BACKGROUND:Obstructive sleep apnoea (OSA) pathogenesis during rapid-eye movement (REM) sleep has been linked to dips in ventilatory drive and downstream genioglossus hypotonia. The carbonic anhydrase inhibitor acetazolamide is known to increase ventilatory drive and improve OSA severity. Therefore, we tested the effect of acetazolamide on REM-predominant OSA severity (apnoea hypopnoea index (AHI) and hypoxic burden, co-primary outcomes) and underlying physiological mechanisms (ventilatory drive, ventilation and pharyngeal muscle activity). METHODS:11 participants with REM-predominant OSA per baseline polysomnography (REM AHI/non-REM AHI≥2) were allocated to receiving acetazolamide 500 mg for three nights (first night at half dose) or placebo according to a randomised, crossover, double-blind design. Detailed physiological polysomnography with recording of diaphragm and genioglossus electromyography was conducted after each intervention, with a 1-week washout in between. RESULTS:As hypothesised, acetazolamide reduced AHI by 35.5% (95% CI 23.1% to 46.3%) and hypoxic burden by 35.9% (95% CI 21.1% to 48.4%) vs placebo (p<0.001), meeting the primary endpoint. Mechanistic analysis in REM revealed that, unexpectedly, acetazolamide did not mitigate dips in ventilatory drive versus placebo (first decile (+0.1 (-1.0 to 1.3) L/min, p=0.8). Rather, acetazolamide reduced collapsibility (increased ventilation at eupneic drive: +1.4 (1.2 to 1.8) L/min) and raised muscle responsiveness (ventilation vs drive slope: +32 (25 to 41) %ventilation/drive, p<0.001; genioglossus versus drive slope: +0.33 (0.13 to 0.54) %max/(L/min), p=0.001). CONCLUSIONS:Acetazolamide modestly improved REM OSA, with meaningful improvements in upper airway physiology, but failed to mitigate the dips in ventilatory drive responsible for REM OSA. TRIAL REGISTRATION NUMBER:NCT05589792.

Background:Modified continuous positive airway pressure (CPAP) modalities providing pressure support (bilevel PAP (BPAP) or expiratory pressure relief algorithms (EPRAs)) are routinely used for obstructive sleep apnea (OSA) treatment, despite little evidence of increased adherence and improved downstream outcomes. An updated, comprehensive systematic review and meta-analysis of pressure support on adherence is needed. Methods:MEDLINE, EMBASE, CENTRAL, Clinicaltrials.gov and major abstract repositories were searched from database inception until 4/7/2026 for randomized and non-randomized control trials of varying design assessing the effect of pressure support (BPAP, EPRA, or both) on adherence (primary outcome) vs. CPAP in adults with OSA and in those exhibiting CPAP intolerance (exploratory). Subgroup analyses and meta-regressions assessed potential causes of heterogeneity. Publication bias was examined via Eggers' test. Epworth Sleepiness Scale (ESS) changes from baseline, residual apnoea-hypopnea index (AHI) and leak (secondary outcomes) were also analysed when available. GRADE was used for certainty of evidence (CoE) rating. This study is registered with PROSPERO (CRD420251086824). Findings:In twenty-one studies (N = 1462 participants), pressure support did not affect adherence vs. CPAP (mean difference [95% CI]: 0.21 [-0.01, 0.44] h/night, P = 0.06; heterogeneity = 45%; CoE: very-low-to-moderate). BPAP had a larger effect amongst those exhibiting PAP intolerance (0.68 [0.14, 1.23] h/night, P = 0.01), but CoE was very-low. Longer follow-up duration was associated with decreasing adherence to pressure support vs. CPAP (-0.18 [-0.36, -0.03] h/night per additional trimester beyond 3 months, P = 0.03). There was no difference in ESS and residual AHI between interventions, but leak was reduced on pressure support (CoE: low-to-moderate). No publication bias was detected for any outcome. Interpretation:Pressure support yields similar adherence and residual AHI to CPAP. Given increased research and development demands and device cost, its use in OSA is not supported. Future work will need to clarify the exact role of pressure support in patients intolerant to CPAP. Funding:None.

