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Jean-Louis Pepin,1,* Nhat-Nam Le-Dong,2,* Valérie Cuthbert,3 Nathalie Coumans,3 Renaud Tamisier,1 Atul Malhotra,4 Jean-Benoit Martinot3,5 1HP2 Laboratory, Inserm U1300, University Grenoble Alpes, Grenoble, France; 2Sunrise, Namur, Belgium; 3Sleep Laboratory, CHU Université Catholique de Louvain (UCL) Namur Site Sainte-Elisabeth, Namur, Belgium; 4University of California San Diego, La Jolla, CA, USA; 5Institute of Experimental and Clinical Research, UCL Bruxelles Woluwe, Brussels, Belgium*These authors contributed equally to this workCorrespondence: Jean-Benoit Martinot, Centre du Sommeil et de la Vigilance, CHU-UCL Namur Site Ste Elisabeth, 15 Place Louise Godin, Namur, 5000, Belgium, Tel +32 495502608, Fax +32 81570754, Email martinot.j@respisom.bePurpose: Differentiation between obstructive and central apneas and hypopneas requires quantitative measurement of respiratory effort (RE) using esophageal pressure (PES), which is rarely implemented. This study investigated whether the sleep mandibular movements (MM) signal recorded with a tri-axial gyroscopic chin sensor (Sunrise, Namur, Belgium) is a reliable surrogate of PES in patients with suspected obstructive sleep apnea (OSA).Patients and Methods: In-laboratory polysomnography (PSG) with PES and concurrent MM monitoring was performed. PSGs were scored manually using AASM 2012 rules. Data blocks (n=8042) were randomly sampled during normal breathing (NB), obstructive or central apnea/hypopnea (OA/OH/CA/CH), respiratory effort-related arousal (RERA), and mixed apnea (MxA). Analyses were evaluation of the similarity and linear correlation between PES and MM using the longest common subsequence (LCSS) algorithm and Pearson’s coefficient; description of signal amplitudes; estimation of the marginal effect for crossing from NB to a respiratory disturbance for a given change in MM signal using a mixed linear-regression.Results: Participants (n=38) had mild to severe OSA (median AH index 28.9/h; median arousal index 23.2/h). MM showed a high level of synchronization with concurrent PES signals. Distribution of MM amplitude differed significantly between event types: median (95% confidence interval) values of 0.60 (0.16– 2.43) for CA, 0.83 (0.23– 4.71) for CH, 1.93 (0.46– 12.43) for MxA, 3.23 (0.72– 18.09) for OH, and 6.42 (0.88– 26.81) for OA. Mixed regression indicated that crossing from NB to central events would decrease MM signal amplitude by – 1.23 (CH) and – 2.04 (CA) units, while obstructive events would increase MM amplitude by +3.27 (OH) and +6.79 (OA) units (all p< 10− 6).Conclusion: In OSA patients, MM signals facilitated the measurement of specific levels of RE associated with obstructive, central or mixed apneas and/or hypopneas. A high degree of similarity was observed with the PES gold-standard signal.Keywords: obstructive sleep apnea, respiratory effort, mandibular movements, esophageal pressure

Jean-Benoit Martinot,1,2 Nhat-Nam Le-Dong,3 Valérie Cuthbert,1 Stéphane Denison,3 David Gozal,4 Gilles Lavigne,5 Jean-Louis Pépin6 1Sleep Laboratory, CHU Université Catholique de Louvain (UCL) Namur Site Sainte-Elisabeth, Namur, 5000, Belgium; 2Institute of Experimental and Clinical Research, UCL Bruxelles Woluwe, Brussels, 1200, Belgium; 3Sunrise, Namur, 5101, Belgium; 4Department of Child Health and Child Health Research Institute, University of Missouri, Columbia, MO, 65201, USA; 5Faculté de médecine dentaire, Université de Montréal, Montréal, Québec, H3C 3J7, Canada; 6HP2 Laboratory, Inserm U1042, University Grenoble Alpes, Grenoble, 38000, FranceCorrespondence: Jean-Benoit MartinotCentre du Sommeil et de la Vigilance, CHU UCL Namur Site Ste Elisabeth, 15, Place Louise Godin, Namur, 5000, BelgiumTel +32 81 720 411Fax +32 81 570 754Email martinot.j@respisom.bePurpose: Sleep bruxism (SBx) activity is classically identified by capturing masseter and/or temporalis masticatory muscles electromyographic activity (EMG-MMA) during in-laboratory polysomnography (PSG). We aimed to identify stereotypical mandibular jaw movements (MJM) in patients with SBx and to develop rhythmic masticatory muscles activities (RMMA) automatic detection using an artificial intelligence (AI) based approach.Patients and Methods: This was a prospective, observational study of 67 suspected obstructive sleep apnea (OSA) patients in whom PSG with masseter EMG was performed with simultaneous MJM recordings. The system used to collect MJM consisted of a small hardware device attached on the chin that communicates to a cloud-based infrastructure. An extreme gradient boosting (XGB) multiclass classifier was trained on 79,650 10-second epochs of MJM data from the 39 subjects with a history of SBx targeting 3 labels: RMMA episodes (n=1072), micro-arousals (n=1311), and MJM occurring at the breathing frequency (n=77,267).Results: Validated on unseen data from 28 patients, the model showed a very good epoch-by-epoch agreement (Kappa = 0.799) and balanced accuracy of 86.6% was found for the MJM events when using RMMA standards. The RMMA episodes were detected with a sensitivity of 84.3%. Class-wise receiver operating characteristic (ROC) curve analysis confirmed the well-balanced performance of the classifier for RMMA (ROC area under the curve: 0.98, 95% confidence interval [CI] 0.97– 0.99). There was good agreement between the MJM analytic model and manual EMG signal scoring of RMMA (median bias − 0.80 events/h, 95% CI − 9.77 to 2.85).Conclusion: SBx can be reliably identified, quantified, and characterized with MJM when subjected to automated analysis supported by AI technology.Keywords: masticatory muscular activities, machine learning, jaw movement

