Effect of sleep disordered breathing severity in children with Down syndrome on parental wellbeing and social support.

INTRODUCTION: Sleep disorders, particularly sleep disordered breathing (SDB), are common in children with Down syndrome (DS). We investigated the relationship between SDB severity and parental psychological wellbeing and their perception of social support. METHODS: 44 children with DS (3-19 years) underwent overnight polysomnography and were categorised into three groups: primary snoring, Mild and Moderate/Severe obstructive sleep apnoea (OSA). Parents completed questionnaires about their child's behaviour (Child Behavior Checklist), sleep symptoms (Pediatric Sleep Survey Instrument) and SDB-related quality of life (OSA-18), together with the DUKE-UNC Functional Social Support (DUKE) and Psychological General Well-Being Index (PGWBI) questionnaires for themselves. 34 children completed a follow-up study after 2 years. RESULTS: There were no significant differences between SDB severity groups for parental perceived social support or psychological wellbeing. Total scores on the DUKE were below average and PGWBI scores were indicative of moderate psychological distress in all three groups. Reduced perceived levels of social support were significantly correlated with externalising child behaviour and sleep disturbance. Diminished parental psychological wellbeing was also significantly correlated with increased sleep disturbances and reduced quality of life in children. At follow-up there were no significant changes in any questionnaire outcome, however parents of children with improved SDB severity had improved PGWBI vitality scores. CONCLUSION: The degree of parent-reported sleep disturbance in children with DS was linked to suboptimal perceived parental social support and poor psychological wellbeing. Our results emphasise the need for enhanced awareness of the detrimental effects of sleep problems in children with DS on parental wellbeing.

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.

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.

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.

Developmental consequences of short apneas and periodic breathing in preterm infants.

OBJECTIVE: We investigated the relationship between respiratory events experienced before and after hospital discharge and developmental outcomes at 6 months corrected age (CA). STUDY DESIGN: Preterm infants born between 28-32 weeks gestational age (GA) were studied at 32-36 weeks postmenstrual age (PMA), 36-40 weeks PMA, 3- and 6-months CA. Percentage total sleep time (%TST) with respiratory events (isolated apneas, sequential apneas and periodic breathing (PB)) at each study was calculated. Stepwise multiple linear regressions determined significant predictors of developmental outcomes at 6 months. RESULT: %TST with respiratory events at term were significant predictors of language (R2 = 0.165, ß = -0.416) and motor (R2 = 0.180, ß = -0.485) composite scores of the Bayley Scales of Infant Development at 6 months, independent of GA, birth weight and sex. CONCLUSIONS: In clinically stable very preterm infants at term equivalent age, time spent having respiratory events, was related to a reduction in language and motor outcomes at 6 months.

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.

Cortical grey matter changes, behavior and cognition in children with sleep disordered breathing.

This paper investigated cortical thickness and volumetric changes in children to better understand the impact of obstructive sleep disordered breathing (SDB) on the neurodevelopment of specific regions of the brain. We also aimed to investigate how these changes were related to the behavioral and cognitive deficits observed in the condition. Neuroimaging, behavioral, and sleep data were obtained from 30 children (15 non-snoring controls, 15 referred for assessment of SDB) aged 7 to 17 years. Gyral-based regions of interest were identified using the Desikan-Killiany atlas. Student's t-tests were used to compare regions of interest between the controls and SDB groups. We found that the cortical thickness was significantly greater in the right caudal anterior cingulate and right cuneus regions and there were volumetric increases in the left caudal middle frontal, bilateral rostral anterior cingulate, left, right, and bilateral caudate brain regions in children with SDB compared with controls. Neither cortical thickness nor volumetric changes were associated with behavioral or cognitive measures. The findings of this study indicate disruptions to neural developmental processes occurring in structural regions of the brain; however, these changes appear unrelated to behavioural or cognitive outcomes.

Assessing sleep in children with Down syndrome: Comparison of parental sleep diaries, actigraphy and polysomnography.

BACKGROUND: This study compared measurements of sleep and wake assessed with actigraphy, sleep diary and polysomnography in children with Down syndrome (DS) and also compared measures of actigraphic sleep recording in children with DS and typically developing (TD) children. METHODS: Children with DS aged 3-19 years (N = 44) referred for assessment of sleep disordered breathing (SDB) underwent overnight polysomnography, together with 1 week of actigraphy with sleep diary. Actigraphy data from the children with DS were compared with data collected from TD children, matched for age and sex. RESULTS: 22 children (50%) with DS completed >3 consecutive nights of actigraphy with a matched sleep diary. There were no differences between bedtimes, wake times or time in bed on weeknights, weekends or over 7 nights between actigraphy and sleep diary. Total sleep time was over estimated by the sleep diary by almost 2 h and the number of night awakenings under-reported. Compared to matched TD children (N = 22), there was no difference in total sleep time, however children with DS fell asleep more quickly (p < 0.001), had more awakenings (p = 0.001) and more time awake after sleep onset (p = 0.007). Children with DS exhibited less variability in both bedtimes and wake times, and fewer had >1 h sleep schedule variability. CONCLUSIONS: Parental sleep diaries over-estimate total sleep time but accurately report bed and wake times compared to actigraphy in children with DS. Children with DS have more regular sleep patterns than TD children of the same age, which is important for optimising daytime functioning. The reasons behind this warrant further investigation.

