestingly, the number of chondroblasts in the hypertrophic zone of the growth plate was significantly reduced. This was underlined by RNAseq and expression data from developing SMA mice vertebral bodies, which revealed molecular changes related to cell division and cartilage remodeling. Together, these findings suggest a bone intrinsic defect in SMA. This phenotype may not be rescued by novel drugs that enhance SMN levels in the central nervous system only.

Sleep-disordered breathing and sleep macro- and micro-architecture in children with Down syndrome.

BACKGROUND: Children with Down syndrome (DS) are at increased risk of sleep-disordered breathing (SDB), which is associated with intermittent hypoxia and sleep disruption affecting daytime functioning. We aimed to compare the impact of SDB on sleep quality in children with DS compared to typically developing (TD) children with and without SDB. METHODS: Children with DS and SDB (n = 44) were age- and sex-matched with TD children without SDB (TD-) and also for SDB severity with TD children with SDB (TD+). Children underwent overnight polysomnography with sleep macro- and micro-architecture assessed using electroencephalogram (EEG) spectral analysis, including slow-wave activity (SWA, an indicator of sleep propensity). RESULTS: Children with DS had greater hypoxic exposure, more respiratory events during REM sleep, higher total, delta, sigma, and beta EEG power in REM than TD+ children, despite the same overall frequency of obstructive events. Compared to TD- children, they also had more wake after sleep-onset and lower sigma power in N2 and N3. The DS group had reduced SWA, indicating reduced sleep drive, compared to both TD groups. CONCLUSIONS: Our findings suggest that SDB has a greater impact on sleep quality in children with DS compared to TD children. IMPACT: SDB in children with DS exacerbates disruption of sleep quality, compared to TD children. The prevalence of SDB is very high in children with DS; however, studies on the effects of SDB on sleep quality are limited in this population. Our findings suggest that SDB has a greater impact on sleep quality in children with DS compared to TD children, and should be screened for and treated as soon as possible.

Children with Down syndrome and sleep disordered breathing have altered cardiovascular control.

BACKGROUND: Sleep disordered breathing (SDB) in typically developing (TD) children is associated with adverse cardiovascular effects. As children with Down syndrome (DS) are at increased risk for SDB, we aimed to compare the cardiovascular effects of SDB in children with DS to those of TD children with and without SDB. METHODS: Forty-four children with DS (3-19 years) were age and sex matched with 44 TD children without SDB (TD-) and with 44 TD children with matched severity of SDB (TD+). Power spectral density was calculated from ECG recordings, for low frequency (LF), high frequency (HF), total power and the LF/HF ratio. RESULTS: Children with DS had lower HF power, and higher LF/HF during sleep and when awake. There were no differences between groups for LF power. SpO2 nadir, average SpO2 drop and SpO2 > 4% drop were larger in the DS group compared to the TD+ group (p < 0.05 for all). CONCLUSIONS: Our findings demonstrate significantly reduced parasympathetic activity (reduced HF power) and increased LF/HF (a measure of sympathovagal balance) in children with DS, together with greater exposure to hypoxia, suggesting SDB has a greater effect in these children that may contribute to an increased risk of adverse cardiovascular outcomes. IMPACT: Sleep disordered breathing in children with Down syndrome exacerbates impaired autonomic control and increases exposure to hypoxia, compared to typically developing children. In typically developing children sleep disordered breathing has adverse effects on autonomic cardiovascular control. The prevalence of sleep disordered breathing is very high in children with Down syndrome; however, studies on the effects on cardiovascular control are limited in this population. This study supports screening and early treatment of sleep disordered breathing in children with Down syndrome.

Light modulation ameliorates expression of circadian genes and disease progression in spinal muscular atrophy mice.

Physiology and behaviour are critically dependent on circadian regulation via a core set of clock genes, dysregulation of which leads to metabolic and sleep disturbances. Metabolic and sleep perturbations occur in spinal muscular atrophy (SMA), a neuromuscular disorder caused by loss of the survival motor neuron (SMN) protein and characterized by motor neuron loss and muscle atrophy. We therefore investigated the expression of circadian rhythm genes in various metabolic tissues and spinal cord of the Taiwanese Smn-/-;SMN2 SMA animal model. We demonstrate a dysregulated expression of the core clock genes (clock, ARNTL/Bmal1, Cry1/2, Per1/2) and clock output genes (Nr1d1 and Dbp) in SMA tissues during disease progression. We also uncover an age- and tissue-dependent diurnal expression of the Smn gene. Importantly, we observe molecular and phenotypic corrections in SMA mice following direct light modulation. Our study identifies a key relationship between an SMA pathology and peripheral core clock gene dysregulation, highlights the influence of SMN on peripheral circadian regulation and metabolism and has significant implications for the development of peripheral therapeutic approaches and clinical care management of SMA patients.

