Sleep deprivation and recovery: Endurance racing as a novel model.

The aim of this study was to investigate sleep-wake behavior and gain insights into perceived impairment (sleep, fatigue, and cognitive function) of athletes competing in two international multi-day adventure races. Twenty-four athletes took part across two independent adventure races: Queensland, Australia and Alaska, USA. Individual sleep periods were determined via actigraphy, and racers self-reported their perceived sleep disturbances, sleep impairment, fatigue and cognitive function. Each of these indices was calculated for pre-, during- and post-race periods. Sleep was severely restricted during the race period compared to pre-race (Queensland, 7:46 [0:29] vs. 2:50 [1:01]; Alaska, 7:39 [0:58] vs. 2:45 [2:05]; mean [SD], hh:mm). As a result, there was a large cumulative sleep debt at race completion, which was not 'reversed' in the post-race period (up to 1 week). The deterioration in all four self-reported scales of perceived impairment during the race period was largely restored in the post-race period. This is the first study to document objective sleep-wake behaviors and subjective impairment of adventure racers, in the context of two geographically diverse, multi-day, international adventure races. Measures of sleep deprivation indicate that sleep debt was extreme and did not recover to pre-race levels within 1 week following each race. Despite this objective debt continuing, perceived impairment returned to pre-race levels quickly post-race. Therefore, further examination of actual and perceived sleep recovery is warranted. Adventure racing presents a unique scenario to examine sleep, performance and recovery.

Adverse pregnancy outcomes and pharyngeal flow limitation during sleep: Nulliparous Pregnancy Outcomes Study Monitoring Mothers-to-be (nuMoM2b).

BACKGROUND: Pharyngeal flow limitation during pregnancy may be a risk factor for adverse pregnancy outcomes but was previously challenging to quantify. Our objective was to determine whether a novel objective measure of flow limitation identifies an increased risk of pre-eclampsia (primary outcome) and other adverse outcomes in a prospective cohort: Nulliparous Pregnancy Outcomes Study Monitoring Mothers-to-be (nuMoM2b). METHODS: Flow limitation severity scores (0%=fully obstructed, 100%=open airway), quantified from breath-by-breath airflow shape, were obtained from home sleep tests during early (6-15 weeks) and mid (22-31 weeks) pregnancy. Multivariable logistic regression quantified associations between flow limitation (median overnight severity, both time-points averaged) and pre-eclampsia, adjusting for maternal age, body mass index (BMI), race, ethnicity, chronic hypertension and flow limitation during wakefulness. Secondary outcomes were hypertensive disorders of pregnancy (HDP), gestational diabetes mellitus (GDM) and infant birthweight. RESULTS: Of 1939 participants with flow limitation data at both time-points (mean±sd age 27.0±5.4 years and BMI 27.7±6.1 kg·m-2), 5.8% developed pre-eclampsia, 12.7% developed HDP and 4.5% developed GDM. Greater flow limitation was associated with increased pre-eclampsia risk: adjusted OR 2.49 (95% CI 1.69-3.69) per 2sd increase in severity. Findings persisted in women without sleep apnoea (apnoea-hypopnoea index <5 events·h-1). Flow limitation was associated with HDP (OR 1.77 (95% CI 1.33-2.38)) and reduced infant birthweight (83.7 (95% CI 31.8-135.6) g), but not GDM. CONCLUSIONS: Greater flow limitation is associated with increased risk of pre-eclampsia, HDP and lower infant birthweight. Flow limitation may provide an early target for mitigating the consequences of sleep disordered breathing during pregnancy.

Flow Limitation Is Associated with Excessive Daytime Sleepiness in Individuals without Moderate or Severe Obstructive Sleep Apnea.