Sleep disordered breathing improvement prevents worsening of autonomic dysfunction in children with Down syndrome.

BACKGROUND: Resolution of sleep disordered breathing (SDB) in typically developing children normalises heart rate variability (HRV), a measure of autonomic control, to that of non-snoring controls. Children with Down Syndrome (DS) have dampened heart rate variability (HRV) but the effect of treatment is not known. To assess the effect of improvement of SDB on autonomic control we compared HRV in children with DS whose SDB improved over 2 y, to those whose SDB did not improve. METHODS: 24 children (3-19 y) had a baseline and follow-up polysomnographic study 2 y later. Improved SDB was defined as a reduction in obstructive apnea hypopnea index (OAHI) to ≤ 50% of baseline. Children were grouped into Improved (n = 12) and Unimproved (n = 12). Power spectral analysis of the ECG determined low frequency (LF), high frequency (HF) power and the LF/HF ratio. Seven children in the Improved and 2 in the Unimproved group were treated following the baseline study. RESULTS: In the Unimproved group at follow-up, LF power was lower compared to baseline during N3 and Total Sleep (p < 0.05 for both). HF power was lower during REM (p < 0.05). HRV remained unchanged between studies in the Improved group. CONCLUSION: Autonomic control worsened as indicated by lower LF and HF power in children whose SDB was not improved. In contrast, in those children with improved SDB, autonomic control remained the same, suggesting improvement in SDB severity prevents further worsening of autonomic control in children with DS.

Periodic breathing in clinically stable very preterm infants.

OBJECTIVE: We aimed to investigate the frequency and severity of periodic breathing (PB) in clinically stable very preterm infants and identify infant and maternal factors associated with increased time spent and severity of PB in these infants. METHOD: Thirty-eight infants (28-32 weeks gestational age) who were ≥3 days off noninvasive respiratory support, were studied for 2-3 h with a daytime sleep study at 31-36 weeks postmenstrual age. Percent total sleep time spent in PB (%TSTPB) and time spent with SpO2 <90%, <80%, and cerebral oxygenation <55% during PB were calculated. Infant and maternal characteristics were correlated with %TSTPB and hypoxia during PB. RESULTS: The majority of infants (92%) had at least one episode of PB and infants spent a median 9.1 [interquartile range: 1.2, 15.5] %TSTPB. 80%, 37%, and 37% of infants experienced SpO2 <90%, <80% and cerebral oxygenation <55%, respectively, during PB. Shorter duration of respiratory support, multigravida, multiparity, and maternal vitamin D deficiency were associated with higher %TSTPB. Multigravida, shorter duration on respiratory support, apnea of prematurity, and resuscitation at birth were associated with hypoxia during PB. CONCLUSIONS: The majority of very preterm infants exhibited PB when they were off respiratory support and considered clinically stable. The time spent in PB was very variable between infants and was associated with significant hypoxia in some infants. Fewer days spent on respiratory support was associated with both increased frequency and severity of PB. However, the potential contribution of PB to neurocognitive outcomes remains uncertain and warrants further investigations.

The effects of sleep disordered breathing on sleep spindle activity in children and the relationship with sleep, behavior and neurocognition.

STUDY OBJECTIVES: Obstructive sleep disordered breathing (SDB), has adverse neurocognitive and behavioral sequelae in children, despite conventional measures of sleep disruption being unaffected. There is growing evidence that sleep spindles may serve as a more sensitive marker of sleep quality. We investigated the relationship between sleep spindles and sleep fragmentation and neurocognition across the spectrum of SDB severity in children. METHODS: Children 3-12 years old referred for clinical assessment of SDB and age matched control children from the community were recruited and underwent polysomnography. Sleep spindles were identified manually during N2 and N3 sleep. Spindle activity was characterised as spindle number, density (number of spindles/h) and intensity (spindle density x average spindle duration). Children completed a battery of tests assessing global intellectual ability, language, attention, visuospatial ability, sensorimotor skills, adaptive behaviors and skills and problem behaviors and emotional difficulties. RESULTS: Children were grouped into control, Primary Snoring, Mild OSA and Moderate/severe OSA, N = 10/group. All measures of spindle activity were lower in the SDB groups compared to the Control children and this reached statistical significance for Mild OSA (p < 0.05 for all). Higher spindle indices were associated with better performance on executive function and visual ability assessments but poorer performance on auditory attention and communication skills. Higher spindle indices were associated with better behavior. CONCLUSION: The reduced spindle activity observed in the children with SDB, particularly Mild OSA, indicates that sleep micro-architecture is disrupted and that this disruption may underpin the negative effects of SDB on attention, learning and memory.

