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Children with obstructive sleep apnea syndrome (OSAS) have more collapsible airways compared with normal subjects, yet sustain stable breathing during wakefulness and part of sleep. This indicates successful neuromuscular compensation. Using a custom intraoral surface electrode to record pharyngeal dilator muscle activity (the genioglossus [EMGgg] normalized to the wakeful baseline), we performed overnight polysomnograms in three groups of children: (1) patients with OSAS without continuous positive airway pressure (CPAP) (n = 13); (2) patients with OSAS with CPAP (n = 5); and (3) control subjects without CPAP (n = 13). Our objective was to evaluate the EMGgg as a function of sleep state and during disordered breathing, compared with stable sleep and wakefulness. In control subjects, the EMGgg decreased from wakefulness to Stage 2 (mean +/- SD, 65 +/- 6%), and further during REM (51 +/- 9%) (p < 0.05). In patients with OSAS, the EMGgg for apneic breaths during REM (37 +/- 9%) was lower than during stable breathing (83 +/- 17%) (p < 0.05) and wakefulness (p < 0.05). CPAP lowered the EMGgg in patients with OSAS during all sleep states. These data indicate that (1) EMGgg compensatory mechanisms remain active during sleep in patients with severe OSAS; (2) EMGgg reductions are temporally associated with sleep apnea events; and (3) REM sleep is associated with the lowest and most variable EMGgg. [ABSTRACT FROM AUTHOR]

Objectives: Despite the well-recognized consequences of obstructive sleep apnea (OSA), its treatment remains unsatisfactory. Therapeutic strategies are complicated by often poor adherence in the case of continuous positive airway pressure or the highly variable efficacy in the case of many upper airway surgeries. Computational models of the upper airway using finite element analysis to simulate the effects of various anatomic and physiologic manipulations on pharyngeal mechanics could be helpful in predicting surgical success.Study Design: Computational and physiologic study.Methods: Using representative OSA magnetic resonance images and experimentally measured upper airway dilator muscle activities, we developed a working two-dimensional and a partial three-dimensional model of the upper airway.Results: As predicted from experimental measurements, the OSA model airway has a closing pressure of -2 cm H2O. Manipulations such as palatal stiffening, palatal resection, and tongue stiffening all have demonstrable effects on pharyngeal mechanics. We have also developed a partial three-dimensional OSA model in which we simulate the mechanics of the pharyngeal airway in the mid-sagittal and parasagittal slices, spanning more than 1 inch in thickness. Using this model, we have observed important effects of tongue and palatal stiffening on anteroposterior collapse of the pharyngeal airway.Conclusions: Our data suggest that computational modeling is feasible and can be used to generate hypotheses for subsequent clinical trials regarding anatomic manipulations in OSA. We further believe that the goal of individualizing OSA therapy on the basis of underlying mechanisms could be facilitated by computational modeling. [ABSTRACT FROM AUTHOR]

Rationale: Most children with obstructive sleep apnea are able to sustain stable breathing during portions of sleep, despite an anatomic predisposition toward airway collapse. This suggests that additional determinants of airway patency are active, such as neuromuscular compensation.Objectives/methods: Using a custom intraoral surface electrode to record pharyngeal dilator muscle activity (the genioglossus [EMGgg]), we evaluated the muscle, ventilatory, and arousal responses to negative-pressure challenges during sleep in 19 healthy control children.Measurements and Main Results: In response to these challenges, we observed (1) marked variability in individual EMGgg responsiveness (peak EMGgg [mean+/-SD], 214+/-101% baseline), which was consistent within subjects; (2) a relationship between EMGgg activity and inspiratory flow and airway collapsibility; (3) reflex increases in flow (peak flow increase from challenge breaths 1-5 [mean+/-SD], 49+/-41% baseline) and respiratory rate often sufficient to sustain minute ventilation near baseline levels, without arousal; and (4) arousal threshold to be highest in stage 4, intermediate in stage 2, and lowest in REM sleep.Conclusions: Healthy children have wide variation in upper airway neuromuscular compensatory responses and arousal thresholds that could represent intermediate phenotypes affecting the expression of sleep apnea. Children with robust upper airway neuromuscular responsiveness, or a very high arousal threshold, may be able to sustain minute ventilation when challenged with negative airway pressure. [ABSTRACT FROM AUTHOR]

Considerable progress has been made over the last several decades in our understanding of the pathophysiology of both central and obstructive sleep apnea. Central sleep apnea, in its various forms, is generally the product of an unstable ventilatory control system (high loop gain) with increased controller gain (high hypercapnic responsiveness) generally being the cause. High plant gain can contribute under certain circumstances (hypercapnic patients). On the other hand, obstructive sleep apnea can develop as the result of a variety of physiologic characteristics. The combinations of these may vary considerably between patients. Most obstructive apnea patients have an anatomically small upper airway with augmented pharyngeal dilator muscle activation maintaining airway patency awake, but not asleep. However, individual variability in several phenotypic characteristics may ultimately determine who develops apnea and how severe the apnea will be. These include: (1) upper airway anatomy, (2) the ability of upper airway dilator muscles to respond to rising intrapharyngeal negative pressure and increasing Co2 during sleep, (3) arousal threshold in response to respiratory stimulation, and (4) loop gain (ventilatory control instability). As a result, patients may respond to different therapeutic approaches based on the predominant abnormality leading to the sleep-disordered breathing. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated that lung volume during wakefulness influences upper airway size and resistance, particularly in patients with sleep apnea. We sought to determine the influence of lung volume on the level of continuous positive airway pressure (CPAP) required to prevent flow limitation during non-REM sleep in subjects with sleep apnea. Seventeen subjects (apnea-hypopnea index, 42.6 +/- 6.2 [SEM]) were studied during stable non-REM sleep in a rigid head-out shell equipped with a positive/negative pressure attachment for manipulation of extrathoracic pressure. An epiglottic pressure catheter plus a mask/pneumotachometer were used to assess flow limitation. When lung volume was increased by 1,035 +/- 22 ml, the CPAP level could be decreased from 11.9 +/- 0.7 to 4.8 +/- 0.7 cm H(2)O (p < 0.001) without flow limitation. The decreased CPAP at the same negative extrathoracic pressure yielded a final lung volume increase of 421 +/- 36 ml above the initial value. Conversely, when lung volume was reduced by 732 +/- 74 ml (n = 8), the CPAP level had to be increased from 11.9 +/- 0.7 to 17.1 +/- 1.0 cm H(2)O (p < 0.001) to prevent flow limitation, with a final lung volume decrease of 567 +/- 78 ml. These results demonstrate that relatively small changes in lung volume have an important effect on the upper airway in subjects with sleep apnea during non-REM sleep. [ABSTRACT FROM AUTHOR]