Objective:Several endotypes contribute to the development of Obstructive Sleep Apnea (OSA). However, efforts to measure these endotypes have been challenging. In this paper, we propose a new method that overcomes some of these challenges. Methods:To test the feasibility of this new method, data from the Sleep Heart Health Study (SHHS) were analyzed and two oxygen-based endotypes were identified and plotted on a graphical model: the steady-state SpO2 and the SpO2 arousal threshold. The first is the oxygen saturation that would occur during sleep if there were no arousals, and it is a measure of upper airway collapsibility (a more collapsible airway produces a lower SpO2). The latter is the oxygen saturation that triggers arousals. These endotypes were validated by assessing their ability to detect positional and state-related changes in airway collapsibility and arousal threshold. Results:The study showed that it was feasible to measure oxygen-based endotypes in 95% of SHHS participants. As expected, steady-state SpO2 was lower during supine vs. non-supine sleep, as well as during REM vs. NREM sleep. Also, the SpO2 arousal threshold was similar between supine and non-supine sleep. However, SpO2 arousal threshold was not lower in REM sleep vs. NREM sleep. Therefore, in 3 of the 4 conditions, the oxygen-based endotypes moved in the expected direction due to positional or sleep state changes. Conclusion:Although further validation experiments are required, this study indicates that OSA endotyping using the pulse oximetry signal is feasible. The oxygen-based endotypes could be used to aid therapeutic decision making.

Obstructive sleep apnea is traditionally described as an inspiratory disorder because obstructive events are most commonly visualized in-vivo during inspiration. However, pharyngeal narrowing has also been well-documented during expiration. Thus, an important unresolved question is which phase of the respiratory cycle is most relevant for positive airway pressure (PAP) therapy. Here we propose that the upper airway has a "Kairos" (ancient Greek for "critical time"), a brief interval in late expiration where therapy must be maintained to optimize pharyngeal patency. Our hypothesis is supported by several observations: 1) end-expiration has been associated with the smallest upper airway cross-sectional area throughout the respiratory cycle, and increasing surface area through PAP raises dilating wall force; 2) end-expiration coincides with the lowest end-expiratory lung volume, thus minimizing caudal traction on the upper airway; 3) reductions in expiratory pressure produced by some expiratory pressure relief algorithms have been associated with diminished pharyngeal airway size. Therefore, optimizing positive pressure in late expiration may maximize airway size and stiffness, thus preparing the airway for the subsequent inspiration, when negative intraluminal pressure would otherwise promote collapse. These mechanisms suggest that preventing late expiratory narrowing may be more important for maintaining pharyngeal patency than previously appreciated. Pilot studies examining novel PAP technologies preserving expiratory pressure during the "Kairos" have provided evidence that upper airway stability can be maintained despite substantial reductions in inspiratory pressure. Assuming these concepts are correct, PAP therapies should be calibrated not only to pressure magnitude, but also to the timing of pressure delivery.

Abstract Introduction Obstructive sleep apnea (OSA) first-line therapy, continuous positive airway pressure (CPAP), is highly efficacious but limited by adherence. We propose that an underrecognized factor influencing adherence is circuit rebreathing. The current study sought to carefully quantify levels of rebreathing under various exhaust flow conditions. Methods 13 participants with moderate-to-severe OSA performed wakefulness testing while breathing on a modified CPAP circuit that allowed independent manipulation of exhaust flow. Exhaust flow levels of 8, 13, 18, 23, and 35 L/min were studied. Patients breathed on the circuit at 5 cmH2O for 1-2 min for each exhaust flow level, repeated in duplicate. We also assess effects of lowered exhaust flow on the global breathing discomfort scale. Mean inspired CO2 and inspired O2 levels were carefully estimated using delay-corrected gas sampling. Effects of circuit exhaust on inspired CO2 and inspired O2 were assessed using mixed model analysis. Impact of circuit rebreathing was also examined during sleep (5-10 min periods). Results In the five participants studied to date (4M:1F; age 61±6 y; BMI 29±4 kg/m2), inspired CO2 increased progressively with reduced exhaust flow (continuous model: inspired CO2 [mmHg] ~ 1/exhaust, β = 19.6 [14.6, 24.6], estimate[95%CI]; P< 0.0001). Compared to exhaust at 35 L/min, progressive exhaust reductions to 23, 18, 13, and 8 L/min led to inspired CO2 increases by +0.4 [−0.5, 1.2], +0.35 [−0.5, 1.2], +0.7 [−0.3, 1.7], and +2.1 [1.3, 2.9] mmHg respectively. Likewise, we found that inspired O2 reduced significantly with reduced exhaust flow (continuous model β = −25.1 [−31.0, −19.1]; P< 0.0001). Compared to exhaust at 35 L/min, exhaust reductions to 23, 18, 13, and 8 L/min led to inspired O2 changes by −0.7 [−1.8, 0.4], −0.6 [−1.7, 0.4], −1.3 [−2.5, −0.03], and −2.7 [−3.7, −1.6] mmHg respectively. With reductions to 23, 18, 13, and 8 L/min, the global breathing discomfort scale changed by −0.2, 0, +0.4, and +1.4 respectively. Similar effects appeared present during sleep. Conclusion Our study suggests that rebreathing can occur at exhaust flow levels observed in commercially-available CPAP circuits, and may impact patient comfort. Support (if any)