Sleep macro-architecture and micro-architecture in children born preterm with sleep disordered breathing.

BACKGROUND: Both preterm birth and sleep disordered breathing (SDB) affect sleep in children. We compared the effects of SDB on sleep macro-architecture and micro-architecture in children born preterm (N = 50) and children born at term (N = 50). We hypothesized that sleep would be more disrupted in children born preterm. METHODS: Polysomnographic studies matched for age (3-12 years) and SDB severity were analyzed. Sleep macro-architecture was assessed using standard criteria and micro-architecture was evaluated using spectral analysis of the electroencephalogram and slow wave activity (SWA) calculated for each sleep stage across the night. RESULTS: Ex-preterm children (gestational age 29.3 ± 3.6 weeks, mean ± standard error of the mean) were not different from controls for demographic or respiratory parameters or sleep macro-architecture. Theta power in N2 tended to be higher for F4 (p < 0.05) and C4 (p < 0.07). In the second non-rapid eye movement period, SWA was significantly higher in the preterm group compared to the term group for both F4 and C4 (p < 0.05 for both). CONCLUSIONS: Sleep micro-architecture in children born preterm showed increased theta power and SWA. These differences provide evidence of increased sleep debt and reduced dissipation of sleep debt across the night. Further studies are required to identify if these findings are related to impaired neurocognition and behavior.

Role of ventilatory control instability in children with sleep-disordered breathing.

BACKGROUND AND OBJECTIVE: The contribution of non-anatomical factors, such as ventilatory control instability (i.e. LG), to the pathogenesis of obstructive SDB in children is unclear. Therefore, we aimed to identify the relationship between LG and severity of SDB, demographic, anthropometric and anatomical characteristics in a clinically representative cohort of children. METHODS: Children (aged 3-18 years) with various severities of SDB (n = 110) and non-snoring controls (n = 36) were studied. Children were grouped according to their OAHI. Anthropometric and upper airway anatomical characteristics were measured. Spontaneous sighs were identified on polysomnography and LG, a measure of the sensitivity of the negative feedback loop that controls ventilation, was estimated by fitting a mathematical model of ventilatory control to the post-sigh ventilatory pattern. RESULTS: There was no difference in LG between controls and any of the SDB severity groups. However, LG was significantly lower in children with larger tonsils (tonsil grade 4) compared with children with smaller tonsils (tonsil grade 1) (median LG (range): 0.25 (0.20-0.42) vs 0.32 (0.25-0.44); P = 0.009) and in children with a modified Mallampati score of class III/IV compared with class I (0.28 (0.24-0.33) vs 0.37 (0.27-0.44); P = 0.009). CONCLUSION: A direct relationship was not found between the severity of paediatric SDB and LG. However, an altered ventilatory control sensitivity may contribute to SDB in a subgroup of children depending on their degree of anatomical compromise of the airway.

Sleep disordered breathing in children disrupts the maturation of autonomic control of heart rate and its association with cerebral oxygenation.