Rationale: Moderate-severe obstructive sleep apnea (OSA) (apnea-hypopnea index [AHI], >15 events/h) disturbs sleep through frequent bouts of apnea and is associated with daytime sleepiness. However, many individuals without moderate-severe OSA (i.e., AHI <15 events/h) also report sleepiness. Objectives: To test the hypothesis that sleepiness in the AHI <15 events/h group is a consequence of substantial flow limitation in the absence of overt reductions in airflow (i.e., apnea/hypopnea). Methods: A total of 1,886 participants from the MESA sleep cohort were analyzed for frequency of flow limitation from polysomnogram-recorded nasal airflow signal. Excessive daytime sleepiness (EDS) was defined by an Epworth Sleepiness Scale score ⩾11. Covariate-adjusted logistic regression assessed the association between EDS (binary dependent variable) and frequency of flow limitation (continuous) in individuals with an AHI <15 events/h. Results: A total of 772 individuals with an AHI <15 events/h were included in the primary analysis. Flow limitation was associated with EDS (odds ratio, 2.04; 95% confidence interval, 1.17-3.54; per 2-standard deviation increase in flow limitation frequency) after adjusting for age, sex, body mass index, race/ethnicity, and sleep duration. This effect size did not appreciably change after also adjusting for AHI. Conclusions: In individuals with an AHI <15 events/h, increasing flow limitation frequency by 2 standard deviations is associated with a twofold increase in the risk of EDS. Future studies should investigate addressing flow limitation in low-AHI individuals as a potential mechanism for ameliorating sleepiness.

Polysomnographic airflow shapes and site of collapse during drug-induced sleep endoscopy.

BACKGROUND: Differences in the pharyngeal site of collapse influence efficacy of non-continuous positive airway pressure therapies for obstructive sleep apnoea (OSA). Notably, complete concentric collapse at the level of the palate (CCCp) during drug-induced sleep endoscopy (DISE) is associated with reduced efficacy of hypoglossal nerve stimulation, but CCCp is currently not recognisable using polysomnography. Here we develop a means to estimate DISE-based site of collapse using overnight polysomnography. METHODS: 182 OSA patients provided DISE and polysomnography data. Six polysomnographic flow shape characteristics (mean during hypopnoeas) were identified as candidate predictors of CCCp (primary outcome variable, n=44/182), including inspiratory skewness and inspiratory scoopiness. Multivariable logistic regression combined the six characteristics to predict clear presence (n=22) versus absence (n=128) of CCCp (partial collapse and concurrent tongue base collapse excluded). Odds ratios for actual CCCp between predicted subgroups were quantified after cross-validation. Secondary analyses examined complete lateral wall, tongue base or epiglottis collapse. External validation was performed on a separate dataset (ntotal=466). RESULTS: CCCp was characterised by greater scoopiness (ß=1.5±0.6 per 2sd, multivariable estimate±se) and skewness (ß=11.4±2.4) compared with non-CCCp. The odds ratio for CCCp in predicted positive versus negative subgroups was 5.0 (95% CI 1.9-13.1). The same characteristics provided significant cross-validated prediction of lateral wall (OR 6.3, 95% CI 2.4-16.5), tongue base (OR 3.2, 95% CI 1.4-7.3) and epiglottis (OR 4.4, 95% CI 1.5-12.4) collapse. CCCp and lateral wall collapse shared similar characteristics (skewed, scoopy), diametrically opposed to tongue base and epiglottis collapse characteristics. External validation confirmed model prediction. CONCLUSIONS: The current study provides a means to recognise patients with likely CCCp or other DISE-based site of collapse categories using routine polysomnography. Since site of collapse influences therapeutic responses, polysomnographic airflow shape analysis could facilitate precision site-specific OSA interventions.

Reducing crash risk for young drivers: Protocol for a pragmatic randomised controlled trial to improve young driver sleep.