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.

Heart rate surge at respiratory event termination in preterm and term born children with sleep disordered breathing.

BACKGROUND: Repetitive surges in heart rate (HR) at respiratory event termination underpin the altered autonomic HR control associated with sleep disordered breathing (SDB). As children born preterm are at greater risk of adverse cardiovascular outcomes, we aimed to determine whether the HR response to obstructive respiratory events was elevated compared to term-born children. METHODS: Fifty children (3-12 years) born preterm, were matched for SDB severity, age and gender with term born children. Multilevel modelling determined the effect of preterm birth and arousal on HR changes between a 10s baseline to the latter half of respiratory events and 15s post event during NREM and REM. RESULTS: 1203 events were analysed (NREM: term 380; preterm 383; REM: term 207; preterm 233). During NREM fewer events terminated in arousal in the preterm compared with term group (preterm 68%; term 84%; χ2 = 27.2, p < 0.001). There were no differences in REM. During NREM, HR was lower in the preterm group at all event phases, with and without associated arousals (P < 0.01 for all). % change in HR from baseline to post event was higher in the preterm compared with term group (preterm: median 23% IQR (12%,34%); term: 18% (10%,29%); p < 0.01) and late event to post event (preterm: 30% (21%, 32%); term 28% (20%,39%); p < 0.01) in events associated with arousals. CONCLUSION: The greater magnitude of surges in HR following respiratory events terminating with arousal in preterm born children, although small, occur repeatedly throughout the night and may contribute to adverse cardiovascular outcomes, although further studies are required.

Nucleon Transversity Distribution in the Continuum and Physical Mass Limit from Lattice QCD.

We report a state-of-the-art lattice QCD calculation of the isovector quark transversity distribution of the proton in the continuum and physical mass limit using large-momentum effective theory. The calculation is done at four lattice spacings a={0.098,0.085,0.064,0.049} fm and various pion masses ranging between 220 and 350 MeV, with proton momenta up to 2.8 GeV. The result is nonperturbatively renormalized in the hybrid scheme with self-renormalization, which treats the infrared physics at large correlation distance properly, and extrapolated to the continuum, physical mass, and infinite momentum limit. We also compare with recent global analyses for the nucleon isovector quark transversity distribution.

Effects of Treatment of Sleep Disordered Breathing on Sleep Macro- and Micro-Architecture in Children with Down Syndrome.

Background: Children with Down syndrome (DS) are at increased risk of obstructive sleep disordered breathing (SDB), which is associated with intermittent hypoxia and sleep disruption affecting daytime functioning. We aimed to examine the effects of treatment of SDB on sleep quality and daytime functioning in children with DS. Methods: Children with DS and SDB (n = 24) completed a baseline and follow-up overnight polysomnographic (PSG) study 22 ± 7 months (mean ± SD) later. Sleep micro-architecture was assessed using EEG spectral analysis, and parents completed a number of questionnaires assessing sleep, behavior, daytime functioning, and quality of life (QOL). Results: A total of nine children (38%) were treated. At baseline, the treated group had more severe SDB compared to the untreated group. SDB severity was significantly improved from 40.3 ± 46.9 events/h to 17.9 ± 26.9 events/h (p < 0.01) at follow up in children who were treated. There were no significant differences in sleep macro-architecture parameters from baseline to follow up in either the treated or untreated group. Sleep micro-architecture was not different between studies in the treated group, however this tended to improve in the untreated group, particularly in REM sleep. Daytime functioning and behavior were not different between the studies in either group, however, QOL improved after treatment. Conclusions: Our study identified that treatment of SDB improves severity of the disease as defined by PSG, and this was associated with parental reports of improved QOL, despite treatment having no demonstrable impacts on sleep quality, behavior, or daytime functioning.

Revealing and Controlling Energy Barriers and Valleys at Grain Boundaries in Ultrathin Organic Films.