Background: Chronic mountain sickness (CMS) is characterized by a combination of excessive erythrocytosis,severe hypoxemia, and pulmonary hypertension, all of which affect exercise capacity.Methods: Thirteen patients with CMS and 15 healthy highlander and 15 newcomer lowlander control subjects were investigated at an altitude of 4,350 m (Cerro de Pasco, Peru). All of them underwent measurements of diffusing capacity of lung for nitric oxide and carbon monoxide at rest, echocardiography for estimation of mean pulmonary arterial pressure and cardiac output at rest and at exercise, and an incremental cycle ergometer cardiopulmonary exercise test.Results: The patients with CMS, the healthy highlanders, and the newcomer lowlanders reached a similar maximal oxygen uptake at 32 1, 32 2, and 33 2 mL/min/kg, respectively, mean SE( P 5 .8), with ventilatory equivalents for C O 2 vs end-tidal P CO 2 , measured at the anaerobic threshold,of 0.9 0.1, 1.2 0.1, and 1.4 0.1 mm Hg, respectively ( P , .001); arterial oxygen content of 26 1, 21 2, and 16 1 mL/dL, respectively ( P , .001); diffusing capacity for carbon monoxide corrected for alveolar volume of 155% 4%, 150% 5%, and 120% 3% predicted, respectively( P , .001), with diffusing capacity for nitric oxide and carbon monoxide ratios of 4.7 0.1 at sea level decreased to 3.6 0.1, 3.7 0.1, and 3.9 0.1, respectively ( P , .05) and a maximal exercise mean pulmonary arterial pressure at 56 4, 42 3, and 31 2 mm Hg, respectively ( P , .001).Conclusions: The aerobic exercise capacity of patients with CMS is preserved in spite of severe pulmonary hypertension and relative hypoventilation, probably by a combination of increased oxygen carrying capacity of the blood and lung diffusion, the latter being predominantly due to an increased capillary blood volume. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To compare a step-down approach in well-controlled asthma patients, as recommended by treatment guidelines, from fluticasone propionate 250 microg twice daily (FP250 BID), or equivalent, to ciclesonide 160 microg once daily (CIC160 OD) with continued FP250 BID treatment. Research design and methods: Patients with well-controlled asthma prior to study entry were included in two identical, randomized, double-blind, double-dummy, parallel-group studies. After a 2-week run-in period with FP250 BID, patients were randomized to CIC160 OD (n = 58) or FP250 BID (n = 53) for 12 weeks. Primary endpoints were percentage of days with asthma control, asthma symptom-free days, rescue medication-free days and nocturnal awakening-free days. Secondary endpoints included lung function variables, asthma symptom scores, rescue medication use and asthma exacerbations. Safety variables were also recorded. RESULTS: Patients had >or= 97% of days with asthma control, 98% asthma symptom-free days and 100% of days free from rescue medication use and nocturnal awakenings in both treatment groups (median values). There were no significant between-treatment differences for any of the primary or secondary efficacy variables. Overall, 42 treatment-emergent adverse events (TEAEs) were reported in the CIC160 OD group and 49 TEAEs were reported in the FP250 BID group. There were no clinically relevant changes from baseline in the safety variables in either treatment group. CONCLUSIONS: Patients well controlled on FP250 BID, or equivalent, who were stepped down to CIC160 OD, maintained similar asthma control compared with patients who received continued treatment standardized to FP250 BID. [ABSTRACT FROM AUTHOR]

Objectives:  The primary objective was to evaluate the influence of sagittal skeletal pattern on mandibular movement (MM) during sleep in growing orthodontic populations. The secondary objective was to compare MM according to obstructive sleep apnea (OSA) status., Materials and Methods:  This cross-sectional study included subjects between 6 and 17 years old, presenting with class I, II, and III skeletal patterns and no previous history of orthodontic treatment. A wireless sensor connected to the patient's chin before bedtime and removed the next day was used to record MM signals. The signals were analyzed using a machine learning algorithm to measure sleep and MM outcomes. MM variables included percentage change in waveform prominence (%), variance in peak prominence, mean prominence values, length of events (seconds), respiratory rate per minute, dominant frequency, and amplitude of dominant frequency. The obstructive respiratory disturbance index determined from the sensor was used to confirm OSA status., Results:  There was no statistically significant difference in MM variables between class I, II, and III subjects. When compared according to OSA status, the amplitude of dominant frequency was significantly higher in the OSA than the non-OSA group ( p  = 0.005). When evaluated according to both skeletal classification and OSA status, the class I OSA subjects showed a higher median value than the non-OSA class I group ( p  = 0.016)., Conclusion:  Within the limits of this study, the sagittal skeletal pattern had no effect on the respiratory MM. This study did not find a correlation between craniofacial pattern and MM and OSA., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Purpose: This review aims to highlight the pivotal role of the mandibular jaw movement (MJM) signal in advancing artificial intelligence (AI)-powered technologies for diagnosing obstructive sleep apnea (OSA)., Methods: A scoping review was conducted to evaluate various aspects of the MJM signal and their contribution to improving signal proficiency for users., Results: The comprehensive literature analysis is structured into four key sections, each addressing factors essential to signal proficiency. These factors include (1) the comprehensiveness of research, development, and application of MJM-based technology; (2) the physiological significance of the MJM signal for various clinical tasks; (3) the technical transparency; and (4) the interpretability of the MJM signal. Comparisons with the photoplethysmography (PPG) signal are made where applicable., Conclusions: Proficiency in biosignal interpretation is essential for the success of AI-driven diagnostic tools and for maximizing the clinical benefits through enhanced physiological insight. Through rigorous research ensuring an enhanced understanding of the signal and its extensive validation, the MJM signal sets a new benchmark for the development of AI-driven diagnostic solutions in OSA diagnosis., (© 2024 by the American College of Prosthodontists.)