Background: Road trauma is a leading cause of death and disability for young Australians (15-24 years). Young adults are overrepresented in crashes due to sleepiness, with two-thirds of their fatal crashes attributed to sleepy driving. This trial aims to examine the effectiveness of a sleep extension and education program for improved road safety in young adults. Methods: Young adults aged 18-24 years (n = 210) will be recruited for a pragmatic randomised controlled trial employing a placebo-controlled, parallel-groups design. The intervention group will undergo sleep extension and receive education on sleep, whereas the placebo control group will be provided with information about diet and nutrition. The primary outcomes of habitual sleep and on-road driving performance will be assessed via actigraphy and in-vehicle accelerometery. A range of secondary outcomes including driving behaviours (driving simulator), sleep (diaries and questionnaire) and socio-emotional measures will be assessed. Discussion: Sleep is a modifiable factor that may reduce the risk of sleepiness-related crashes. Modifying sleep behaviour could potentially help to reduce the risk of young driver sleepiness-related crashes. This randomised control trial will objectively assess the efficacy of implementing sleep behaviour manipulation and education on reducing crash risk in young adult drivers.

The obstructive sleep apnoea endotypes are similar in elderly trauma-exposed veterans with and without diagnosed PTSD.

BACKGROUND: Approximately 60% of veterans living with posttraumatic stress disorder (PTSD) experience obstructive sleep apnoea (OSA). Why OSA is so prevalent in individuals with PTSD remains unknown, though PTSD may influence the underlying endotypes known to cause OSA. We examined whether these endotypes (upper airway collapsibility, muscle compensation, loop gain, and the arousal threshold) differ between those with comorbid OSA and PTSD relative to their counterparts with OSA-only. METHODS: Using the ventilatory flow pattern from diagnostic polysomnography, the OSA endotypes were measured in a retrospective cohort of 21 OSA patients with PTSD and 27 OSA-only patients. All participants were trauma exposed elderly male Australian Vietnam War veterans with mild-to-severe OSA (median Apnoea-Hypopnea index: 20.2 vs. 23.6 events/h). Age and BMI were similar between groups (70.7 vs. 71.7 years, and 28.4 vs. 28.4 kg/m2). RESULTS: There were no significant differences in the OSA endotype traits between PTSD + OSA and OSA-only patients for upper airway collapsibility (76.68 [71.53-83.56] vs. 78.35 [72.81-83.82] %Veupnea, median [IQR]), muscle compensation (4.27 [0.34-9.18] vs. 5.41 [1.83-7.21] %Veupnea), loop gain (0.56(0.17) vs. 0.60(0.14)), and arousal threshold (135.76 [126.59-147.54] vs. 146.95 [128.64-151.28] %Veupnea). CONCLUSION: The OSA endotypes in veterans with PTSD were similar to their trauma exposed OSA-only counterparts. PTSD appears to exert little influence on the OSA endotypes beyond the effect that age and trauma exposure may have. The aetiology of increased prevalence of OSA in PTSD remains unclear. Further work examining OSA endotypes using larger and more diverse samples is needed before robust conclusions can be made.

Physiological Determinants of Snore Loudness.

Rationale: The physiological factors modulating the severity of snoring have not been adequately described. Airway collapse or obstruction is generally the leading determinant of snore sound generation; however, we suspect that ventilatory drive is of equal importance. Objective: To determine the relationship between airway obstruction and ventilatory drive on snore loudness. Methods: In 40 patients with suspected or diagnosed obstructive sleep apnea (1-98 events/hr), airflow was recorded via a pneumotachometer attached to an oronasal mask, ventilatory drive was recorded using calibrated intraesophageal diaphragm electromyography, and snore loudness was recorded using a calibrated microphone attached over the trachea. "Obstruction" was taken as the ratio of ventilation to ventilatory drive and termed flow:drive, i.e., actual ventilation as a percentage of intended ventilation. Lower values reflect increased flow resistance. Using 165,063 breaths, mixed model analysis (quadratic regression) quantified snore loudness as a function of obstruction, ventilatory drive, and the presence of extreme obstruction (i.e., apneic occlusion). Results: In the presence of obstruction (flow:drive = 50%, i.e., doubled resistance), snore loudness increased markedly with increased drive (+3.4 [95% confidence interval, 3.3-3.5] dB per standard deviation [SD] change in ventilatory drive). However, the effect of drive was profoundly attenuated without obstruction (at flow:drive = 100%: +0.23 [0.08-0.39] dB per SD change in drive). Similarly, snore loudness increased with increasing obstruction exclusively in the presence of increased drive (at drive = 200% of eupnea: +2.1 [2.0-2.2] dB per SD change in obstruction; at eupneic drive: +0.14 [-0.08 to 0.28] dB per SD change). Further, snore loudness decreased substantially with extreme obstruction, defined as flow:drive <20% (-9.9 [-3.3 to -6.6] dB vs. unobstructed eupneic breathing). Conclusions: This study highlights that ventilatory drive, and not simply pharyngeal obstruction, modulates snore loudness. This new framework for characterizing the severity of snoring helps better understand the physiology of snoring and is important for the development of technologies that use snore sounds to characterize sleep-disordered breathing.