Ventilatory instability may play an important role in the pathogenesis of obstructive sleep apnea. We hypothesized that the influence of ventilatory instability in this disorder would vary depending on the underlying collapsibility of the upper airway. To test this hypothesis, we correlated loop gain with apnea-hypopnea index during supine, nonrapid eye movement sleep in three groups of patients with obstructive sleep apnea based on pharyngeal closing pressure: negative pressure group (pharyngeal closing pressure less than -1 cm H(2)O), atmospheric pressure group (between -1 and +1 cm H(2)O), and positive pressure group (greater than +1 cm H(2)O). Loop gain was measured by sequentially increasing proportional assist ventilation until periodic breathing developed, which occurred in 24 of 25 subjects. Mean loop gain for all three groups was 0.37 +/- 0.11. A significant correlation was found between loop gain and apnea-hypopnea index in the atmospheric group only (r = 0.88, p = 0.0016). We conclude that loop gain has a substantial impact on apnea severity in certain patients with sleep apnea, particularly those with a pharyngeal closing pressure near atmospheric. [ABSTRACT FROM AUTHOR]

Background: During most of the cruise, submarines are detached from their environment. Therefore, O(2) levels are relatively low (19 kPa, 144 mm Hg) and CO(2) levels are high (1 kPa, 7.6 mm Hg). There are, however, periods during ventilation of the submarine in which CO(2) levels drop and O(2) levels increase. The objective of this study was to determine whether these unique gas changes might result in sleep-disordered breathing in submariners.Methods and Materials: The sleep of eight healthy soldiers was assessed three times: (1) control night, in submarine docking; (2) at the beginning of the cruise (reflecting acute exposure to gas changes); and (3) at the end of the cruise (chronic exposure to gas changes). Each night was divided to three parts because of different CO(2) levels (secondary to ventilation of the submarine). Sleep and breathing were measured using the portable Watch PAT100 device (Itamar Medical, Ltd; Caesarea, Israel) to detect breathing abnormalities during sleep.Results: Sleep and breathing data were categorized according to four CO(2) conditions: acute moderate (inhaled CO(2) levels of 2.3 to 5 mm Hg during first 1 to 2 nights of the cruise); acute high (inhaled CO(2) levels of 5 to 9.2 mm Hg during the first 1 to 2 nights of the cruise); chronic moderate (inhaled CO(2) levels of 2.3 to 5 mm Hg during nights 9 to 10 of the cruise); and chronic high (inhaled CO(2) levels of 5 to 9.2 mm Hg during nights 9 to 10 of the cruise). Respiratory disturbance index (RDI) was significantly higher in the chronic moderate CO(2) condition than the chronic high condition (18.9/h vs 8/h, p < 0.005). RDI did not correlate with CO(2) levels during the first nights of the cruise (R = - 0.2, not significant), but significantly negatively correlated with it during the last nights of the cruise (R = - 0.56, p < 0.05).Conclusions: We conclude that during an 11-day cruise, submariners adapt to high CO(2) levels, as evidenced by the significant dependence of RDI on CO(2) during the final but not initial days of the cruise. This adaptation resulted in a significant increase in RDI when CO(2) levels declined during the later nights of the cruise. [ABSTRACT FROM AUTHOR]