KEY POINTS: Sleep disordered breathing (SDB) affects 4-11% of children and is associated with adverse neurocognitive, behavioural and cardiovascular outcomes, including reduced autonomic control. The relationship between heart rate variability (HRV; a measure of autonomic control) and age found in non-snoring control children was absent during sleep in children with SDB. Age significantly predicted increasing cerebral oxygenation during wake in non-snoring control children, whereas during sleep, HRV significantly predicted decreasing cerebral oxygenation. Cerebral oxygenation was not associated with either age or HRV in children with SDB during both wake and sleep. SDB significantly disrupts the normal maturation of autonomic control and the positive association between autonomic control and cerebral oxygenation found in non-snoring children, and we speculate that the dampened autonomic control exhibited by children with SDB may have an attenuating effect on cerebral autoregulation via the moderating influence of HRV on cerebral blood flow. ABSTRACT: The repetitive episodes of hypoxia that are features of sleep disordered breathing (SDB) in children are associated with alterations in autonomic control of heart rate in an age-dependent manner. We aimed to relate heart rate variability (HRV) parameters to age and measures of cerebral oxygenation in children (3-12 years old) with SDB and non-snoring controls. Children (SDB, n = 117; controls, n = 42; 3-12 years) underwent overnight polysomnography. Total (TP), low- (LF) and high-frequency (HF) power, tissue oxygenation index (TOI) and fractional tissue oxygen extraction (FTOE) were analysed during wake and sleep. Pearson's correlations determined the association between age and HRV parameters, and multiple linear regressions between HRV, age and cerebral oxygenation parameters. During wake, age had a positive association with LF power, reflecting increased parasympathetic and sympathetic activity with increasing age for both control and SDB groups. This association was also evident during sleep in controls, but was absent in children with SDB. In controls, during wake TOI had a positive, and FTOE a negative association with age. During sleep, TP, LF and HF power were significant, negative determinants of TOI and positive determinants of FTOE. These associations were not seen in children with SDB during wake or sleep. SDB disrupts the normal maturation of the autonomic control of heart rate and the association between HRV and cerebral oxygenation exhibited by non-snoring control children of primary school age. These results highlight the impact SDB has on cardiovascular control and the potential impact on adverse cardiovascular outcomes.

Cardiovascular Autonomic Control Is Altered in Children Born Preterm with Sleep Disordered Breathing.

BACKGROUND: To assess if the effects of sleep disordered breathing (SDB) on heart rate (HR) and HR variability, as a measure of autonomic control, were more severe in a group of children born preterm compared with a group of children born at term referred to our sleep laboratory for assessment of SDB. STUDY DESIGN: Children (3-12 years of age) referred for polysomnographic assessment of SDB were recruited; 50 born preterm (<37 weeks of gestation) and 50 at term, matched for age and SDB severity. The mean HR and HR variability using power spectral analysis were calculated for each child for wake and sleep, and stages N1, N2, N3, and rapid eye movement sleep. RESULTS: Ex-preterm children were born between 23 and 35 weeks of gestational age (29.3 ± 3.6; mean ± SEM). There were no differences in the demographic, sleep, or respiratory characteristics between the groups. High-frequency power (reflecting parasympathetic activity) was greater in the ex-preterm children in both N2 and N3 (P < .05 for both) and total power was greater in N3 (P < .05). When the children were divided by SDB severity, these effects were most marked in those preterm born children with moderate to severe disease. CONCLUSIONS: Preterm born children matched for age and SDB severity with children born at term showed no differences in sleep characteristics; however, they did exhibit increased parasympathetic tone during non-rapid eye movement sleep.

Age Effects on Cerebral Oxygenation and Behavior in Children with Sleep-disordered Breathing.

RATIONALE: Childhood sleep-disordered breathing ranges in severity from primary snoring to obstructive sleep apnea and is associated with behavioral and neurocognitive deficits. It remains unknown why children with primary snoring, who do not experience peripheral oxygen desaturation or sleep fragmentation, experience similar daytime deficits as those with obstructive sleep apnea or why effects are age-dependent. OBJECTIVES: To examine cerebral tissue oxygenation and oxygen extraction as an explanation for daytime deficits in children with primary snoring. METHODS: Children referred for suspected sleep-disordered breathing and nonsnoring control subjects underwent overnight polysomnography with near-infrared spectroscopy. Children were categorized into 3- to 6-year (n = 87) and 7- to 12-year (n = 72) old groups, and according to the obstructive apnea-hypopnea index into primary snoring (≤1 event/h), mild (>1-5 events/h), and moderate/severe obstructive sleep apnea (>5 events/h). Cognitive and behavioral performance were assessed. MEASUREMENTS AND MAIN RESULTS: In the 3- to 6-year group, there were no differences in cerebral oxygenation or oxygen extraction between severity groups. In the 7- to 12-year group, cerebral oxygenation was significantly lower, although these differences were small, in control subjects versus primary snoring during quiet wakefulness before sleep onset, N1, and REM. Oxygen extraction was significantly higher in control subjects versus primary snoring during N1 sleep, with no differences between primary snoring and obstructive sleep apnea groups. Cerebral oxygenation was not associated with cognitive performance in either age group or behavior in the 3- to 6-year group; however, it was associated with behavior in the school-aged children. CONCLUSIONS: Children with sleep-disordered breathing are able to maintain cerebral oxygenation, and the small changes observed are not related to cognitive deficits. However, in older children these differences were related to behavioral measures.