Increased Flow Limitation During Sleep Is Associated With Increased Psychomotor Vigilance Task Lapses in Individuals With Suspected OSA.

BACKGROUND: Impaired daytime vigilance is an important consequence of OSA, but several studies have reported no association between objective measurements of vigilance and the apnea-hypopnea index (AHI). Notably, the AHI does not quantify the degree of flow limitation, that is, the extent to which ventilation fails to meet intended ventilation (ventilatory drive). RESEARCH QUESTION: Is flow limitation during sleep associated with daytime vigilance in OSA? STUDY DESIGN AND METHODS: Nine hundred ninety-eight participants with suspected OSA completed a 10-min psychomotor vigilance task (PVT) before same-night in-laboratory polysomnography. Flow limitation frequency (percent of flow-limited breaths) during sleep was quantified using airflow shapes (eg, fluttering and scooping) from nasal pressure airflow. Multivariable regression assessed the association between flow limitation frequency and the number of lapses (response times > 500 ms, primary outcome), adjusting for age, sex, BMI, total sleep time, depression, and smoking status. RESULTS: Increased flow limitation frequency was associated with decreased vigilance: a 1-SD (35.3%) increase was associated with 2.1 additional PVT lapses (95% CI, 0.7-3.7; P = .003). This magnitude was similar to that for age, where a 1-SD increase (13.5 years) was associated with 1.9 additional lapses. Results were similar after adjusting for AHI, hypoxemia severity, and arousal severity. The AHI was not associated with PVT lapses (P = .20). In secondary exploratory analysis, flow limitation frequency was associated with mean response speed (P = .012), median response time (P = .029), fastest 10% response time (P = .041), slowest 10% response time (P = .018), and slowest 10% response speed (P = .005). INTERPRETATION: Increased flow limitation during sleep was associated with decreased daytime vigilance in individuals with suspected OSA, independent of the AHI. Flow limitation may complement standard clinical metrics in identifying individuals whose vigilance impairment most likely is explained by OSA.

Nasal Pressure Derived Airflow Limitation and Ventilation Measurements are Resilient to Reduced Signal Quality.

Obstructive sleep apnea is a disorder characterized by partial or complete airway obstructions during sleep. Our previously published algorithms use the minimally invasive nasal pressure signal routinely collected during diagnostic polysomnography (PSG) to segment breaths and estimate airflow limitation (using flow:drive) and minute ventilation for each breath. The first aim of this study was to investigate the effect of airflow signal quality on these algorithms, which can be influenced by oronasal breathing and signal-to-noise ratio (SNR). It was hypothesized that these algorithms would make inaccurate estimates when the expiratory portion of breaths is attenuated to simulate oronasal breathing, and pink noise is added to the airflow signal to reduce SNR. At maximum SNR and 0% expiratory amplitude, the average error was 2.7% for flow:drive, -0.5% eupnea for ventilation, and 19.7 milliseconds for breath duration (n = 257,131 breaths). At 20 dB and 0% expiratory amplitude, the average error was -15.1% for flow:drive, 0.1% eupnea for ventilation, and 28.4 milliseconds for breath duration (n = 247,160 breaths). Unexpectedly, simulated oronasal breathing had a negligible effect on flow:drive, ventilation, and breath segmentation algorithms across all SNRs. Airflow SNR ≥ 20 dB had a negligible effect on ventilation and breath segmentation, whereas airflow SNR ≥ 30 dB had a negligible effect on flow:drive. The second aim of this study was to explore the possibility of correcting these algorithms to compensate for airflow signal asymmetry and low SNR. An offset based on estimated SNR applied to individual breath flow:drive estimates reduced the average error to ≤ 1.3% across all SNRs at patient and breath levels, thereby facilitating for flow:drive to be more accurately estimated from PSGs with low airflow SNR.Clinical Relevance- This study demonstrates that our airflow limitation, ventilation, and breath segmentation algorithms are robust to reduced airflow signal quality.