Importance: Mouth breathing is associated with increased airway resistance, pharyngeal collapsibility, and obstructive sleep apnea (OSA) severity. The common belief is that closing the mouth can mitigate the negative effects of mouth breathing during sleep. However, mouth breathing may serve as an essential route to bypassing obstruction along the nasal route (eg, the velopharynx)., Objective: To investigate the role of mouth breathing as an essential route in some patients with OSA and its association with upper airway anatomical factors., Design, Setting, and Participants: This nonrandomized clinical trial included participants diagnosed with OSA who underwent drug-induced sleep endoscopy. Patients were stratified into 3 quantiles based on oral-breathing level (quantile 1: oral airflow < 0.05 L/min; quantile 2: oral airflow 0.05-2.2 L/min; quantile 3: oral airflow > 2.2 L/min)., Interventions: Closing the mouth during sleep during alternating breaths by applying pressure to the mentum until teeth are in occlusion., Main Outcomes and Measures: The primary outcome was total inspiratory flow defined as the change in airflow in the transition from mouth relaxed to mouth closed, analyzed overall and by 3 oral-breathing quantiles. The association of velopharyngeal obstruction on the change in total inspiratory airflow was also investigated., Results: Of 66 enrolled patients with OSA, 12 were excluded due to insufficient baseline airflow. The analytic cohort consisted of 54 patients (39 [72%] male; median [IQR] age, 55 [46-64] years; apnea-hypopnea index, 26.9 [17.6-39.9] events/h; and body mass index calculated as weight in kilograms divided by height in meters squared, 28.9 [27.1-31.6]). Mouth closure increased total inspiratory flow by 27.8 percentage points overall (β, 1.0 [95% CI, 0.4-1.9] L/min). However, outcomes varied based on the degree of baseline oral breathing. No association was found for 10 patients with near-zero mouth breathing (0.9 [95% CI, -0.2 to 2.1] L/min). Airflow improved with mouth closure in 32 patients with moderate levels of mouth breathing (2.0 [95% CI, 1.3-2.7] L/min), whereas it worsened in patients with high levels of mouth breathing (-1.9 [95% CI, -3.1 to -0.6] L/min). Velopharyngeal obstruction was associated with increased mouth breathing (0.6 [95% CI, 0.1-3.0] L/min) and reduced airflow with mouth closure (-1.9 [95% CI, -3.1 to -0.7] L/min)., Conclusion and Relevance: Although mouth closure increased inspiratory airflow in the overall cohort of this nonrandomized clinical trial, the outcomes were heterogeneous. In patients who breathe primarily through their mouth during sleep and have velopharyngeal obstruction, airflow worsens with mouth closure. Hence, personalized approaches to treating mouth breathing should be considered., Trial Registration: ClinicalTrials.gov Identifier: NCT06547658.

Study Objectives: A recent study challenged the prevailing clinical view that maintaining inspiratory positive airway pressure (IPAP) is necessary for upper airway patency, demonstrating no differences in apnea hypopnea index (AHI) between continuous PAP (CPAP) with and without a resistor to reduce IPAP. In this study, we assessed the effect of Kairos PAP (KPAP), a new algorithm which features multiple drops in IPAP, only returning to therapeutic pressure near the end expiration, on sleep apnea severity and subjective comfort., Methods: Two randomized clinical trials were conducted. In the Efficacy trial, the effect of KPAP vs. CPAP on AHI in PAP-treated OSA patients was examined using a split-night design, adjusting for period, sequence and fraction of supine sleep (mixed models). Unintentional leak differences between treatments were also examined. Exploratory analyses assessed the effect of KPAP vs. CPAP on key polysomnography outcomes. In the Comfort trial, we tested subjective preference for KPAP vs. CPAP at 9 and 13 cmH 2 O in PAP-naïve OSA patients., Results: In the Efficacy trial (N = 48), KPAP reduced AHI more than CPAP (mean difference [95%CI]: -0.5 [-0.8, -0.2] events/h, P = 0.007). Unintentional leak was also reduced by over 50 % (-2.5 [-3.2, -1.7] L/min, P < 0.001). No significant change was observed in the exploratory variables assessed. In the Comfort trial (N = 150), 69 [61, 77] % and 84 [77, 89] % of participants preferred KPAP over CPAP at 9 and 13 cmH 2 O, respectively (P < 0.001)., Conclusions: KPAP is as effective as CPAP in reducing respiratory events, but is more comfortable and potentially better tolerated., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: David P White reports a relationship with SleepRes that includes: consulting or advisory. William Noah reports a relationship with SleepRes that includes: board membership. William Noah has patent pending to William Noah. LM received industry grants from Apnimed, Inc and Prosomnus unrelated to this work. DPW received consultancy fees for Bairitone, Cerebra Health, Cryosa, Mosanna, Onera, Philips Respironics, Resonea, Xtrodes, and Apnimed unrelated to this work. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Despite the commonly-accepted paradigm that patients with obstructive sleep apnea (OSA) also invariably have obesity, OSA prevalence extends beyond obesity. This necessitates a reevaluation of screening strategies, biomarkers of increased OSA risk, and heightened awareness among healthcare providers about the array of OSA treatments for diverse adult populations. While obesity contributes importantly to OSA pathogenesis, there is substantial evidence that non-anatomical factors also play a crucial role, especially in patients who do not have obesity. In recent years, notwithstanding the recognition of diverse contributors to OSA pathogenesis, research has frequently focused on weight reduction to address OSA. Insights from past experiences with bariatric surgery in OSA serve as a lens to anticipate potential outcomes of emerging anti-obesity pharmacotherapies. Pharmacological alternatives, particularly incretin agonists, exhibit promise in weight reduction and OSA improvement, but encounter obstacles such as potential side effects and high costs. With this comprehensive narrative review, we delve into the complex epidemiological and pathophysiological connections between OSA and obesity. Additionally, we emphasize the importance of a multifaceted approach to OSA treatment, recognizing that while weight management is crucial, there is a need for comprehensive strategies that go beyond traditional weight-centric perspectives., Competing Interests: Declaration of competing interest LM reports consultancy fees from Apnimed. LM received grant support from Prosomnus and Apnimed, unrelated to this work. JPB reports stock/shares in Philips and Signifier Medical Technologies, and salary/consulting income from Apnimed, Koneksa Health, and the non-profit Digital Medicine Society. JC is the Senior Vice President of Medical Development at Apnimed, JY is the Senior Vice President of Medical Affairs at Apnimed. DPW is a consultant for Philips Respironics, Apnimed, Mosanna, SleepRes, Onera, Xtrodes, Cerebra Health, Cryosa, Resonea, and Bairitone., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Tetragnathid spiders have been used as sentinels to study the biotransport of contaminants between aquatic and terrestrial environments because a significant proportion of their diet consists of adult aquatic insects. A key knowledge gap in assessing tetragnathid spiders as sentinels is understanding the consistency of the year-to-year relationship between contaminant concentrations in spiders and sediment, water, and macroinvertebrates. We collected five years of data over a seven-year investigation at a PCB contaminated-sediment site to investigate if concentrations in spiders were consistently correlated with concentrations in sediment, water, and aquatic macroinvertebrates. Despite significant year-to-year variability in spider PCB concentrations, they were not correlated with sediment concentrations (p = 0.186). However, spider PCB concentrations were significantly, positively correlated with PCB concentrations in water (p < 0.0001, annual r 2  = 0.35-0.84) and macroinvertebrates (p < 0.0001; annual r 2  = 0.59-0.71). Analysis of covariance (ANCOVA) showed that spider PCB concentrations varied consistently with water (β = 0.63) and macroinvertebrate PCB concentrations (β = 1.023) among years. Overall, this study filled a critical knowledge gap in the utilization of tetragnathid spiders as sentinels of aquatic pollution by showing that despite year-to-year changes in PCB concentrations across environmental compartments, consistent relationships existed between spiders and water and aquatic macroinvertebrates., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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.