BACKGROUND AND AIMS:Randomized trials of continuous positive airway pressure (CPAP) treatment for obstructive sleep apnoea (OSA) in patients with cardiovascular disease have not detected reduced risk of major adverse cardiovascular and cerebrovascular events (MACCEs). This study tested whether the cardiovascular benefit of CPAP occurs preferentially in high-risk OSA, characterized by greater OSA-related heart rate acceleration or hypoxaemia. METHODS:In a post hoc analysis of pooled Randomized Intervention with Continuous Positive Airway Pressure in Coronary Artery Disease and Obstructive Sleep Apnoea, Impact of Continuous Positive Airway Pressure on Patients with Acute Coronary Syndrome and Nonsleepy Obstructive Sleep Apnoea, and Sleep Apnoea Cardiovascular Endpoints Study randomized trials; outcomes were stratified by high-risk OSA status, defined by heart rate response following OSA respiratory events >9.4 b.p.m. (third tertile) or oxygen desaturation area under baseline (hypoxic burden) > 87.1% min/h (third tertile). Cox mixed models quantified the CPAP treatment effect on MACCE (including cardiovascular mortality, myocardial infarction, and stroke) within high-risk OSA and the difference vs low-risk status (primary test). Secondary analyses examined participants without excessive sleepiness (Epworth <11 points) or without increased blood pressure (systolic/diastolic <140/90 mmHg). RESULTS:In 3549 participants, 16.6% and 16.3% reached the MACCE endpoint with CPAP (n = 1778) and usual care (n = 1771), respectively. The CPAP treatment effect was greater in participants with vs without high-risk OSA [interaction hazard ratio (iHR) .69, 95% confidence interval (CI) .50-.95, Pinteraction = .024; Nhigh-risk = 1832]. The differential effect was stronger in those without excessive sleepiness (iHR .59, 95% CI .41-.84; Nhigh-risk = 1509), or without increased blood pressure (iHR .54, 95% CI .36-.81; Nhigh-risk = 1244). Continuous positive airway pressure benefits in high-risk OSA were observed alongside harm in low-risk OSA. CONCLUSIONS:Continuous positive airway pressure preferentially improves cardiovascular outcomes in high-risk OSA, while harm in low-risk OSA may counteract this effect. These findings provide a pathway to identify patients likely to benefit.

Abstract Introduction Modified continuous positive airway pressure (CPAP) modalities providing pressure support—bilevel PAP (BPAP) or expiratory pressure relief algorithms (EPRAs)—are routinely used for OSA treatment, despite little evidence of increased adherence and improved downstream outcomes. Therefore, we sought an answer to the following question: Does the use of pressure support increase treatment adherence in OSA patients? To answer this question, an updated, more comprehensive systematic review and meta-analysis of pressure support on adherence is needed. Methods MEDLINE, EMBASE, CENTRAL, Clinicaltrials.gov and major abstract repositories were searched for randomized and non-randomized control trials assessing the effect of pressure support (BPAP, EPRA or both) on adherence (primary outcome) vs. CPAP in adults with OSA and in those exhibiting CPAP intolerance (exploratory). Subgroup analyses and meta-regressions assessed potential causes of heterogeneity. Epworth Sleepiness Scale (ESS) changes from baseline, residual apnea-hypopnea index (AHI) and leak (secondary outcomes) were also analyzed when available. GRADE was used for certainty of evidence (CoE) rating. Results In twenty-one studies (N=1462 participants), pressure support did not affect adherence vs. CPAP (mean difference [95%CI]: 0.21 [-0.01, 0.44] h/night, P=0.06; heterogeneity=45%; CoE: very-low-to-moderate). BPAP had a larger effect amongst those exhibiting PAP intolerance (0.68 [0.14, 1.23] h/night, P=0.01), but CoE was very-low. Longer follow-up duration was associated with decreasing adherence to pressure support vs. CPAP (-0.18 [-0.36, -0.03] h/night per additional trimester beyond 3 months, P=0.03). There was no difference in ESS and residual AHI between interventions, but leak was reduced on pressure support (CoE: low-to-moderate). Conclusion Pressure support yields similar adherence and residual AHI to CPAP. Given increased research and development demands and device cost, its use in OSA cannot be recommended. Support (if any) None