Sleep mediates the relationship between precarious employment and mental health.

Background: Current evidence suggests that precarious employment is a risk factor for poor mental health. Although the mechanisms underpinning this relationship are unclear, poor sleep has been proposed to have a role in this relationship. This study explored the mediating effects of poor sleep quality and duration on the relationship between precarious employment and mental health. Methods: Data were obtained from wave 17 of the Household, Income and Labour Dynamics in Australia survey. A novel precarious employment score (PES) was developed using exploratory and confirmatory factor analyses (CFA) in 8127 workers (4195 female, aged 18-65). Structural equation modelling (SEM) was used to evaluate the mediating effect of sleep quality and duration on the relationship between precarious employment and mental health (SF-36 mental health subscale). Results: The PES identified 650 workers with a high level of precariousness, 2417 with a moderate level of precariousness, and 5060 workers with a low level of precariousness out of 8127 in total. There was a significant direct association between precarious employment and mental health; with higher precarity increasing the likelihood of poor mental health. The SEM results revealed that sleep quality partially mediated the association between precarious employment and mental health (Coefficient = 0.025, 95 % CI [0.015, 0.034], P ≤ 0.001). However, a mediation effect was not found for sleep duration. Conclusion: Encouraging precarious employees to improve sleep quality may mitigate the adverse effects of precarious work on their mental health. Further objective measurement of sleep duration warrants a more accurate insight into this mediating effect in this group.

Precarious employment and associated health and social consequences; a systematic review.

OBJECTIVE: This systematic review aims to identify, evaluate, and summarise the consequences of precarious employment. METHODS: We included studies published within the last ten years (Jan 2011-July 2021) that employed at least two of three key dimensions of precarious employment: employment insecurity, income inadequacy, and lack of rights and protection. RESULTS: Of the 4,947 initially identified studies, only five studies met our eligibility criteria. These five studies were of moderate quality as assessed by the Newcastle-Ottawa Scale. Our review found that the current literature predominantly defines precarity based on the single criterion of employment insecurity. Our review identified evidence for the negative consequences of precarious employment, including poorer workplace wellbeing, general health, mental health, and emotional wellbeing. The findings indicated an increase in the magnitude of these adverse outcomes with a higher degree of job precariousness. CONCLUSIONS: The rise of employment precariousness will likely continue to be a major issue in the coming years. More research is needed to inform effective policies and practices using a consensus definition of precarious employment. IMPLICATIONS FOR PUBLIC HEALTH: The presence of adverse effects of precarious employment suggests workplace initiatives are essential to mitigate the negative consequences of precarity.

Oronasal vs Nasal Masks: The Impact of Mask Type on CPAP Requirement, Pharyngeal Critical Closing Pressure (Pcrit), and Upper Airway Cross-Sectional Areas in Patients With OSA.