Rationale: Obstructive sleep apnea is characterized by frequent reductions in ventilation, leading to oxygen desaturations and/or arousals. Objectives: In this study, association of hypoxic burden with incident cardiovascular disease (CVD) was examined and compared with that of "ventilatory burden" and "arousal burden." Finally, we assessed the extent to which the ventilatory burden, visceral obesity, and lung function explain variations in hypoxic burden. Methods: Hypoxic, ventilatory, and arousal burdens were measured from baseline polysomnograms in the Multi-Ethnic Study of Atherosclerosis (MESA) and the Osteoporotic Fractures in Men (MrOS) studies. Ventilatory burden was defined as event-specific area under ventilation signal (mean normalized, area under the mean), and arousal burden was defined as the normalized cumulative duration of all arousals. The adjusted hazard ratios for incident CVD and mortality were calculated. Exploratory analyses quantified contributions to hypoxic burden of ventilatory burden, baseline oxygen saturation as measured by pulse oximetry, visceral obesity, and spirometry parameters. Measurements and Main Results: Hypoxic and ventilatory burdens were significantly associated with incident CVD (adjusted hazard ratio [95% confidence interval] per 1 SD increase in hypoxic burden: MESA, 1.45 [1.14, 1.84]; MrOS, 1.13 [1.02, 1.26]; ventilatory burden: MESA, 1.38 [1.11, 1.72]; MrOS, 1.12 [1.01, 1.25]), whereas arousal burden was not. Similar associations with mortality were also observed. Finally, 78% of variation in hypoxic burden was explained by ventilatory burden, whereas other factors explained only <2% of variation. Conclusions: Hypoxic and ventilatory burden predicted CVD morbidity and mortality in two population-based studies. Hypoxic burden is minimally affected by measures of adiposity and captures the risk attributable to ventilatory burden of obstructive sleep apnea rather than a tendency to desaturate.

Rationale: Loss of pharyngeal dilator muscle activity is a key determinant of respiratory events in obstructive sleep apnea (OSA). After the withdrawal of wakefulness stimuli to the genioglossus at sleep onset, mechanoreceptor negative pressure and chemoreceptor ventilatory drive feedback govern genioglossus activation during sleep, but the relative contributions of drive and pressure stimuli to genioglossus activity across progressive obstructive events remain unclear. We recently showed that drive typically falls during events, whereas negative pressures increase, providing a means to assess their individual contributions to the time course of genioglossus activity. Objectives: For the first time, we critically test whether the loss of drive could explain the loss of genioglossus activity observed within events in OSA. Methods: We examined the time course of genioglossus activity (EMGgg; intramuscular electromyography), ventilatory drive (intraesophageal diaphragm electromyography), and esophageal pressure during spontaneous respiratory events (using the ensemble-average method) in 42 patients with OSA (apnea-hypopnea index 5-91 events/h). Results: Multivariable regression demonstrated that the falling-then-rising time course of EMGgg may be well explained by falling-then-rising drive and rising negative pressure stimuli (model R  = 0.91 [0.88-0.98] [95% confidence interval]). Overall, EMGgg was 2.9-fold (0.47-∞) more closely associated with drive than pressure stimuli (ratio of standardized coefficients, β drive :β pressure ; ∞ denotes absent pressure contribution). However, individual patient results were heterogeneous: approximately one-half ( n  = 22 of 42) exhibited drive-dominant responses (i.e., β drive :β pressure  > 2:1), and one-quarter ( n  = 11 of 42) exhibited pressure-dominant EMGgg responses (i.e., β drive :β pressure  < 1:2). Patients exhibiting more drive-dominant EMGgg responses experienced greater event-related EMGgg declines (12.9 [4.8-21.0] % baseline /standard deviation of β drive :β pressure ; P  = 0.004, adjusted analysis). Conclusions: Loss of genioglossus activity precipitating events in patients with OSA is strongly associated with a contemporaneous loss of drive and is greatest in those whose activity tracks drive rather than pressure stimuli. These findings were upheld for events without prior arousal. Responding to falling drive rather than rising negative pressure during events may be deleterious; future therapeutic strategies whose aim is to sustain genioglossus activity by preferentially enhancing responses to rising pressure rather than falling drive are of interest.