Monitoring unintentional air leaks in continuous positive airway pressure (CPAP) treatment for obstructive sleep apnea (OSA) is essential for therapy success. While leaks are often attributed to improperly sealed masks, mouth openings may also cause them, requiring interventions. Recent studies demonstrated distinctive mandibular jaw movement (MJM) signal patterns during sleep related to respiratory events and sleep stages. Analysing MJM during CPAP treatment reveals air leak peaks coinciding with maximal MJM amplitude during obstructive events, and air leak decreases corresponding to arousals. Examining leaks with MJM offers valuable insights into their origins and might open new avenues for CPAP management., Competing Interests: Dr. Martinot reported being a scientific advisor to Sunrise and being an investigator in pharmacy trials for Jazz Pharmaceuticals and Theranexus. Dr. Pépin reported being a scientific advisor to Sunrise; receiving grants and/or personal fees from ResMed, Philips, Fisher & Paykel, Sefam, AstraZeneca, AGIR à dom, Elevie, VitalAire, Boehringer Ingelheim, Jazz Pharmaceuticals, and Itamar Medical Ltd.; and receiving research support for clinical studies from Mutualia and Air Liquide Foundation. He is supported by the French National Research Agency in the framework of the “Investissements d'avenir” program (ANR‐15‐IDEX‐02) and the ‘e‐health and integrated care and trajectories medicine and MIAI artificial intelligence’ chairs of excellence from the Grenoble Alpes University Foundation. This work has been partially supported by MIAI @ Grenoble Alpes (ANR‐19‐P3IA‐0003). Dr. Malhotra is funded by the NIH. He reports income from Jazz, Zoll, Sunrise, Livanova, Eli Lilly related to medical education. ResMed provided a philanthropic donation to UCSD. Dr. Hwang is funded by the NIH and the Kaiser Permanente Clinical Investigator Program. There are no other disclosures to report in relation to this work. This research did not receive any funding or other financial support from Sunrise company. The funding sources had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; the preparation, review, or approval of the manuscript; of the decision to submit the manuscript for publication., (© 2024 The Author(s). Respirology Case Reports published by John Wiley & Sons Australia, Ltd on behalf of The Asian Pacific Society of Respirology.)

Background: The polysomnography (PSG) is the gold-standard for obstructive sleep apnea (OSA) syndrome diagnosis and assessment under positive airway pressure (PAP) therapies in children. Recently, an innovative digital medicine solution, including a mandibular jaw movement (MJM) sensor coupled with automated analysis, has been validated as an alternative to PSG for pediatric application., Objective: This study aimed to assess the reliability of MJM automated analysis for the assessment of residual apnea/hypopnea events during sleep in children with OSA treated with noninvasive ventilation (NIV) or continuous PAP (CPAP)., Methods: In this open-label prospective non-randomized multicentric trial, we included children aged from 5 to 18 years with a diagnosis of severe OSA. The children underwent in-laboratory PSG with simultaneous MJM monitoring and at-home recording with MJM monitoring 3 months later. Agreement between PSG and MJM analysis in measuring the residual apnea-hypopnea index (AHI) was evaluated by the Bland-Altman method. The treatment effect on residual AHI was estimated for both PSG and MJM analysis., Results: Fifteen (60% males) children were included with a median age of 12 years [interquartile range 8-15]. Two (17%) were ventilated with NIV and 13 (83%) with CPAP. There was a good agreement between MJM-AHI and PSG-AHI with a median bias of -0.25 (95% CI: -3.40 to +2.04) events/h. The reduction in AHI under treatment was consistently significant across the three measurement methods: in-laboratory PSG and MJM recordings in the laboratory and at home., Conclusion: Automated analysis of MJM is a highly reliable alternative method to assess residual events in a small population treated with PAP therapies., (© 2024 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Rationale: Oral appliances are second-line treatments after continuous positive airway pressure for obstructive sleep apnea (OSA) management. However, the need for oral appliance titration limits their use as a result of monitoring challenges to assess the treatment effect on OSA. Objectives: To assess the validity of mandibular jaw movement (MJM) automated analysis compared with polysomnography (PSG) and polygraphy (PG) in evaluating the effect of oral appliance treatment and the effectiveness of MJM monitoring for oral appliance titration at home in patients with OSA. Methods: This observational, prospective study included 135 patients with OSA eligible for oral appliance therapy. The primary outcome was the apnea-hypopnea index (AHI), measured through in-laboratory PSG/PG and MJM-based technology. Additionally, MJM monitoring at home was conducted at regular intervals during the titration process. The agreement between PSG/PG and MJM automated analysis was revaluated using Bland-Altman analysis. Changes in AHI during the home-based oral appliance titration process were evaluated using a generalized linear mixed model and a generalized estimating equation model. Results: The automated MJM analysis demonstrated strong agreement with PG in assessing AHI at the end of titration, with a median bias of 0.24/h (limits of agreement, -11.2 to 12.8/h). The improvement of AHI from baseline in response to oral appliance treatment was consistent across three evaluation conditions: in-laboratory PG (-59.6%; 95% confidence interval, -59.8% to -59.5%), in-laboratory automated MJM analysis (-59.2%; -65.2% to -52.2%), and at-home automated MJM analysis (-59.7%; -67.4% to -50.2%). Conclusions: Incorporating MJM automated analysis into the oral appliance titration process has the potential to optimize oral appliance therapy outcomes for OSA.