BACKGROUND: CPAP delivered via an oronasal mask is associated with lower adherence, higher residual apnea-hypopnea index (AHI), and increased CPAP therapeutic pressure compared with nasal masks. However, the mechanisms underlying the increased pressure requirements are not well understood. RESEARCH QUESTION: How do oronasal masks affect upper airway anatomy and collapsibility? STUDY DESIGN AND METHODS: Fourteen patients with OSA underwent a sleep study with both a nasal and oronasal mask, each for one-half of the night (order randomized). CPAP was manually titrated to determine therapeutic pressure. Upper airway collapsibility was assessed using the pharyngeal critical closing pressure (Pcrit) technique. Cine MRI was done to dynamically assess the cross-sectional area of the retroglossal and retropalatal airway throughout the respiratory cycle with each mask interface. Scans were repeated at 4 cm H2O and at the nasal and oronasal therapeutic pressures. RESULTS: The oronasal mask was associated with higher therapeutic pressure requirements (ΔM ± SEM; +2.6 ± 0.5; P < .001) and higher Pcrit (+2.4 ± 0.5 cm H2O; P = .001) compared with the nasal mask. The change in therapeutic pressure between masks was strongly correlated with the change in Pcrit (r2 = 0.73; P = .003). Increasing CPAP increased both the retroglossal and retropalatal airway dimensions across both masks. After controlling for pressure and breath phase, the retropalatal cross-sectional area was moderately larger when using a nasal vs an oronasal mask (+17.2 mm2; 95% CI, 6.2-28.2, P < .001) while nasal breathing. INTERPRETATION: Oronasal masks are associated with a more collapsible airway than nasal masks, which likely contributes to the need for a higher therapeutic pressure.

Quantitative and Qualitative Changes in Peripheral Chemoreceptor Activity in Preterm Infants.

Rationale: Preterm infants are at risk for ventilatory control instability that may be due to aberrant peripheral chemoreceptor activity. Although term infants have increasing peripheral chemoreceptor contribution to overall ventilatory drive with increasing postnatal age, how peripheral chemoreceptor contribution changes in preterm infants with increasing postmenstrual age is not known. Objectives: To evaluate peripheral chemoreceptor activity between 32 and 52 weeks postmenstrual age in preterm infants, using both quantitative and qualitative measures. Methods: Fifty-five infants born between 24 weeks, 0 days gestation and 28 weeks, 6 days gestation underwent hyperoxic testing at one to four time points between 32 and 52 weeks postmenstrual age. Quantitative [Formula: see text] decreases were calculated, and qualitative responses were categorized as apnea, continued breathing with a clear reduction in [Formula: see text], sigh breaths, and no response. Measurements and Main Results: A total of 280 hyperoxic tests were analyzed (2.2 ± 0.3 tests per infant at each time point). Mean peripheral chemoreceptor contribution to ventilatory drive was 85.2 ± 20.0% at 32 weeks and 64.1 ± 22.0% at 52 weeks. Apneic responses were more frequent at earlier postmenstrual ages. Conclusions: Among preterm infants, the peripheral chemoreceptor contribution to ventilatory drive was greater at earlier postmenstrual ages. Apnea was a frequent response to hyperoxic testing at earlier postmenstrual ages, suggesting high peripheral chemoreceptor activity. A clearer description of how peripheral chemoreceptor activity changes over time in preterm infants may help explain how ventilatory control instability contributes to apnea and sleep-disordered breathing later in childhood. Clinical trial registered with www.clinicaltrials.gov (NCT03464396).

Pathophysiology Underlying Demographic and Obesity Determinants of Sleep Apnea Severity.