Study Objectives: There is uncertainty on best approaches for defining apnea-hypopnea events. To clarify the contributions of desaturation vs arousal to defining hypopneas, we examined the associations of events with desaturation (≥ 3%) but not arousal (apnea-hypopnea index [AHI] ≥3%Only ) vs events with arousals but no desaturation (AHI ArOnly ) with obstructive sleep apnea-related comorbidities and incident cardiovascular disease across multiple cohorts., Methods: In the Sleep Heart Health Study (n = 5,473), the Multi-Ethnic Study of Atherosclerosis (n = 1,904), and the Osteoporotic Fractures in Men Study (n = 2,685), we examined the independent associations of AHI ≥3%Only and AHI ArOnly with hypertension, diabetes, and daytime sleepiness, and incident cardiovascular disease., Results: After adjusting for covariates and AHI based on events with electroencephalogram arousal (regardless of desaturation), AHI ≥3%Only was associated with hypertension in Sleep Heart Health Study (odds ratio: 1.12; 95% confidence interval: 1.04,1.21), per 1 standard deviation increase). Similar associations were observed in the Multi-Ethnic Study of Atherosclerosis and Osteoporotic Fractures in Men Study, as well as for associations with diabetes (odds ratio: 1.30; 1.09,1.54, and 1.25; 1.07,1.47, respectively), sleepiness (odds ratio: 1.19; 1.00,1.41; and 1.17; 1.01-1.35), and incident cardiovascular disease (hazard ratio: 1.37; 1.05,1.77 and 1.14; 1.00,1.29). In contrast, after adjusting for events with desaturation (regardless of arousal), AHI ArOnly was unassociated with these outcomes. In Sleep Heart Health Study, greater baseline obstructive sleep apnea severity was associated with a reduction in arousal frequency over 5 years ( P < .0001)., Conclusions: In middle-aged and older individuals, addition of events with arousals does not improve the strength of associations with comorbidities or incident cardiovascular disease. Research is needed to understand generalizability to younger individuals and the mechanistic role of arousals in obstructive sleep apnea., Citation: Azarbarzin A, Sands SA, Han S, et al. Relevance of cortical arousals for risk stratification in sleep apnea: a 3 cohort analysis. J Clin Sleep Med . 2023;19(8):1475-1484., (© 2023 American Academy of Sleep Medicine.)

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/m 2 [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.

Polychlorinated dibenzo-p-dioxin and polychlorinated dibenzofuran (PCDD/F) are persistent, toxic, and bioaccumulative. Currently, PCDD/F monitoring programs primarily use fish and birds with potentially large home ranges to monitor temporal trends over broad spatial scales; sentinel organisms that provide targeted sediment contaminant information across small geographic areas have yet to be developed. Riparian orb-weaving spiders, which typically have small home ranges and consume primarily adult aquatic insects, are potential PCDD/F sentinels. Recent studies have demonstrated that spider tissue concentrations indicate the source and magnitude of dioxin-like chlorinated compounds in contaminated sediments, including polychlorinated biphenyls (PCBs). Our aim in the present study was to assess the utility of riparian spiders as sentinels for PCDD/F-contaminated sediments. We measured PCDD/F (total [Σ] and homologs) in surface sediments and spiders collected from three sites within the St. Louis River basin (Minnesota and Wisconsin, USA). We then compared (1) patterns in ΣPCDD/F concentrations between sediment and spiders, (2) the distribution of homologs within sediments and spiders when pooled across sites, and (3) the relationship between sediment and spider concentrations of PCDD/F homologs across 13 stations sampled across the three sites. The ΣPCDD/F concentrations in sediment (mean ± standard error 286 591 ± 97 614 pg/g) were significantly higher than those in riparian spiders (2463 ± 977 pg/g, p < 0.001), but the relative abundance of homologs in sediment and spiders were not significantly different. Spider homolog concentrations were significantly and positively correlated with sediment concentrations across a gradient of sediment PCDD/F contamination (R 2  = 0.47, p < 0.001). Our results indicate that, as has been shown for other legacy organic chemicals like PCBs, riparian spiders are suitable sentinels of PCDD/F in contaminated sediment. Environ Toxicol Chem 2023;42:414-420. © 2022 SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA., (© 2022 SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Conventional measures of obstructive sleep apnea (OSA) severity, such as the apnea-hypopnea index (AHI) and oxygen desaturation index (ODI) are commonly used to quantify OSA severity and guide therapeutical decision-making processes. However, it is widely recognized that both AHI and ODI have important limitations and novel physiologically-informed metrics are needed to better capture the severity of OSA and characterize its physiological consequences, particularly the severity of recurrent nocturnal hypoxemia, ensuing the respiratory events. According to recent studies, the sleep apnea-specific "hypoxic burden (HB)", defined as the sum of individual areas under the oxygen desaturation curve, has shown some promise in identifying high risk individuals with OSA. In addition to the frequency of respiratory events, HB capture the depth and duration of OSA-related hypoxemia that may prove to be important disease characterizing features, not captured by the conventional "frequency-based" metrics, such as AHI and ODI. In this "perspective" paper the methods to quantify the HB, its characteristics, associations with health outcomes, and its limitations will be discussed., (Copyright © 2022. Published by Elsevier España, S.L.U.)