Rationale: A major challenge for the development of an effective and tolerable pharmacological intervention for obstructive sleep apnea (OSA) is that noradrenergic muscle stimulants like atomoxetine have wake-promoting properties. Pimavanserin, a promising serotonin 2A receptor antagonist, may increase arousal threshold and help reduce OSA severity. With this randomized, crossover, double-blind clinical trial, we tested the effect of this drug combination on apnea-hypopnea index (AHI; primary outcome), arousal index and nadir oxygen saturation (SpO2; secondary outcomes). Methods: Following baseline polysomnography, 18 OSA participants (AHI>15events/h) took pimavanserin-plus-atomoxetine (34/80mg; 34/40mg for the first 3 days) or placebo for one-week; follow-up polysomnography was performed to provide study outcomes. Safety outcomes (including corrected QT (QTc) as both drugs can potentially increase QTc length), subjective sleep quality, and flow-estimated endotypes (using oronasal pneumotachograph flow) were also explored. Results: The atomoxetine-plus-pimavanserin combination reduced AHI by 42 [95%CI: 18, 60] % vs. placebo, meeting the primary outcome (P<0.001). Absolute AHI reduction was 16.9 [8.1, 23.6] events/h greater than placebo. Nadir SpO2 and arousal index were also improved, by 5.0 [1, 8] % and 10.9 [2.4, 18.1] events/h vs. placebo. Overnight heart rate was increased (+4.8 [1.5, 8.1]), but no change in QTc, subjective sleep quality or next-morning vital signs was evident. There was no increased risk for side effects on the combination vs. placebo. Treatment vs. placebo improved pharyngeal collapsibility (+7.9 [1.6, 14.1]%VEUPNEA), reduced loop gain by 20% (0.15 [-0.23, -0.07]), and did not reduce the arousal threshold. Individuals with less-severe collapsibility (greater VPASSIVE) at baseline experienced a more favorable AHI reduction on atomoxetine-pimavanserin compared to placebo (additional 25.0 [-11.5, 48.7] % for each 1SD increase in VPASSIVE). Conclusions: The combination of atomoxetine and pimavanserin significantly reduced OSA severity, lowering arousal index and overnight hypoxemia. Compared to placebo, the combination did not raise the risk of many adverse effects seen in similar trials (e.g., insomnia, headache, tachycardia), except for a mild heart rate increase. Pimavanserin shows promise to be associated to atomoxetine for treating OSA and merits further, larger trials.

Rationale: Randomized trials of continuous positive airway pressure (CPAP) treatment for obstructive sleep apnea (OSA) have not detected clear evidence of reduced risk of major adverse cardiovascular and cerebrovascular events (MACE) in unselected patients, contrasting with observational studies that have shown cardiovascular benefits of CPAP. Here, we evaluated whether cardiovascular benefit of CPAP occurs preferentially in “high-risk” patients, identified by high levels of OSA-related heart rate acceleration or hypoxemia (effect modification). Methods: In a post-hoc analysis of pooled RICCADSA, ISAACC, and SAVE randomized trials, outcomes were stratified by high-risk OSA status, defined by heart rate response following OSA respiratory events >9.4 beats/min (highest tertile) or oxygen desaturation area-under-baseline (hypoxic burden) >87.1 %.min/hr (highest tertile). Cox mixed models quantified the CPAP treatment effect on MACE (composite including cardiovascular mortality, myocardial infarction, stroke) within high-risk OSA and the difference versus low-risk status (treatment×subgroup interaction, primary hypothesis test). Secondary analyses examined participants without excessive sleepiness (Epworth <11 points) or without increased blood pressure (systolic/diastolic <140/90 mmHg). Other definitions of high-risk were evaluated in sensitivity analyses. Results: In the 3549 participants analyzed, 16.6% and 16.3% met the MACE endpoint with CPAP and usual care respectively. The CPAP treatment effect was greater in participants with versus without high-risk OSA (interaction hazard ratio [iHR]=0.69, 95% confidence interval [CI]: 0.50-0.95, Pinteraction=0.024; overall CPAP benefit within high-risk OSA: hazard ratio [HRhigh-risk] = 0.83[0.66-1.05], Nhigh-risk=1832; CPAP effect within low-risk OSA: HRlow-risk = 1.22 [0.96-1.54], Nlow-risk=1717). Stronger effect modifications were observed after excluding those with excessive sleepiness (iHR=0.59[0.41-0.84]; HRhigh-risk=0.76[0.60-0.98], Nhigh-risk=1509), or those with increased blood pressure (iHR=0.54[0.36-0.81]; HRhigh-risk=0.72[0.54-0.96], Nhigh-risk=1244). Notably, CPAP benefit in high risk OSA was accompanied by an increased hazard in CPAP versus usual care within low-risk OSA (without excessive sleepiness: HRlow-risk = 1.30 [1.01-1.66]; without increased blood pressure, HRlow-risk = 1.33 [1.00-1.76]; Figure 1). Other definitions of high-risk OSA revealed similar findings. Conclusions: High-risk OSA, per OSA-related heart rate acceleration or hypoxemia, modifies the effect of CPAP on MACE, especially in individuals without excessive sleepiness or increased blood pressure. Our study provides novel evidence that a definable subgroup of patients with OSA may benefit from CPAP for major cardiovascular event prevention.