Rationale: Sleep apnea is the manifestation of key endotypic traits, including greater pharyngeal collapsibility, reduced dilator muscle compensation, and elevated chemoreflex loop gain. Objectives: We investigated how endotypic traits vary with obesity, age, sex, and race/ethnicity to influence sleep apnea disease severity (apnea-hypopnea index [AHI]). Methods: Endotypic traits were estimated from polysomnography in a diverse community-based cohort study (Multi-Ethnic Study of Atherosclerosis, N = 1,971; age range, 54-93 yr). Regression models assessed associations between each exposure (continuous variables per 2 standard deviations [SDs]) and endotypic traits (per SD) or AHI (events/h), independent of other exposures. Generalizability was assessed in two independent cohorts. Results: Greater AHI was associated with obesity (+19 events/h per 11 kg/m2 [2 SD]), male sex (+13 events/h vs. female), older age (+7 events/h per 20 yr), and Chinese ancestry (+5 events/h vs. White, obesity adjusted). Obesity-related increase in AHI was best explained by elevated collapsibility (+0.40 SD) and greater loop gain (+0.38 SD; percentage mediated, 26% [95% confidence interval (CI), 20-32%]). Male-related increase in AHI was explained by elevated collapsibility (+0.86 SD) and reduced compensation (-0.40 SD; percentage mediated, 57% [95% CI, 50-66%]). Age-related AHI increase was explained by elevated collapsibility (+0.37 SD) and greater loop gain (+0.15 SD; percentage mediated, 48% [95% CI, 34-63%]). Increased AHI with Chinese ancestry was explained by collapsibility (+0.57 SD; percentage mediated, 87% [95% CI, 57-100]). Black race was associated with reduced collapsibility (-0.30 SD) and elevated loop gain (+0.29 SD). Similar patterns were observed in the other cohorts. Conclusions: Different subgroups exhibit different underlying pathophysiological pathways to sleep apnea, highlighting the variability in mechanisms that could be targeted for intervention.

A single dose of noradrenergic/serotonergic reuptake inhibitors combined with an antimuscarinic does not improve obstructive sleep apnoea severity.

Previous trials have demonstrated that the combination of noradrenergic reuptake inhibitors with an antimuscarinic can substantially reduce the apnoea-hypopnoea index (AHI) and improve airway collapsibility in patients with obstructive sleep apnoea (OSA). However, some studies have shown that when administered individually, neither noradrenergic or serotonergic agents have been effective at alleviating OSA. This raises the possibility that serotonergic agents (like noradrenergic agents) may also need to be delivered in combination to be efficacious. Therefore, we investigated the effect of an antimuscarinic (oxybutynin) on OSA severity when administered with either duloxetine or milnacipran, two dual noradrenergic/serotonergic reuptake inhibiters. A randomized, double-blind, 4 way cross-over, placebo-controlled trial in ten OSA patients was performed. Patients received each drug condition separately across four overnight in-lab polysomnography (PSG) studies ~1-week apart. The primary outcome measure was the AHI. In addition, the four key OSA endotypes (collapsibility, muscle compensation, arousal threshold, loop gain) were measured non-invasively from the PSGs using validated techniques. There was no significant effect of either drug combinations on reducing the total AHI or improving any of the key OSA endotypes. However, duloxetine+oxybutynin did significantly increase the fraction of hypopnoeas to apnoeas (FHypopnoea ) compared to placebo (p = 0.02; d = 0.54). In addition, duloxetine+oxybutynin reduced time in REM sleep (p = 0.009; d = 1.03) which was positively associated with a reduction in the total AHI (R2  = 0.62; p = 0.02). Neither drug combination significantly improved OSA severity or modified the key OSA endotypes when administered as a single dose to unselected OSA patients.

The impact of daytime transoral neuromuscular stimulation on upper airway physiology - A mechanistic clinical investigation.

There is a need for alternatives to positive airway pressure for the treatment of obstructive sleep apnea and snoring. Improving upper airway dilator function might alleviate upper airway obstruction. We hypothesized that transoral neuromuscular stimulation would reduce upper airway collapse in concert with improvement in genioglossal muscle function. Subjects with simple snoring and mild OSA (AHI < 15/h on screening) underwent in-laboratory polysomnography with concurrent genioglossal electromyography (EMGgg) before and after 4-6 weeks of twice-daily transoral neuromuscular stimulation. Twenty patients completed the study: Sixteen males, mean ± SD age 40 ± 13 years, and BMI 26.3 ± 3.8 kg/m2 . Although there was no change in non-rapid eye movement EMGgg phasic (p = 0.66) or tonic activity (p = 0.83), and no decrease in snoring or flow limitation, treatment was associated with improvements in tongue endurance, sleep quality, and sleep efficiency. In this protocol, transoral neurostimulation did not result in changes in genioglossal activity or upper airway collapse, but other beneficial effects were noted suggesting a need for additional mechanistic investigation.