An international effort to restore contaminated areas across the Great Lakes has been underway for over 50 years. Although experts have increasingly recognized the inherent connections between ecological conditions and community level benefits, Great Lakes community revitalization continues to be a broad and complex topic, lacking a comprehensive definition. The purpose of this study was to generate a testable "AOC-Revitalization Framework" for linking remediation and restoration success, represented by Beneficial Use Impairment (BUI) removal in U.S. Great Lakes Areas of Concern (AOC), to community revitalization. Using directed content analysis, we conducted a literature review and identified 433 potential revitalization metrics and indicators and grouped them into 15 broader community revitalization attributes to develop the following definition of Great Lakes community revitalization: " locally driven community resurgence resulting in resilient and equitable enhancements to social, economic, and environmental community structures." We surveyed experts within the Great Lakes AOC program on the likelihood remediation and restoration success, would positively impact revitalization attributes. Focus groups triangulated survey results. Results identified BUI removal was expected to positively affect revitalization, but the type of revitalization outcome was based on the BUI being removed. The AOC-Revitalization Framework is the first to empirically outline these possible linkages, providing a clear testable structure for future research; it can be used to better understand how environmental improvements are or are not leading to community revitalization and more accurately identify components of revitalization impacted, thus supporting more equitable representation, communication, and measurement of the relationship., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Rationale: The anatomic orientation of the epiglottis is such that it points in the opposite direction to inspiratory flow, thereby potentially making positive airway pressure (PAP) treatment challenging in patients with epiglottic collapse. However, no previous studies have analyzed PAP adherence in these patients. Objectives: This study aimed to analyze adherence to autotitrating PAP (APAP) treatment in patients with epiglottic collapse. Methods: We performed an age- and sex-matched case-control study. On the basis of their overnight level-I polysomnogram, patients were prescribed APAP in a tertiary hospital between July 2018 and March 2019. The site of airway collapse was diagnosed with drug-induced sleep endoscopy. Demographic factors, sleep questionnaire, polysomnography, and APAP usage statistics were analyzed. Results: Eighteen patients with epiglottic collapse (epi-group) and 36 without epiglottic collapse (control group) were analyzed. We found that 22.8% of patients in the epi-group terminated APAP within 2 weeks, whereas only 2.8% of patients in the control group terminated APAP within 2 weeks ( P  = 0.048). The percentage of days with usage over 4 hours was significantly lower in the epi-group (64.6% vs. 75.6%; P  = 0.008). In addition, the adherence failure rate was 66.7% in the epi-group and 33.3% in the control group ( P  = 0.039). Patients with epiglottic collapse were also found to have lower body mass index, which is an unfavorable predictor of APAP adherence. Conclusions: This study suggests that patients with epiglottic collapse have a higher APAP adherence failure rate than patients without epiglottic collapse. Thus, patients with epiglottic collapse should be followed closely during treatment, and alternative therapies should probably be considered for these patients.

Rationale: Randomized controlled trials of continuous positive airway pressure (CPAP) in patients with obstructive sleep apnea (OSA) have not demonstrated protection against adverse cardiovascular outcomes. Recently, observational studies revealed that OSA-related cardiovascular risk is concentrated in patients with an elevated pulse rate response to respiratory events (ΔHR). Objectives: Here, in this post hoc analysis of a prospective clinical trial, we test the hypothesis that a greater pretreatment ΔHR is associated with greater CPAP-related protection against adverse cardiovascular outcomes. Methods: ΔHR was measured from baseline polysomnography of the RICCADSA (Randomized Intervention with CPAP in CAD and OSA) randomized controlled trial (patients with coronary artery disease [CAD] and OSA [apnea-hypopnea index ⩾ 15 events/h] with Epworth Sleepiness Scale score < 10; n CPAP : n control  = 113:113; male, 85%; age, 66 ± 8 [mean ± SD] yr). The primary outcome was a composite of repeat revascularization, myocardial infarction, stroke, and cardiovascular mortality. Multivariable Cox regression assessed whether the effect of CPAP was moderated by ΔHR (treatment-by-ΔHR interaction). Measurements and Main Results: The CPAP-related reduction in risk increased progressively with increasing pretreatment ΔHR (interaction hazard ratio [95% confidence interval], 0.49 [0.27 to 0.90] per SD increase in ΔHR; P  < 0.05). This means that in patients with a ΔHR of 1 SD above the mean (i.e., 10 beats/min), CPAP was estimated to reduce cardiovascular risk by 59% (6% to 82%) ( P  < 0.05), but no significant risk reduction was estimated in patients with a mean ΔHR (6 beats/min; CPAP risk reduction, 16% [-53% to 54%]; P  = 0.6). Conclusions: The protective effect of CPAP in patients with CAD and OSA without excessive sleepiness was modified by the ΔHR. Specifically, patients with higher ΔHR exhibit greater cardiovascular benefit from CPAP therapy.

The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.arbres.2022.08.005. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/policies/article-withdrawal, (Copyright © 2022 SEPAR. Published by Elsevier España, S.L.U. All rights reserved.)