Background: SARS-CoV-2 binding to ACE2 is potentially associated with severe pneumonia due to COVID-19. The aim of the study was to test whether Mas-receptor activation by 20-hydroxyecdysone (BIO101) could restore the Renin-Angiotensin System equilibrium and limit the frequency of respiratory failure and mortality in adults hospitalized with severe COVID-19., Methods: Double-blind, randomized, placebo-controlled phase 2/3 trial. Randomization: 1:1 oral BIO101 (350 mg BID) or placebo, up to 28 days or until an endpoint was reached. Primary endpoint: mortality or respiratory failure requiring high-flow oxygen, mechanical ventilation, or extra-corporeal membrane oxygenation. Key secondary endpoint: hospital discharge following recovery (ClinicalTrials.gov Number, NCT04472728)., Findings: Due to low recruitment the planned sample size of 310 was not reached and 238 patients were randomized between August 26, 2020 and March 8, 2022. In the modified ITT population (233 patients; 126 BIO101 and 107 placebo), respiratory failure or early death by day 28 was 11.4% lower in the BIO101 (13.5%) than in the placebo (24.3%) group, (p = 0.0426). At day 28, proportions of patients discharged following recovery were 80.1%, and 70.9% in the BIO101 and placebo group respectively, (adjusted difference 11.0%, 95% CI [-0.4%, 22.4%], p = 0.0586). Hazard Ratio for time to death over 90 days: 0.554 (95% CI [0.285, 1.077]), a 44.6% mortality reduction in the BIO101 group (not statistically significant). Treatment emergent adverse events of respiratory failure were more frequent in the placebo group., Interpretation: BIO101 significantly reduced the risk of death or respiratory failure supporting its use in adults hospitalized with severe respiratory symptoms due to COVID-19., Funding: Biophytis., Competing Interests: Biophytis declares that potential commercial interests had no impact on the scientific conduct of the study nor on the analysis/interpretation of data. Cendrine Tourette, Luis Esmeraldino, Pierre Jean Dilda, René Lafont, Serge Camelo, Sandrine Rabut, Waly Dioh, Rob van Maanen and Stanislas veillet are Biophytis company employees, Anait Azbekyan Samuel Agus and Mounia Chabane are former Biophytis company employees. Jean Mariani is emeritus professor at Sorbonne University and consultant for Biophytis, Richard Kay is a consultant for Biophytis. Alpesh Amin, MD declares that as principal investigator or co-investigator of clinical trials sponsored by NIH/NIAID, NeuroRx Pharma, Pulmotect, Blade Therapeutics, Novartis, Takeda, Humanigen, Eli Lilly, PTC Therapeutics, OctaPharma, Fulcrum Therapeutics, Alexion, BioPhysitis its institution received payments and that he personnally received consultant fees from BMS, Pfizer, BI, Portola, Sunovion, Mylan, Salix, Alexion, AstraZeneca, Novartis, Nabriva, Paratek, Bayer, Tetraphase, Achogen LaJolla, Ferring, Seres, Spero, Eli Lilly, Gilead, Millenium, HeartRite, Aseptiscope, and Sprightly; but that these relationships were unrelated to the current work. Shaheen Islam, MD declares that he received grants or was in contract as a principal or sub investigator from the following companies:–Pliant therapeutics: INTEGRIS-ARDS, drug (PLN74809) Covid -trial 2021 (PI).—CytoDyn, Inc.: CD12-COVID 19 Drug: Leronlimab COVID trial 2020 (PI). -Pluristem Ltd.: PLX-COV-01. Drug PLX-PAD, COVID Trial 2020 (Sub-I).—Edesa Biotech Inc.: EB05-04-2020. Drug: EB05 COVID Trial 2020 (Sub-I). Fabiano Ramos, MD declares that its institution: Hospital São Lucas da Pontíficia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Rio Grande do Sul, Brazil received financial resources to conduct the study from Biophytis. Brian Snyder, MD declares that he receives research funding from Biophytis as part of the present clinical trial. Moreover, he declares that he received grants or has contracts with Behring, and Rheonix as part of COVID research studies. None of the other investigators declare any relationship related to the current work., (© 2023 The Author(s).)

A strong and specific comprehensive physiological association has been documented between mandibular jaw movements and related periods of normal or disturbed breathing across different sleep stages. The mandibular jaw movement biosignal can be incorporated in the polysomnography, displayed on the screen as a function of time like any standard polysomnography signal (eg, airflow, oxygen saturation, respiratory inductance plethysmography bands) and interpreted in the context of the target period of breathing and its associated respiratory effort level. Overall, the mandibular jaw movement biosignal that depicts the muscular trigeminal respiratory drive is a highly effective tool for differentiating between central and obstructive sleep episodes including hypopneas and for providing clinicians with valuable insights into wake/sleep states, arousals, and sleep stages. These fundamental characteristics of the mandibular jaw movement biosignal contrast with photoplethysmography, airflow, or oxygen saturation signals that provide information more about the consequence of the disturbed breathing episode than about the event itself., Citation: Malhotra A, Martinot J-B, Pépin J-L. Insights on mandibular jaw movements during polysomnography in obstructive sleep apnea. J Clin Sleep Med . 2024;20(1):151-163., (© 2024 American Academy of Sleep Medicine.)

Background: A single-night attended in-laboratory polysomnography or home sleep testing are common approaches for obstructive sleep apnea (OSA) diagnosis. However, internight variability in apnea-hypopnea index value is common, and may result in misclassification of OSA severity and inapropriate treatment decisions., Objective: To investigate factors determining short-term apnea-hypopnea index variability using multi-night automated home sleep testing, and to determine how this variability impacts clinical decisions., Patients/methods: Adults with suspected OSA who successfully performed three home sleep tests using measurements of mandibular jaw movements (Sunrise, Namur, Belgium) combined with automated machine learning analysis were enrolled. Data analysis included principal component analysis, generalized estimating equation regression and qualitative agreement analysis., Results: 160 individuals who performed three sleep tests over a mean of 8.78 ± 8.48 days were included. The apnea-hypopnea index varied by -0.88 events/h (5th-95th percentile range: -14.33 to 9.72 events/h). Based on a single-night recording, rates of overtreatment and undertreatment would have been of 13.5% and 6.0%, respectively. Regression analysis adjusted for age, sex, body mass index, total sleep time, and time between home sleep tests showed that time spent in deep non-rapid eye movement sleep and with head in supine position were independent significant predictors of the apnea-hypopnea index variability., Conclusions: At the individual level, short-term internight variability in the apnea-hypopnea index was significantly associated with time spent in deep non-rapid eye movement sleep and head in supine position. Clinical decisions based on a single-night testing may lead to errors in OSA severity classification and incorrect therapeutic decisions., Competing Interests: Declaration of competing interest Jean-Benoît Martinot is a scientific advisor to Sunrise and has been an investigator in pharmaceutical trials for Jazz Pharmaceuticals and Theranexus. Nhat-Nam Le-Dong is an employee of Sunrise. Jean-Louis Pépin is a scientific advisor to Sunrise, has received grants and/or personal fees from ResMed, Philips, Fisher & Paykel, Sefam, AstraZeneca, AGIR à dom, Elevie, VitalAire, Boehringer Ingelheim, Jazz Pharmaceuticals and Itamar Medical, and has received research support for clinical studies from Mutualia and Air Liquide Foundation. There was no funding or other financial support for this research from Sunrise. Renaud Tamisier