Ventilatory control instability as a predictor of persistent periodic breathing in preterm infants.

BACKGROUND: Periodic breathing (PB) is common in preterm infants. We aimed to characterize the contribution of ventilatory control instability to the presence and persistence of PB longitudinally. METHODS: Infants born between 28 and 32 weeks of gestation were studied using daytime polysomnography at: 32-36 weeks postmenstrual age (PMA) (N = 32), 36-40 weeks PMA (N = 20), 3 months corrected age (CA) (N = 18) and 6 months CA (N = 19). Loop gain, a measure of sensitivity of the ventilatory control system, was estimated by fitting a mathematical model to ventilatory patterns associated with spontaneous sighs. RESULTS: The time spent in PB decreased from 32-36 weeks PMA to 6 months CA (P = 0.005). Across all studies, studies with PB (N = 62) were associated with higher loop gain compared to those without PB (N = 23) (estimated marginal mean ± SEM: 0.445 ± 0.01 vs 0.388 ± 0.02; P = 0.020). A threshold of loop gain >0.415 (measured at 32-36 weeks PMA) provided a sensitivity of 86% and a specificity of 75% to detect the presence of PB at 6 months CA. CONCLUSIONS: The course of PB in preterm infants is related to changes in loop gain. Higher loop gain at 32-36 weeks PMA was associated with a greater risk of persistent PB at 6 months CA. IMPACT: The developmental trajectory of periodic breathing and its relationship to ventilatory control instability is currently unclear. Unstable ventilatory control is a determinant of periodic breathing in preterm infants up to 6 months corrected age. Infants who display greater ventilatory control instability at 32-36 weeks postmenstrual age may be at increased risk of persistent periodic breathing at 6 months corrected age. Assessment of ventilatory control stability may assist in the early identification of infants at risk of persistent periodic breathing and its potential adverse effects.

Frequency of flow limitation using airflow shape.

STUDY OBJECTIVES: The presence of flow limitation during sleep is associated with adverse health consequences independent of obstructive sleep apnea (OSA) severity (apnea-hypopnea index, AHI), but remains extremely challenging to quantify. Here we present a unique library and an accompanying automated method that we apply to investigate flow limitation during sleep. METHODS: A library of 117,871 breaths (N = 40 participants) were visually classified (certain flow limitation, possible flow limitation, normal) using airflow shape and physiological signals (ventilatory drive per intra-esophageal diaphragm EMG). An ordinal regression model was developed to quantify flow limitation certainty using flow-shape features (e.g. flattening, scooping); breath-by-breath agreement (Cohen's ƙ); and overnight flow limitation frequency (R2, %breaths in certain or possible categories during sleep) were compared against visual scoring. Subsequent application examined flow limitation frequency during arousals and stable breathing, and associations with ventilatory drive. RESULTS: The model (23 features) assessed flow limitation with good agreement (breath-by-breath ƙ = 0.572, p < 0.001) and minimal error (overnight flow limitation frequency R2 = 0.86, error = 7.2%). Flow limitation frequency was largely independent of AHI (R2 = 0.16) and varied widely within individuals with OSA (74[32-95]%breaths, mean[range], AHI > 15/h, N = 22). Flow limitation was unexpectedly frequent but variable during arousals (40[5-85]%breaths) and stable breathing (58[12-91]%breaths), and was associated with elevated ventilatory drive (R2 = 0.26-0.29; R2 < 0.01 AHI v. drive). CONCLUSIONS: Our method enables quantification of flow limitation frequency, a key aspect of obstructive sleep-disordered breathing that is independent of the AHI and often unavailable. Flow limitation frequency varies widely between individuals, is prevalent during arousals and stable breathing, and reveals elevated ventilatory drive. Clinical trial registration: The current observational physiology study does not qualify as a clinical trial.