Pollen levels on the day of polysomnography influence sleep disordered breathing severity in children with allergic rhinitis.

PURPOSE: Allergic rhinitis (AR) is a common risk factor for sleep disordered breathing (SDB) in children. Allergy to pollen is a trigger for allergic rhinitis, causing nasal inflammation, upper airway congestion and obstruction. We aimed to determine if the pollen count on the day of diagnostic polysomnography for SDB affected the result. METHODS: Children (3-18 years; n = 90) who participated in research studies between 1 October and 31 December, when daily regional pollen counts were available, in the years 2005-2016 were eligible for inclusion. All children underwent overnight polysomnography for assessment of SDB severity. Pollen was categorised as grass or other pollen. Multiple stepwise linear regression was performed to determine whether the pollen count for that day, a diagnosis of asthma, age, and BMI-z-score were determinants of respiratory parameters measured on polysomnography, including the obstructive apnoea hypopnoea index (OAHI), SpO2 nadir, average SpO2 drop, SpO2 < 90%, oxygen desaturation index > 4% (ODI4), and average transcutaneous CO2 (TCM). RESULTS: Sixteen/90 children had AR. In children with AR, an increase in grass pollen of 1 grain/m3 predicted an increase in OAHI of 0.2 events/h, ODI4 of 0.18 times/h, SpO2 < 90% of 0.03 times/h, and TCM of 0.07 mmHg. None of the factors were determinants of SDB severity in children without AR. CONCLUSION: Our findings highlight that daily pollen counts may be an important factor influencing the severity of SDB on a single night of polysomnography in children with clinical allergic rhinitis and should be taken into account when determining treatment options.

Obesity and anthropometric determinants of autonomic control in children with sleep-disordered breathing-which measurements matter?

BACKGROUND: Obesity and anthropometric measurements predict more severe sleep-disordered breathing (SDB) in children, and are associated with cardiovascular risk factors in children without SDB. We aimed to investigate whether anthropometric measurements predicted autonomic control in children with SDB. We hypothesised that anthropometric measures would be significant predictors of decreased heart rate variability. METHODS: Children (3-17 years) with SDB (n = 298) and non-snoring controls (n = 126) underwent polysomnography. BMI z-score, neck, waist and hip circumference were recorded. Heart rate variability, indicating autonomic control, was analysed during wake, non-rapid eye movement stages N1, N2 and N3, and rapid eye movement (REM) sleep. The determinants of heart rate variability (low-frequency power [LF], high-frequency power [HF] and LF/HF ratio) were analysed using multiple stepwise linear regression. Independent variables were age, neck, waist and hip circumference, neck-to-waist ratio, waist-to-hip ratio and waist-to-height ratio, obstructive apnoea hypopnoea index, arousal index and SpO2 nadir. RESULTS: Waist and hip circumference, and waist-to-height ratio were significant negative determinants of both HF and LF power during wake, reflecting dampened autonomic control (LF: waist/height ratio, B = -1917 (95% CI: -3640, -194), p = 0.03; HF: hip circumference, B = -27, (-48, -7), p = 0.01), N1&2 (LF/HF: hip circumference, B = 0.01 (0.004, 0.024), p = 0.005) and N3 (LF: waist/height ratio, B = -2495, (-4005, -986), p = 0.001; HF, hip circumference, B = -54, (-102, -6), p = 0.03; LF/HF, waist circumference, B = 0.01, (0.004, 0.015), p = 0.002). Age was the strongest determinant of heart rate variability during wake and sleep. CONCLUSION: This study suggests that while age is a determinant of autonomic control in children with SDB, the strongest modifiable factor determining dampened autonomic control is increased central adiposity, as reflected in the waist and hip circumference and the waist-to-height ratio.

How Well Do Children with Cystic Fibrosis Sleep? An Actigraphic and Questionnaire-Based Study.