Rationale: Patient selection for hypoglossal nerve stimulation (HGNS) for obstructive sleep apnea (OSA) requires assessment of the pharyngeal site of collapse using drug-induced sleep endoscopy (DISE). The current study addresses two key knowledge gaps: First, we prospectively assessed whether, among HGNS candidates, reduced HGNS efficacy is associated with oropharyngeal lateral wall (OLW) collapse (Aim 1). Second, given DISE is a resource-intensive procedure that delays treatment, we evaluate whether a recently-developed non-invasive method for identifying OLW collapse using airflow shapes is associated with reduced HGNS efficacy (Aim 2). Methods: Patients who underwent DISE, HGNS implantation, and follow-up sleep testing were included in Aim 1 (n=347). For Aim 2, airflow data estimating OLW collapse probability (Pr. OLW) were collected during DISE via pneumotachograph (n=133, DISE Flow cohort). In a separate cohort, airflow data was obtained from home sleep testing (Nox A1) via nasal cannula for validation (n=41, HST cohort). Pr. OLW was computed from our validated flow shape analysis model. Linear regression models quantified the association between HGNS efficacy (%AHI reduction from baseline) and DISE-determined OLW collapse (Aim 1) or flow-shape-determined OLW collapse (likelihood score per 2SD; Aim 2), adjusting for baseline AHI. A probability cutoff for OLW collapse was developed to categorize patients into likely HGNS successes (who may skip DISE), and those needing further assessment (e.g., DISE). This cutoff maximized the difference in HGNS efficacy from the DISE Flow cohort and then was validated in the HST cohort. In both cohorts, we quantified the degree to which HGNS efficacy was greater in “likely successes” (Pr. OLW>0.6) versus patients “needing further assessment” using the same modelling approach as above. Results: Compared to non-OLW collapse, patients with DISE-determined OLW collapse had lower HGNS efficacy [95%CI] by -13.9%[-26.7,-3.1]. Increased flow-shape-determined OLW collapse probability was associated with reduced HGNS efficacy in both DISE Flow (-19.4%[-33.1,-7.7]) and HST (-30.3 [-61.6, -7.6]%) cohorts. Further, patients in the needs further assessment group (Pr. OLW>0.60, n=30/133) exhibited lower HGNS efficacy than patients in the likely success group (n=103/133), by -20.6 [-35.7,-7.9]% (Figure 1B). Validation in HST cohort also demonstrated lower HGNS efficacy in the needs further assessment group (n=25/41) versus likely successes (Figure 1C), by -21.7 [-46.3,-3.2], p=0.020. Conclusion: This study prospectively validates OLW collapse as a key factor in HGNS failure and shows that airflow-based identification of OLW collapse can effectively estimate HGNS efficacy, presenting a significant advancement in opportunities for patient selection for HGNS.