Study Objectives: Obstructive sleep apnea (OSA) is characterized by multiple "endotypic traits," including pharyngeal collapsibility, muscle compensation, loop gain, and arousal threshold. Here, we examined (1) within-night repeatability, (2) long-term consistency, and (3) influences of body position and sleep state, of endotypic traits estimated from in-home polysomnography in mild-to-severe OSA (apnea-hypopnea index, AHI > 5 events/h)., Methods: Within-night repeatability was assessed using Multi-Ethnic Study of Atherosclerosis (MESA): Traits derived separately from "odd" and "even" 30-min periods were correlated and regression (error vs. N windows available) provided a recommended amount of data for acceptable repeatability (Rthreshold = 0.7). Long-term consistency was assessed using the Osteoporotic Fractures in Men Study (MrOS) at two time points 6.5 ± 0.7 years apart, before and after accounting for across-year body position and sleep state differences. Within-night dependence of traits on position and state (MESA plus MrOS data) was estimated using bootstrapping., Results: Within-night repeatability for traits ranged from R = 0.62-0.79 and improved to R = 0.69-0.83 when recommended amounts of data were available (20-35 7-min windows, available in 94%-98% of participants); repeatability was similar for collapsibility, loop gain, and arousal threshold (R = 0.79-0.83), but lower for compensation (R = 0.69). Long-term consistency was modest (R = 0.30-0.61) and improved (R = 0.36-0.63) after accounting for position and state differences. Position/state analysis revealed reduced loop gain in REM and reduced collapsibility in N3., Conclusions: Endotypic traits can be obtained with acceptable repeatability. Long-term consistency was modest but improved after accounting for position and state changes. These data support the use of endotypic assessments in large-scale epidemiological studies., Clinical Trial Information: The data used in the manuscript are from observational cohort studies and are not a part of the clinical trial., (© The Author(s) 2022. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: This pilot trial aimed to provide evidence for whether the integration of a wearable device with digital behavioral therapy for insomnia (dBTi) improves treatment outcomes and engagement., Participants and Methods: One hundred and twenty-eight participants with insomnia symptoms were randomized to a 3-week dBTi program (SleepFix®) with a wearable device enabling sleep data synchronization (dBTi+wearable group; n = 62) or dBTi alone (n = 66). Participants completed the Insomnia Severity Index (ISI) and modified Pittsburgh Sleep Quality Index (PSQI) parameters: wake-after-sleep-onset (WASO), sleep-onset-latency (SOL), and total sleep time (TST) at baseline and weeks 1, 2, 3, and primary endpoint of week 6 and follow-up at 12 weeks. Engagement was measured by the number of daily sleep diaries logged in the app., Results: There was no difference in ISI change scores between the groups from pre- to post-treatment (Cohen's d = 0.7, p = .061). The dBTi+wearable group showed greater improvements in WASO ( d = 0.8, p = .005) and TST ( d = 0.3, p = .049) compared to the dBTi group. Significantly greater engagement (sleep diary entries) was observed in the dBTi+wearable group (mean = 22.4, SD = 10.0) compared to the dBTi group (mean = 14.1, SD = 14.2) ( p = .010)., Conclusions: This pilot trial found that integration of wearable device with a digital insomnia therapy enhanced user engagement and led to improvements in sleep parameters compared to dBTi alone. These findings suggest that adjunctive wearable technologies may improve digital insomnia therapy effectiveness.

Rationale: Mouth breathing increases upper airway collapsibility, leading to decreased efficacy of obstructive sleep apnea (OSA) treatments. We hypothesized that the use of mandibular advancement devices (MAD) increases mouth breathing, and thus, using an adhesive mouthpiece (AMT) to prevent mouth breathing in combination with MAD can improve the treatment efficacy. Objectives: To evaluate the efficacy of MAD + AMT in comparison with MAD alone. Methods: A prospective crossover pilot study was designed to test this hypothesis. Briefly, adult participants with an apnea-hypopnea index (AHI) between 10 and 50 events/h at the screening visit were randomized to no treatment (baseline), MAD treatment, AMT treatment, and MAD + AMT treatment. As a primary analysis, absolute AHI was compared between MAD and MAD + AMT arms. Secondary analyses included quantifying the percent change in AHI, percentage of complete (AHI < 5 events/h) and incomplete (5-10 events/h) responders, and the efficacy of AMT alone in comparison with other treatment arms. Results: A total of 21 participants were included (baseline AHI = 24.3 ± 9.9 events/h). The median AHI (interquartile range) in the MAD and MAD + AMT arms were 10.5 (5.4-19.6) events/h and 5.6 (2.2-11.7) events/h ( P  = 0.02), respectively. A total of 76% of individuals achieved an AHI of <10 events/h in the MAD + AMT arm versus 43% in the MAD arm ( P  < 0.01). Finally, the observed effect was similar in moderate to severe OSA (AHI ⩾ 15 events/h) in terms of absolute reduction and treatment responders, and AMT alone did not significantly reduce the AHI compared with baseline. Conclusions: A combination of an adhesive mouthpiece and MAD is a more effective therapy than MAD alone. These findings may help improve clinical decision making in sleep apnea.