OBJECTIVE: To measure sleep patterns and quality, objectively and subjectively, in clinically stable children with cystic fibrosis (CF) and healthy control children, and to examine the relationship between sleep quality and disease severity. STUDY DESIGN: Clinically stable children with CF and healthy control children (7-18 years of age) were recruited. Sleep patterns and quality were measured at home with actigraphy (14 days). Overnight peripheral capillary oxygen saturation was measured via the use of pulse oximetry. Daytime sleepiness was evaluated by the Pediatric Daytime Sleepiness Scale (PDSS) and subjective sleep quality by the Sleep Disturbance Scale for Children and Obstructive Sleep Apnea-18. RESULTS: A total of 87 children with CF and 55 control children were recruited with no differences in age or sex. Children with CF had significantly lower total sleep time and sleep efficiency than control children due to frequent awakenings and more wake after sleep onset. In children with CF, forced expiratory volume in 1 second and overnight peripheral capillary oxygen saturation nadir correlated positively with total sleep time and sleep efficiency and negatively with frequency of awakenings and wake after sleep onset. Patients with CF had significantly greater Sleep Disturbance Scale for Children (45 vs 35; P < .001), Obstructive Sleep Apnea-18 (35 vs 24; P < .001), and PDSS scores (14 vs 11; P < .001). There was a negative correlation between PDSS and forced expiratory volume in 1 second (r = -0.23; P < .05). CONCLUSIONS: Even in periods of clinical stability, children with CF get less sleep than their peers due to more time in wakefulness during the night rather than less time spent in bed. Objective measures of sleep disturbance and subjective daytime sleepiness were related to disease severity. In contrast, parents of children with CF report high levels of sleep disturbance unrelated to disease severity.

Improved long-term autonomic function following resolution of sleep-disordered breathing in preschool-aged children.

PURPOSE: Sleep-disordered breathing (SDB) prevalence peaks in preschool children and is associated with deficits in cardiovascular functioning during sleep. No long-term studies have investigated the effects of SDB resolution in mitigating these outcomes. We hypothesized that following 3 years, normalization of alterations to heart rate (HR), pulse transit time (PTT), heart rate variability (HRV), and urinary catecholamines identified at the initial diagnosis would be associated with resolution of SDB. METHODS: Forty-five children with SDB and 28 non-snoring controls underwent polysomnography at baseline (3-5 years) and follow-up (6-9 years). Children were classified into control, resolved, and unresolved SDB. Resolution was defined as an obstructive apnea-hypopnea index (OAHI) ≤1 event/h, no snoring on polysomnography (PSG), or indicated by parents. PTT is an inverse surrogate measure of blood pressure change. HRV was assessed using power spectral analysis. RESULTS: There was no change in PTT or HR between studies for any group. Our HRV data suggest reduced parasympathetic activity in children whose SDB resolved and increased parasympathetic activity in children whose SDB remained the same or worsened at follow-up. We identified a significant correlation between low frequency power and urinary dopamine and adrenaline levels at follow-up in the unresolved group, suggesting increased sympathetic activity in children with unresolved SDB. CONCLUSION: Our findings suggest an association between resolution of SDB and normalization of HRV in the long term in these preschool children and an augmented sympathetic activity in the children with residual SDB. This highlights the autonomic impact of SDB in young children and the importance of detection and treatment.

The efficacy of the OSA-18 as a waiting list triage tool for OSA in children.

PURPOSE: Sleep disordered breathing (SDB) is common in children, resulting in extensive waiting lists for specialist clinics. There is an urgent need for a valid method of triaging patients and the OSA-18, a disease-specific tool, is an attractive candidate for this role. We aimed to examine the OSA-18 as a measurement tool in detail and to determine whether the score or aspects of it could be used as a screening tool for SDB in children. METHODS: Retrospective analysis of 582 children (6 months to 16.4 years)-216 underwent overnight PSG and 366 overnight oximetry. Confirmatory factor analysis (CFA) and exploratory factor analysis (EFA) were conducted. Receiver operating characteristic curve analysis assessed the diagnostic accuracy of the factors for the presence of OSA. Rasch analysis was used to assess the structure of the items (1-18) and categories of response (Likert scale). RESULTS: The CFA with a forced five-factor structure, revealed three factors with Eigenvalues >1, and explained 73.7 % of the variance. EFA resulted in a two-factor structure, explaining 60.3 % of the variance. Assessment of sensitivity and specificity showed a high false-positive rate, irrespective of the factor structure tested. Rasch analysis showed poor discrimination between adjacent categories on the Likert scale. CONCLUSION: This study confirmed that the predictive value of the OSA-18 for SDB severity is weak. Some questions perform better than others statistically, and the seven categories of response introduce significant statistical noise, raising the possibility that modification of the OSA-18 may improve its performance in the prediction of OSA severity.