BACKGROUND:Patient selection for hypoglossal nerve stimulation (HGNS) for obstructive sleep apnoea (OSA) requires assessment of pharyngeal site of collapse using drug-induced sleep endoscopy (DISE). The current study aims to address two key knowledge gaps. First, we prospectively confirm that, among HGNS candidates, reduced HGNS efficacy is associated with oropharyngeal lateral wall (OLW) collapse (Aim 1). Second, given DISE is a resource-intensive procedure and delays treatment, we evaluate whether a recently developed non-invasive method for identifying OLW collapse using airflow shapes is associated with reduced HGNS efficacy (Aim 2). METHODS:Patients who underwent DISE, HGNS implantation and follow-up sleep testing were included in Aim 1 (n=369) as part of an observational cohort study. For Aim 2, airflow data estimating OLW collapse probability were collected during DISE via a pneumotachograph (n=138; DISE Flow cohort) and from a home sleep test (HST) via nasal cannula for validation (n=46; HST cohort). Linear regression quantified associations between HGNS efficacy (percent reduction in apnoea-hypopnoea index (AHI)) and DISE-determined OLW collapse (Aim 1) or flow shape-determined OLW collapse (probability score per 2sd) (Aim 2), adjusting for baseline AHI. RESULTS:Compared to non-OLW collapse, DISE-determined OLW collapse reduced HGNS efficacy by -18.0% (95% CI -31.9- -6.2%). Increased flow shape-determined OLW collapse probability (Δ2sd) was associated with reduced HGNS efficacy in both DISE Flow (-24.8%, 95% CI -40.4- -11.7%) and HST (-22.7%, 95% CI -50.0- -2.6%) cohorts. CONCLUSION:This study prospectively validates OLW collapse as a key factor in HGNS failure and shows that airflow-based identification of OLW collapse can effectively estimate HGNS efficacy, representing a significant advancement in patient selection for HGNS.

Rationale: Obstructive sleep apnea (OSA) is a highly prevalent disorder that is associated with adverse health outcomes. A major cause of OSA is considered to be sleep-related genioglossus (GG) hypotonia, which has become a target for therapeutic device intervention. However, for many patients, GG activity is not actually reduced during events, when ventilation is lowered, challenging its causal role in OSA pathophysiology, and suggesting that hypotonia of other pharyngeal muscles may be more relevant for respiratory events. In the current study, we investigated the time course of GG and another representative palatal dilator (tensor palatini, TP) to determine which best explains the loss of ventilation during events. Methods: 10 OSA patients to date underwent a physiological sleep study with measurement of pneumotach ventilation plus genioglossus and tensor palatini intramuscular electromyography (EMGGG and EMGTP). For each patient, univariable regression (correlation, unadjusted) and multivariable regression (adjusted) quantified the patient-specific association between the ensemble-averaged time course of ventilation during events and the time courses of EMGGG and EMGTP (peak and tonic, all signals SD-standardized). Multivariable model: Ventilation ∼ β1EMGGGpeak + β2EMGGGtonic + β3EMGTPpeak + β4EMGTPtonic. The total estimated contribution of EMGTP (via peak or tonic activity, β3+β4) to event-related loss of ventilation was compared to the EMGGG contribution (β1+β2) using mixed model analysis; a patient's events were TP dominan t if the EMGTP contribution was 2-fold greater than the EMGGG contribution. Results: Patient characteristics: 8M:2F, median [IQR] age=45[37-54] years, BMI=30[26-37] kg/m2, AHI=20[13-38] events/hr. In unadjusted analysis, the fall and rise in ventilation during events was strongly associated with EMGTP (βunadjusted; peak=0.72±0.39, tonic=0.93±0.09; mean±SD) but only modestly associated with EMGGG (peak=0.35±0.48, tonic=0.34±0.57), see Figure 1. In multivariable analysis, ventilation during events was also more strongly associated with EMGTP (βadjusted: peak=0.18±0.22, tonic=0.58±0.31) than EMGGG (peak=0.05±0.13, tonic=0.15±0.25); the total TP contribution (peak+tonic=0.77±0.36) was significantly greater than the GG contribution (peak+tonic=0.20±0.32; difference [95%CI] = 0.56 [0.26, 0.87], P=0.0012). A clear majority of patients (7/10) were TP dominant ; 2/10 were GG dominant, and 1/10 was balanced. Conclusion: The current study demonstrated that TP activity better tracks the fall and rise of ventilation during events than GG activity, inferring that TP provides a stronger explanation for the event-related loss of ventilation than the GG. The study provides unique evidence that TP—or other non-GG pharyngeal dilators—may have a more important role in the loss of ventilation that characterizes respiratory events than is currently appreciated.