and Sébastien Bailly have no financial disclosures., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: To determine the association between total sleep time (TST) spent in increased respiratory effort (RE) and the prevalence of type 2 diabetes in a large cohort of individuals with suspected obstructive sleep apnoea (OSA) referred for in-laboratory polysomnography (PSG)., Materials and Methods: We conducted a retrospective cross-sectional study using the clinical data of 1128 patients. Non-invasive measurements of RE were derived from the sleep mandibular jaw movements (MJM) bio-signal. An explainable machine-learning model was built to predict prevalent type 2 diabetes from clinical data, standard PSG indices, and MJM-derived parameters (including the proportion of TST spent with increased respiratory effort [REMOV [%TST])., Results: Original data were randomly assigned to training (n = 853) and validation (n = 275) subsets. The classification model based on 18 input features including REMOV showed good performance for predicting prevalent type 2 diabetes (sensitivity = 0.81, specificity = 0.89). Post hoc interpretation using the Shapley additive explanation method found that a high value of REMOV was the most important risk factor associated with type 2 diabetes after traditional clinical variables (age, sex, body mass index), and ahead of standard PSG metrics including the apnoea-hypopnea and oxygen desaturation indices., Conclusions: These findings show for the first time that the proportion of sleep time spent in increased RE (assessed through MJM measurements) is an important predictor of the association with type 2 diabetes in individuals with OSA., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Sleep apnea is nowadays recognized as a treatable chronic disease and awareness of it has increased, leading to an upsurge in demand for diagnostic testing. Conventionally, diagnosis depends on overnight polysomnography in a sleep clinic, which is highly human-resource intensive and ignores the night-to-night variability in classical sleep apnea markers, such as the apnea-hypopnea index. In this review, the authors summarize the main improvements that could be made in the sleep apnea diagnosis strategy; how technological innovations and multi-night home testing could be used to simplify, increase access, and reduce costs of diagnostic testing while avoiding misclassification of severity., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Over recent years, positive airway pressure (PAP) remote monitoring has transformed the management of OSA and produced a large amount of data. Accumulated PAP data provide valuable and objective information regarding patient treatment adherence and efficiency. However, the majority of studies that have analyzed longitudinal PAP remote monitoring have summarized data trajectories in static and simplistic metrics for PAP adherence and the residual apnea-hypopnea index by the use of mean or median values. The aims of this article are to suggest directions for improving data cleaning and processing and to address major concerns for the following data science applications: (1) conditions for residual apnea-hypopnea index reliability, (2) lack of standardization of indicators provided by different PAP models, (3) missing values, and (4) consideration of treatment interruptions. To allow fair comparison among studies and to avoid biases in computation, PAP data processing and management should be conducted rigorously with these points in mind. PAP remote monitoring data contain a wealth of information that currently is underused in the field of sleep research. Improving the quality and standardizing data handling could facilitate data sharing among specialists worldwide and enable artificial intelligence strategies to be applied in the field of sleep apnea., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Mechanisms underlying blood pressure changes in obstructive sleep apnoea (OSA) are incompletely understood. Increased respiratory effort is one of the main features of OSA and is associated with sympathetic overactivity, leading to increased vascular wall stiffness and remodelling. This study investigated associations between a new measure of respiratory effort (percentage of total sleep time spent with increased respiratory effort based on measurement of mandibular jaw movements (MJM): REMOV, %TST) and prevalent hypertension in adults referred for evaluation of suspected OSA., Methods: A machine learning model was built to predict hypertension from clinical data, conventional polysomnography (PSG) indices and MJM-derived parameters (including REMOV). The model was evaluated in a training subset and a test subset., Results: The analysis included 1127 patients: 901 (80%) in the training subset and 226 (20%) in the test subset. The prevalence of hypertension was 31% and 30%, respectively, in the training and test subsets. A risk stratification model based on 18 input features including REMOV had good accuracy for predicting prevalent hypertension (sensitivity 0.75 and specificity 0.83). Using the Shapley additive explanation method, REMOV was the best predictor of hypertension after clinical risk factors (age, sex, body mass index and neck circumference) and time with oxygen saturation <90%, ahead of standard PSG metrics (including the apnoea-hypopnoea index and oxygen desaturation index)., Conclusion: The proportion of sleep time spent with increased respiratory effort automatically derived from MJM was identified as a potential new reliable metric to predict prevalent hypertension in patients with OSA., Competing Interests: Conflict of interest: J-B. Martinot reports being a scientific advisor to Sunrise and being an investigator in pharmacy trials for Jazz Pharmaceuticals, Theranexus and Desitin. N-N. Le-Dong is an employee of Sunrise. A. Malhotra is funded by the NIH, and reports income related to medical education from Livanova, Equillium, Jazz and Sunrise; ResMed provided a philanthropic donation to UCSD. J-L. Pépin reports being a scientific advisor to Sunrise; receiving grants and/or personal fees from ResMed, Philips, Fisher & Paykel, Sefam, AstraZeneca, AGIR à dom, Elevie, VitalAire, Boehringer Ingelheim, Jazz Pharmaceuticals and Itamar Medical Ltd; and receiving research support for clinical studies from Mutualia and Air Liquide Foundation., (Copyright ©The authors 2023.)

Background: Given the high prevalence and risk for outcomes associated with pediatric obstructive sleep apnea (OSA), there is a need for simplified diagnostic approaches. A prospective study in 140 children undergoing in-laboratory polysomnography (PSG) evaluates the accuracy of a recently developed system (Sunrise) to estimate respiratory efforts by monitoring sleep mandibular movements (MM) for the diagnosis of OSA (Sunrise™)., Methods: Diagnosis and severity were defined by an obstructive apnea/hypopnea index (OAHI) ≥ 1 (mild), ≥ 5 (moderate), and ≥ 10 events/h (severe). Agreement between PSG and Sunrise™ was assessed by Bland-Altman method comparing respiratory disturbances hourly index (RDI) (obstructive apneas, hypopneas, and respiratory effort-related arousals) during PSG (PSG&#95;RDI), and Sunrise RDI (Sr&#95;RDI). Performance of Sr&#95;RDI was determined via ROC curves evaluating the device sensitivity and specificity at PSG&#95;OAHI ≥ 1, 5, and 15 events/h., Results: A median difference of 1.57 events/h, 95% confidence interval: -2.49 to 8.11 was found between Sr&#95;RDI and PSG&#95;RDI. Areas under the ROC curves of Sr&#95;RDI were 0.75 (interquartile range [IQR]: 0.72-0.78), 0.90 (IQR: 0.86-0.92) and 0.95 (IQR: 0.90-0.99) for detecting children with PSG&#95;OAHI ≥ 1, PSG&#95;OAHI ≥ 5, or PSG&#95; OAHI ≥ 10, respectively., Conclusion: MM automated analysis shows significant promise to diagnose moderate-to-severe pediatric OSA., (© 2021 Wiley Periodicals LLC.)