Background: In the classic model of obstructive sleep apnoea (OSA), respiratory events occur with sleep-related dilator muscle hypotonia, precipitating increased neural ventilatory 'drive'. By contrast, a drive-dependent model has been proposed, whereby falling drive promotes dilator muscle hypotonia to precipitate respiratory events. Here we determine the extent to which the classic versus drive-dependent models of OSA are best supported by direct physiological measurements., Methods: In 50 OSA patients (5-91 events/hour), we recorded ventilation ('flow', oronasal mask and pneumotach) and ventilatory drive (calibrated intraoesophageal diaphragm electromyography, EMG) overnight. Flow and drive during events were ensemble averaged; patients were classified as drive dependent if flow fell/rose simultaneously with drive. Overnight effects of lower drive on flow, genioglossus muscle activity (EMGgg) and event risk were quantified (mixed models)., Results: On average, ventilatory drive fell (rather than rose) during events (-20 (-42 to 3)% baseline , median (IQR)) and was strongly correlated with flow (R=0.78 (0.24 to 0.94)). Most patients (30/50, 60%) were classified as exhibiting drive-dependent event pathophysiology. Lower drive during sleep was associated with lower flow (-17 (-20 to -14)%/drive) and EMGgg (-3.5 (-3.8 to -3.3)% max /drive) and greater event risk (OR: 2.2 (1.8 to 2.5) per drive reduction of 100% eupnoea ); associations were concentrated in patients with drive-dependent OSA (ie, flow: -37 (-40 to -34)%/drive, OR: 6.8 (5.3 to 8.7)). Oesophageal pressure-without tidal volume correction-falsely suggested rising drive during events ( classic model)., Conclusions: In contrast to the prevailing view, patients with OSA predominantly exhibit drive-dependent event pathophysiology, whereby flow is lowest at nadir drive, and lower drive raises event risk. Preventing ventilatory drive decline is therefore considered a target for OSA intervention., Competing Interests: Competing interests: SS received grant support from Apnimed, Prosomnus and Dynaflex and has served as a consultant for Apnimed, Nox Medical and Merck. DPW is a distinguished scientist with Apnimed and a consultant for RBNC Therateutics, Philips Respironics, Cryosa and Cerebra Health. AA serves as consultant for Somnifix and Apnimed and receives grant support from Somnifix. AW works as a consultant for Apnimed, Nox, Inspire and Somnifix and has received grants from Sanofi and Somnifix. LT-M works as medical director at Apnimed. AW and LT-M have a financial interest in Apnimed Inc, a company developing pharmacological therapies for sleep apnoea; their interests were reviewed and are managed by Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict of interest policies., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Study Objectives: Obstructive sleep apnea has major health consequences but is challenging to treat. For many therapies, efficacy is determined by the severity of underlying pharyngeal collapsibility, yet there is no accepted clinical means to measure it. Here, we provide insight into which polysomnographic surrogate measures of collapsibility are valid, applicable across the population, and predictive of therapeutic outcomes., Methods: Seven promising polysomnography-derived surrogate collapsibility candidates were evaluated: Vpassive (flow at eupneic ventilatory drive), Vmin (ventilation at nadir drive), event depth (depth of the average respiratory event), oxygen desaturation slope and mean oxygen desaturation (events-related averages), Fhypopneas (fraction of events scored as hypopneas), and apnea index. Evaluation included (1) validation by comparison to physiological gold-standard collapsibility values (critical closing pressure, Pcrit), (2) capacity to detect increased collapsibility with older age, male sex, and obesity in a large community-based cohort (Multi-Ethnic Study of Atherosclerosis, MESA), and (3) prediction of treatment efficacy (oral appliances and pharmacological pharyngeal muscle stimulation using atomoxetine-plus-oxybutynin)., Results: Pcrit was significantly correlated with Vmin (r = -0.54), event depth (r = 0.49), Vpassive (r = -0.38), Fhypopneas (r = -0.46), and apnea index (r = -0.46; all p < .01) but not others. All measures detected greater collapsibility with male sex, age, and obesity, except Fhypopneas and apnea index which were not associated with obesity. Fhypopneas and apnea index were associated with oral appliance and atomoxetine-plus-oxybutynin efficacy (both p < .05)., Conclusions: Among several candidates, event depth, Fhypopneas, and apnea index were identified as preferred pharyngeal collapsibility surrogates for use in the clinical arena., (© The Author(s) 2022. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Head rotation is thought to have an effect on obstructive sleep apnea (OSA) severity. However, keeping the head rotated fully during sleep is difficult to maintain, and the effect of head rotation is not the same in all OSA patients. Thus, this study aimed to identify whether less head rotation has an effect on airway patency and determine the responder characteristics to the head rotation maneuver (HRM)., Methods: We recruited 221 patients who underwent overnight polysomnography and drug-induced sleep endoscopy (DISE) in a tertiary hospital from June 2019 to July 2020. Airway patency and the site of airway collapse were determined in the supine position with the head at 0, 30, and 60 degrees of rotation (HRM0°, HRM30°, and HRM60°, respectively) during DISE. The site of collapse was determined using the VOTE classification system: the velum (palate), oropharyngeal lateral walls, tongue base, and epiglottis. Each structure was labeled as 0, 1, or 2 (patent, partially obstructed, and completely obstructed, respectively). Airway response to the HRM30° and 60° and the clinical characteristics associated with airway opening were analyzed., Results: The study population had a median age of 52 (25-61) years, a body mass index of 26.7(24.6-29.4) kg/m2, and the apnea-hypopnea index (AHI) of 28.2(13.7-71.9) events/h. HRM influenced airway patency positively not only with HRM60° (p<0.001) but also following limited rotation (HRM30°, p<0.001). Patients with tongue base (40.0% with HRM 60°) and epiglottic (52.6% with HRM 60°) collapse responded particularly well to HRM. Multivariate analysis revealed that lower AHI (p<0.001) and an absence of oropharyngeal lateral walls collapse (p = 0.011) were significant predictors of responders to HRM., Conclusion: Head rotation improved airway obstruction in OSA patients, even with a small degree of rotation, and should be further explored as a potential form of therapy in appropriately selected patients., Competing Interests: Andrew Wellman works as a consultant for Apnimed, Nox, Inspire, and Somnifix. He has received grants from Regeneron and Somnifix. He also has a financial interest in Apnimed Corp., a company developing pharmacologic therapies for sleep apnea. Dr. Wellman’s interests were reviewed and are managed by Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict of interest policies. This does not alter our adherence to PLOS ONE policies on sharing data and materials. DPW is the Director of Medical Affairs for Apnimed and is a consultant for Cryosa, Cerebra Health, Philips Respironics, and LinguaFlex. This does not alter our adherence to PLOS ONE policies on sharing data and materials.