In organic electronics, local crystalline order is of critical importance for the charge transport. Grain boundaries between molecularly ordered domains are generally known to hamper or completely suppress charge transfer and detailed knowledge of the local electronic nature is critical for future minimization of such malicious defects. However, grain boundaries are typically hidden within the bulk film and consequently escape observation or investigation. Here, a minimal model system in form of monolayer-thin films with sub-nm roughness of a prototypical n-type organic semiconductor is presented. Since these films consist of large crystalline areas, the detailed energy landscape at single grain boundaries can be studied using Kelvin probe force microscopy. By controlling the charge-carrier density in the films electrostatically, the impact of the grain boundaries on charge transport in organic devices is modeled. First, two distinct types of grain boundaries are identified, namely energetic barriers and valleys, which can coexist within the same thin film. Their absolute height is found to be especially pronounced at charge-carrier densities below 1012 cm- 2 -the regime at which organic solar cells and light emitting diodes typically operate. Finally, processing conditions by which the type or energetic height of grain boundaries can be controlled are identified.

Hepatitis D virus-induced interferon response and administered interferons control cell division-mediated virus spread.

BACKGROUND & AIMS: Besides HBV-dependent de novo infection, cell division-mediated spread contributes to HDV persistence and dampens the effect of antivirals that abrogate de novo infection. Nonetheless, the combination of these antivirals with interferons (IFNs) showed strong synergism in recent clinical trials, implying a complementary mode-of-action of IFNs. Therefore, we investigated the effect of IFN response on cell division-mediated HDV spread. METHODS: Cells infected with HDV were passaged to undergo cell division. The effect of the IFN response was evaluated by blocking HDV-induced IFN activation, by applying different IFN treatment regimens, and by adjusting HDV infection doses. RESULTS: Cell division-mediated HDV spread was highly efficient following infection of HuH7NTCP cells (defective in IFN production), but profoundly restricted in infected IFN-competent HepaRGNTCP cells. Treatment with IFN-α/-λ1 inhibited HDV spread in dividing HuH7NTCP cells, but exhibited a marginal effect on HDV replication in resting cells. Blocking the HDV-induced IFN response with the JAK1/2 inhibitor ruxolitinib or knocking down MDA5 augmented HDV spread in dividing HepaRGNTCP cells. The virus-induced IFN response also destabilized HDV RNA in dividing cells. Moreover, the effect of exogenous IFNs on cell division-mediated HDV spread was more pronounced at low multiplicities of infection with weak virus-induced IFN responses. CONCLUSIONS: Both HDV-induced IFN response and exogenous IFN treatment suppress cell division-mediated HDV spread, presumably through acceleration of HDV RNA decay. Our findings demonstrate a novel mode-of-action of IFN, explain the more pronounced effect of IFN therapy in patients with lower HDV serum RNA levels, and provide insights for the development of combination therapies. LAY SUMMARY: Chronic hepatitis D is a major health problem. The causative pathogen hepatitis D virus (HDV) can propagate through viral particle-mediated infection and the division of infected cells. Although viral particle-dependent infection can be blocked by recently developed drugs, therapies addressing the cell division route have not been reported. Taking advantage of relevant cell culture models, we demonstrate that the widely used immune modulator interferon can efficiently suppress HDV spread through cell division. This work unveils a new function of interferon and sheds light on potentially curative combination therapies.

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.

HDV Seroprevalence in HBsAg-Positive Patients in China Occurs in Hotspots and Is Not Associated with HCV Mono-Infection.

HDV infection causes severe liver disease, the global health burden of which may be underestimated due to limited epidemiological data. HDV depends on HBV for infection, but recent studies indicated that dissemination can also be supported by other helper viruses such as HCV. We used a rapid point-of-care test and an ELISA to retrospectively test for antibodies against the Hepatitis Delta antigen (anti-HDV-Ab) in 4103 HBsAg-positive and 1661 HBsAg-negative, anti-HCV-positive sera from China and Germany. We found that the HDV seroprevalence in HBsAg-positive patients in China is limited to geographic hotspots (Inner Mongolia: 35/251, 13.9%; Xinjiang: 7/180, 3.9%) and high-risk intravenous drug users (HBV mono-infected: 23/247, 9.3%; HBV-HCV co-infected: 34/107, 31.8%), while none of the 2634 HBsAg carriers from other metropolitan regions were anti-HDV-Ab-positive. In Germany, we recorded an HDV seroprevalence of 5.3% in a university hospital environment. In a cohort of HBsAg-negative, anti-HCV-positive patients that were not exposed to HBV before (anti-HBc-negative), HDV was not associated with HCV mono-infection (Chinese high-risk cohort: 0/365, 0.0%; German mixed cohort: 0/263, 0.0%). However, 21/1033 (2.0%) high-risk HCV patients in China with markers of a previously cleared HBV infection (anti-HBc-positive) were positive for anti-HDV-Ab, with two of them being positive for both HDV and HCV RNA but negative for HBV DNA. The absence of anti-HDV-Ab in HCV mono-infected patients shows that HCV cannot promote HDV transmission in humans.