Background: The capacity to diagnose obstructive sleep apnoea (OSA) must be expanded to meet an estimated disease burden of nearly one billion people worldwide. Validated alternatives to the gold standard polysomnography (PSG) will improve access to testing and treatment. This study aimed to evaluate the diagnosis of OSA, using measurements of mandibular movement (MM) combined with automated machine learning analysis, compared to in-home PSG., Methods: 40 suspected OSA patients underwent single overnight in-home sleep testing with PSG (Nox A1, ResMed, Australia) and simultaneous MM monitoring (Sunrise, Sunrise SA, Belgium). PSG recordings were manually analysed by two expert sleep centres (Grenoble and London); MM analysis was automated. The Obstructive Respiratory Disturbance Index calculated from the MM monitoring (MM-ORDI) was compared to the PSG (PSG-ORDI) using intraclass correlation coefficient and Bland-Altman analysis. Receiver operating characteristic curves (ROC) were constructed to optimise the diagnostic performance of the MM monitor at different PSG-ORDI thresholds (5, 15, and 30 events/hour)., Results: 31 patients were included in the analysis (58% men; mean (SD) age: 48 (15) years; BMI: 30.4 (7.6) kg/m 2 ). Good agreement was observed between MM-ORDI and PSG-ORDI (median bias 0.00; 95% CI -23.25 to + 9.73 events/hour). However, for 15 patients with no or mild OSA, MM monitoring overestimated disease severity (PSG-ORDI < 5: MM-ORDI mean overestimation + 5.58 (95% CI + 2.03 to + 7.46) events/hour; PSG-ORDI > 5-15: MM-ORDI overestimation + 3.70 (95% CI -0.53 to + 18.32) events/hour). In 16 patients with moderate-severe OSA ( n = 9 with PSG-ORDI 15-30 events/h and n = 7 with a PSG-ORD > 30 events/h), there was an underestimation (PSG-ORDI > 15: MM-ORDI underestimation -8.70 (95% CI -28.46 to + 4.01) events/hour). ROC optimal cut-off values for PSG-ORDI thresholds of 5, 15, 30 events/hour were: 9.53, 12.65 and 24.81 events/hour, respectively. These cut-off values yielded a sensitivity of 88, 100 and 79%, and a specificity of 100, 75, 96%. The positive predictive values were: 100, 80, 95% and the negative predictive values 89, 100, 82%, respectively., Conclusion: The diagnosis of OSA, using MM with machine learning analysis, is comparable to manually scored in-home PSG. Therefore, this novel monitor could be a convenient diagnostic tool that can easily be used in the patients' own home., Clinical Trial Registration: https://clinicaltrials.gov, identifier NCT04262557., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kelly, Ben Messaoud, Joyeux-Faure, Terrail, Tamisier, Martinot, Le-Dong, Morrell and Pépin.)

Background and Objectives: Azithromycin was rapidly adopted as a repurposed drug to treat coronavirus disease 2019 (COVID-19) early in the pandemic. We aimed to evaluate its efficacy in patients hospitalised for COVID-19., Methods: In a series of randomised, open-label, phase 2 proof-of-concept, multicentre clinical trials (Direct Antivirals Working against the novel coronavirus (DAWn)), several treatments were compared with standard of care. In 15 Belgian hospitals, patients hospitalised with moderate to severe COVID-19 were allocated 2:1 to receive standard of care plus azithromycin or standard of care alone. The primary outcome was time to live discharge or sustained clinical improvement, defined as a two-point improvement on the World Health Organization (WHO) ordinal scale sustained for at least 3 days., Results: Patients were included between April 22 and December 17, 2020. When 15-day follow-up data were available for 160 patients (56% of preset cohort), an interim analysis was performed at request of the independent Data Safety and Monitoring Board. Subsequently, DAWn-AZITHRO was stopped for futility. In total, 121 patients were allocated to the treatment arm and 64 patients to the standard-of-care arm. We found no effect of azithromycin on the primary outcome with a hazard ratio of 1.044 (95% CI 0.772-1.413; p=0.7798). None of the predefined subgroups showed significant interaction as covariates in the Fine-Gray regression analysis. No benefit of azithromycin was found on any of the short- and longer-term secondary outcomes., Conclusion: Time to clinical improvement is not influenced by azithromycin in patients hospitalised with moderate to severe COVID-19., Competing Interests: The DAWn-AZITHRO investigators: T. Van Assche, T. Devos, G. Meyfroidt, H. Ceunen, B. Debaveye, M. ‘t Lam, K. Haesendonck, L. Goegebeur, J. Neyts, E. Van Wijngaerden and P. De Munter. Conflict of interest: I. Gyselinck declares funding for the present work from the COVID-19 fund of the KU and UZ Leuven. Conflict of interest: L. Liesenborghs declares funding for the present work from the COVID-19 fund of the KU and UZ Leuven. Conflict of interest: A. Belmans declares funding for the present work from the COVID-19 fund of the KU and UZ Leuven. Conflict of interest: M.M. Engelen declares funding for the present work from the COVID-19 fund of the KU and UZ Leuven. Conflict of interest: A. Betrains declares funding for the present work from the COVID-19 fund of the KU and UZ Leuven. Conflict of interest: Q. Van Thillo declares funding for the present work from the COVID-19 fund of the KU and UZ Leuven. Conflict of interest: P.A.H. Nguyen declares funding for the present work from the COVID-19 fund of the KU and UZ Leuven. Conflict of interest: P. Goeminne declares payment or honoraria for lectures from AstraZeneca, GlaxoSmithKline and Chiesi, and advisory board participation for Chiesi and GlaxoSmithKline, all in the 26 months prior to manuscript submission; in addition they declare the following unpaid roles: EMBARC board member; BeRS board member; ERS group 10 board member. Conflict of interest: A-C. Soenen declares funding for the present work from the COVID-19 fund of the KU and UZ Leuven. Conflict of interest: N. De Maeyer declares funding for the present work from the COVID-19 fund of the KU and UZ Leuven. Conflict of interest: C. Pilette declares funding for the present work from the COVID-19 fund of the KU and UZ Leuven. Conflict of interest: E. Papleux declares funding for the present work from the COVID-19 fund of