Treatment-emergent central sleep apnea (TECSA) is an important problem during therapy with continuous positive airway pressure (CPAP) in patients with obstructive sleep apnea. We tested a device designed to improve CPAP comfort through reducing inspiratory positive airway pressure (IPAP; V̇-Com ) to determine whether such a reduction in IPAP could eliminate central apneas in patients with TECSA. Because increasing tidal volume (potentially via IPAP increments) has been suggested as a possible mechanism contributing to TECSA onset, our hypothesis was that reducing IPAP would yield a drop in the central apnea index. The addition of a known resistance ( V̇-Com device) that reduces IPAP was implemented into the CPAP circuit during the second half of CPAP titrations in a cohort of community-dwelling patients who developed TECSA during a split-night CPAP titration. Central apnea index was quantified from the sleep periods without and with V̇-Com in place. A total of 1,613 patients underwent CPAP titration, with 19 of them developing TECSA during the titration. The addition of V̇-Com resulted in complete resolution of TECSA in all patients with adequate sleep data under all conditions (n = 13), yielding a significant reduction in the central apnea index (17.3 ± 11.0 vs 1.5 ± 1.7 events/h without and with V̇-Com , respectively; P < .001). V̇-Com virtually resolved all instances of TECSA, suggesting that reducing IPAP could be an effective strategy for managing the occurrence of central respiratory events in patients with obstructive sleep apnea using CPAP. Noah WH, Messineo L, Hete B, et al. Treatment-emergent central sleep apnea resolves with lower inspiratory pressure. J Clin Sleep Med. 2025;21(3):559–564.

This study aims to investigate the effects of acoustic therapy on the nasal microbiome, immune responses, and overall well-being in patients with allergic rhinitis (AR) and chronic rhinosinusitis (CRS). Utilizing the Goodair® NoseBuds, a low-cost acoustic device developed by the AUT BioDesign Lab, this research explores the potential of nasal mechanostimulation to increase endogenous nitric oxide production, improve nasal health, and alleviate AR and CRS symptoms. Participants will use the device twice daily over a four-week period, and the study will assess changes in nasal microbiome composition, inflammation markers, and patient-reported outcomes, such as symptom severity and quality of life. Data will be analysed through bioinformatics and statistical methods to identify correlations between acoustic therapy and immune or microbial changes. This research offers an innovative, non-pharmaceutical alternative for managing AR and CRS, with the potential to reduce reliance on traditional medications and improve patient outcomes.

Auto-adjusting positive airway pressure (APAP), unlike continuous PAP (CPAP), dynamically adjusts treatment pressure in response to events detected automatically from a derived flow signal. Introduced in the 90’s, APAP quickly became a key tool in sleep clinics, initially serving as a faster alternative to manual titration for patients with obstructive sleep apnea (OSA), and later also as a long-term treatment option to expedite follow-up visits. APAP and CPAP are overall comparable in terms of adherence, efficacy and control of symptoms. However, concern remains that APAP offers less control of chronic health outcomes, such as blood pressure, kidney function and glycemic values. Other APAP-related challenges entail engineering aspects. A major issue is that APAP algorithms—which govern event detection/identification and pressure adjustments—are proprietary of and vary among manufacturers, making them poorly understood by clinicians. Furthermore, APAP algorithms do not always match-up well when compared to both manual titration or manually scored polysomnography, particularly in the presence of unintentional leak. Variability in event detection, leak compensation, and pressure adjustment algorithms among devices adds another layer of complexity to clinical decision-making. All this complicates the management of OSA patients, who could be left with substantial residual disordered breathing, high leak, and a wide pressure range. This review aims to bridge the gap between the clinical and engineering perspectives of APAP, providing an up-to-date overview of current knowledge and existing challenges that sleep clinicians should consider when managing OSA patients with PAP therapy.

Epiglottic collapse can obstruct the airway in patients with obstructive sleep apnea in an anteroposterior or lateral direction. The present study investigates the concept that lateral or concentric pharyngeal collapse patterns may remodel the epiglottis and predispose it to lateral collapse. To do so, we hypothesized that the presence of-any form of laterally directed pharyngeal collapse, eg, oropharyngeal lateral wall collapse or complete concentric collapse of the soft palate, is associated with increased odds for having concurrent lateral epiglottic collapse (E-lat). We analyzed 582 patients with obstructive sleep apnea from our drug-induced sleep endoscopy cohort. Site of collapse was scored by a single scorer using the VOTE criteria, with patients with epiglottic collapse reviewed by 2 additional independent scorers. Logistic regression evaluated the association between presence of laterally directed pharyngeal collapse and the presence of E-lat. The overall prevalence of E-lat was 2.6

Elevated environmental carbon dioxide (CO2) levels can have important health impacts, including increased anxiety, impaired high-level cognitive performance, reduced sleep quality, and decreased next-day alertness, especially in children. Bedrooms, where people spend a third of their lives, are often poorly ventilated, further exacerbating CO2 exposure during sleep. These symptoms may be of particular concern for individuals with obstructive sleep apnea treated with continuous positive pressure as a result of CO2 trapping within the mask, which is dependent on environmental levels, and circuit CO2 rebreathing. Additionally, lower inhaled oxygen concentrations may be encountered when exhaled gases are rebreathed from the circuit. Low expiratory positive airway pressure, high ventilation levels (eg, in large individuals or at altitude), and small exhaust valves increase rebreathing risk, which can self-propagate due to patient attempts to compensate by increasing tidal volume. Elevated environmental CO2 may further exacerbate the clinical consequences of rebreathing, including reduced continuous positive pressure adherence. Although strategies including higher expiratory positive airway pressure or larger exhaust valves help mitigate CO2 buildup, they can also lead to increased noise, which may potentially affect adherence. With this work, we review the available evidence on the thresholds and effects of classroom, office, bedroom, and rebreathed CO2 levels in healthy individuals and those with obstructive sleep apnea, both adults and children. Importantly, we provide the often-overlooked link between environmental CO2 concentrations and circuit rebreathing for patients with obstructive sleep apnea, underscoring the need to optimize current indoor ventilation standards and thresholds for mask-based CO2 inhalation, as well as continuous positive pressure technology to maximize adherence, abate CO2/hypoxic exposure, and improve health outcomes. Noah WH, White DP, Hete B, Messineo L. Rebreathing during CPAP therapy and its implications in obstructive sleep apnea. J Clin Sleep Med. 2025;21(10):1759–1771.

BACKGROUND:OSA pharmacologic interventions like the noradrenergic muscle stimulant atomoxetine have wake-promoting properties. Pimavanserin, a promising serotonin 2A receptor antagonist, may help to counteract atomoxetine's noradrenergic effects by increasing arousal threshold and possibly reducing OSA severity. RESEARCH QUESTION:What is the effect of the combination of pimavanserin and atomoxetine on apnea-hypopnea index (AHI; primary outcome), arousal index, and nadir oxygen saturation (Spo2; secondary outcomes)? STUDY DESIGN AND METHODS:After baseline polysomnography, 18 participants with OSA (AHI > 15 events/h) took pimavanserin plus atomoxetine (34/80 mg; 34/40 mg for the first 3 days) or placebo for 1 week according to a randomized, crossover, 2-period, double-masked clinical trial. Follow-up polysomnography was performed to provide study outcomes. Safety outcomes, subjective sleep quality, and flow-estimated endotypes (using oronasal pneumotachograph flow) also were explored. RESULTS:Eleven and 7 participants were randomized to atomoxetine plus pimavanserin and placebo first, respectively. The combination reduced AHI by 42% (95% CI, 18%-60%) vs placebo, meeting the primary outcome (P < .001). Absolute AHI reduction was 16.9 events/h (95% CI, 8.1-23.6 events/h) more than placebo. Nadir Spo2 and arousal index also were improved, by 5.0% (95% CI, 1%-8%) and 10.9 events/h (95% CI, 2.4-18.1 events/h) vs placebo. Overnight heart rate was increased (+4.8 beats/min; 95% CI, 1.5-8.1 beats/min), but no other change in subjective sleep quality or next-morning vital signs was evident. No increased risk for side effects was observed for the combination vs placebo. Treatment vs placebo improved pharyngeal collapsibility (+7.9% of stable breathing during sleep; 95% CI, 1.6%-14.1% of stable breathing during sleep), reduced loop gain by 20% (0.15; 95% CI, -0.23 to -0.07), and did not reduce the arousal threshold. INTERPRETATION:Our results indicate that pimavanserin with atomoxetine is a strong pharmacologic therapy candidate for OSA. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov; No.: NCT05350215; URL: www. CLINICALTRIALS:gov.

The incidence of metabolic disorders is increasing at an alarming rate. A theoretically reversible collection of risk factors called metabolic syndrome precedes some of these conditions, such as diabetes. Additionally, treatments designed for diabetes do not often incorporate the individualized real-time lifestyle and physiological data. Monitoring glucose levels for diabetics and stopping prediabetics from progressing further can be aided by continuous glucose monitoring. The ubiquitous and unobtrusive nature of wrist-worn smart watches and continuous glucose monitors allow a longitudinal flow of information rich data. However, a comprehensive inspection or cascaded statistical tests must be performed to draw insights from this data. These methods suffer from subjectivity, observation bias and complexity. To overcome these, Artificial intelligence (AI) can be leveraged to draw these insights due to scalable utility of data. Alongside phenotyping glucose changes AI can also help reduce the costs associated with glucose level monitoring. This study proposes to develop an AI-driven precision medicine framework to incorporate data from wrist-worn sensors and glucose monitors to deliver insights.