the KU and UZ Leuven. Conflict of interest: E. Vanderhelst declares funding for the present work from the COVID-19 fund of the KU and UZ Leuven. Conflict of interest: A. Derweduwen declares funding for the present work from the COVID-19 fund of the KU and UZ Leuven. Conflict of interest: P. Alexander declares funding for the present work from the COVID-19 fund of the KU and UZ Leuven. Conflict of interest: B. Bouckaert declares funding for the present work from the COVID-19 fund of the KU and UZ Leuven. Conflict of interest: J-B. Martinot declares funding for the present work from the COVID-19 fund of the KU and UZ Leuven. Conflict of interest: L. Decoster declares funding for the present work from the COVID-19 fund of the KU and UZ Leuven. Conflict of interest: K. Vandeurzen declares funding for the present work from the COVID-19 fund of the KU and UZ Leuven. Conflict of interest: R. Schildermans declares funding for the present work from the COVID-19 fund of the KU and UZ Leuven. Conflict of interest: P. Verhamme declares funding for the present work from the COVID-19 fund of the KU and UZ Leuven. Conflict of interest: W. Janssens declares participation on an advisory board on antiretrovirals for Gilead Sciences in 2018, and support for attending meetings from Gilead Sciences (EACS 2019) and Sanofi Pasteur (ISTM 2019); in addition, they were secretary of the Belgische Vereniging voor Infectiologie en Klinische Microbiologie until 2020. Conflict of interest: R. Vos declares funding for the present work from the COVID-19 fund of the KU and UZ Leuven., (Copyright ©The authors 2022.)

Preventing the cytokine storm observed in COVID-19 is a crucial goal for reducing the occurrence of severe acute respiratory failure and improving outcomes. Here, we identify Aldo-Keto Reductase 1B10 (AKR1B10) as a key enzyme involved in the expression of pro-inflammatory cytokines. The analysis of transcriptomic data from lung samples of patients who died from COVID-19 demonstrates an increased expression of the gene encoding AKR1B10. Measurements of the AKR1B10 protein in sera from hospitalised COVID-19 patients suggests a significant link between AKR1B10 levels and the severity of the disease. In macrophages and lung cells, the over-expression of AKR1B10 induces the expression of the pro-inflammatory cytokines Interleukin-6 ( IL-6) , Interleukin-1β ( IL-1β ) and Tumor Necrosis Factor a ( TNF α ), supporting the biological plausibility of an AKR1B10 involvement in the COVID-19-related cytokine storm. When macrophages were stressed by lipopolysaccharides (LPS) exposure and treated by Zopolrestat, an AKR1B10 inhibitor, the LPS-induced production of IL-6 , IL-1β , and TNFα is significantly reduced, reinforcing the hypothesis that the pro-inflammatory expression of cytokines is AKR1B10-dependant. Finally, we also show that AKR1B10 can be secreted and transferred via extracellular vesicles between different cell types, suggesting that this protein may also contribute to the multi-organ systemic impact of COVID-19. These experiments highlight a relationship between AKR1B10 production and severe forms of COVID-19. Our data indicate that AKR1B10 participates in the activation of cytokines production and suggest that modulation of AKR1B10 activity might be an actionable pharmacological target in COVID-19 management.

Background: A range of safe and effective vaccines against SARS CoV 2 are needed to address the COVID 19 pandemic. We aimed to assess the safety and efficacy of the COVID-19 vaccine SCB-2019., Methods: This ongoing phase 2 and 3 double-blind, placebo-controlled trial was done in adults aged 18 years and older who were in good health or with a stable chronic health condition, at 31 sites in five countries (Belgium, Brazil, Colombia, Philippines, and South Africa). The participants were randomly assigned 1:1 using a centralised internet randomisation system to receive two 0·5 mL intramuscular doses of SCB-2019 (30 μg, adjuvanted with 1·50 mg CpG-1018 and 0·75 mg alum) or placebo (0·9% sodium chloride for injection supplied in 10 mL ampoules) 21 days apart. All study staff and participants were masked, but vaccine administrators were not. Primary endpoints were vaccine efficacy, measured by RT-PCR-confirmed COVID-19 of any severity with onset from 14 days after the second dose in baseline SARS-CoV-2 seronegative participants (the per-protocol population), and the safety and solicited local and systemic adverse events in the phase 2 subset. This study is registered on EudraCT (2020-004272-17) and ClinicalTrials.gov (NCT04672395)., Findings: 30 174 participants were enrolled from March 24, 2021, until the cutoff date of Aug 10, 2021, of whom 30 128 received their first assigned vaccine (n=15 064) or a placebo injection (n=15 064). The per-protocol population consisted of 12 355 baseline SARS-CoV-2-naive participants (6251 vaccinees and 6104 placebo recipients). Most exclusions (13 389 [44·4%]) were because of seropositivity at baseline. There were 207 confirmed per-protocol cases of COVID-19 at 14 days after the second dose, 52 vaccinees versus 155 placebo recipients, and an overall vaccine efficacy against any severity COVID-19 of 67·2% (95·72% CI 54·3-76·8), 83·7% (97·86% CI 55·9-95·4) against moderate-to-severe COVID-19, and 100% (97·86% CI 25·3-100·0) against severe COVID-19. All COVID-19 cases were due to virus variants; vaccine efficacy against any severity COVID-19 due to the three predominant variants was 78·7% (95% CI 57·3-90·4) for delta, 91·8% (44·9-99·8) for gamma, and 58·6% (13·3-81·5) for mu. No safety issues emerged in the follow-up period for the efficacy analysis (median of 82 days [IQR 63-103]). The vaccine elicited higher rates of mainly mild-to-moderate injection site pain than the placebo after the first (35·7% [287 of 803] vs 10·3% [81 of 786]) and second (26·9% [189 of 702] vs 7·4% [52 of 699]) doses, but the rates of other solicited local and systemic adverse events were similar between the groups., Interpretation: Two doses of SCB-2019 vaccine plus CpG and alum provides notable protection against the entire severity spectrum of COVID-19 caused by circulating SAR-CoV-2 viruses, including the predominating delta variant., Funding: Clover Biopharmaceuticals and the Coalition for Epidemic Preparedness Innovations., Competing Interests: Declaration of interests IS, HHH, PLi, RH, CB, BH, and JL are full-time employees of Clover Biopharmaceuticals. FR is a statistical adviser for Clover Biopharmaceuticals. RC, DA, PR, and GS are scientific advisers for Clover Biopharmaceuticals. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: The earliest possible detection of individuals with COVID-19 has been essential to curb the spread of infection. Existing digital tools have been scaled up to address this issue. Every night telemonitoring data on continuous positive airway pressure (CPAP) device use, the first-line therapy for obstructive sleep apnoea (OSA), is collected worldwide. We asked whether the changes in CPAP adherence patterns of might constitute an alert for COVID-19., Methods: We analysed preliminary results of telemonitoring data, recorded between February 1 and April 30, 2020, on OSA patients followed by our sleep clinics and diagnosed with COVID-19., Results: CPAP telemonitoring data from the first 19 patients diagnosed with COVID-19 showed a clear decrease or halt in adherence in the 20 days immediately preceding COVID-19 diagnosis compared to an earlier period (p < 0.01)., Conclusion: Patterns of continuous positive airway pressure device use by obstructive sleep apnoea patients collected through telemonitoring can indicate the onset of COVID-19 symptoms. Existing telemonitoring platforms could be immediately used to screen for COVID-19, and for other respiratory infections, in this large at-risk population., Competing Interests: Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JLP reports grants from Air Liquide Foundation, grants and personal fees from Agiradom, grants and personal fees from AstraZeneca, grants from Fisher and Paykel, grants from Mutualia, grants and personal fees from Philips, grants and personal fees from Resmed, grants from Vitalaire, grants from Boehringer Ingelheim, grants from Jazz Pharmaceuticals, grants from Night Balance, grants from Sefam, outside the submitted work; SL and JCB are employees of AGiR-à-dom, a French home-care provider; RT reports other from Agir-a-dom, grants from Resmed, outside the submitted work; SB, MS, JBM and PL have no conflict of interest directly related to this work, (© The Author(s) 2021.)

Rationale: Mandibular position and motion during sleep rely on the balance between mandibular elevators and depressors. We hypothesized that vertical mandibular position (VMP) modulates airflow amplitude during sleep., Methods: VMP, tidal nasal flow pressure (NFP) and concurrent surface electromyographic activity of the masseters (sEMG-m) were recorded and processed by a customized algorithm from 100 polysomnographic fragments including a micro-arousal (25 obstructive sleep apnea patients). The relationship between mandibular position and changes in airflow was analysed., Result: Concurrent VMP and sEMG-m activity changes routinely occurred before a new steady state of airflow documented by NFP. Vertical mandible depression was associated with a median (95% CI) reduction in NFP of 40.9% (14.6%-71.3%, p = 0.007) while vertical mandible elevation and mouth closure were associated with a median (95% CI) relative increase in NFP after arousal of 52.6% (17.9%-56.2%, p = 0.001)., Conclusion: Elevation and lowering of the mandible were associated with changes in masseteric EMG activity modulating airflow amplitude during sleep., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Importance: Given the high prevalence of obstructive sleep apnea (OSA), there is a need for simpler and automated diagnostic approaches., Objective: To evaluate whether mandibular movement (MM) monitoring during sleep coupled with an automated analysis by machine learning is appropriate for OSA diagnosis., Design, Setting, and Participants: Diagnostic study of adults undergoing overnight in-laboratory polysomnography (PSG) as the reference method compared with simultaneous MM monitoring at a sleep clinic in an academic institution (Sleep Laboratory, Centre Hospitalier Universitaire Université Catholique de Louvain Namur Site Sainte-Elisabeth, Namur, Belgium). Patients with suspected OSA were enrolled from July 5, 2017, to October 31, 2018., Main Outcomes and Measures: Obstructive sleep apnea diagnosis required either evoking signs or symptoms or related medical or psychiatric comorbidities coupled with a PSG-derived respiratory disturbance index (PSG-RDI) of at least 5 events/h. A PSG-RDI of at least 15 events/h satisfied the diagnosis criteria even in the absence of associated symptoms or comorbidities. Patients who did not meet these criteria were classified as not having OSA. Agreement analysis and diagnostic performance were assessed by Bland-Altman plot comparing PSG-RDI and the Sunrise system RDI (Sr-RDI) with diagnosis threshold optimization via receiver operating characteristic curves, allowing for evaluation of the device sensitivity and specificity in detecting OSA at 5 events/h and 15 events/h., Results: Among 376 consecutive adults with suspected OSA, the mean (SD) age was 49.7 (13.2) years, the mean (SD) body mass index was 31.0 (7.1), and 207 (55.1%) were men. Reliable agreement was found between PSG-RDI and Sr-RDI in patients without OSA (n = 46; mean difference, 1.31; 95% CI, -1.05 to 3.66 events/h) and in patients with OSA with a PSG-RDI of at least 5 events/h with symptoms (n = 107; mean difference, -0.69; 95% CI, -3.77 to 2.38 events/h). An Sr-RDI underestimation of -11.74 (95% CI, -20.83 to -2.67) events/h in patients with OSA with a PSG-RDI of at least 15 events/h was detected and corrected by optimization of the Sunrise system diagnostic threshold. The Sr-RDI showed diagnostic capability, with areas under the receiver operating characteristic curve of 0.95 (95% CI, 0.92-0.96) and 0.93 (95% CI, 0.90-0.93) for corresponding PSG-RDIs of 5 events/h and 15 events/h, respectively. At the 2 optimal cutoffs of 7.63 events/h and 12.65 events/h, Sr-RDI had accuracy of 0.92 (95% CI, 0.90-0.94) and 0.88 (95% CI, 0.86-0.90) as well as posttest probabilities of 0.99 (95% CI, 0.99-0.99) and 0.89 (95% CI, 0.88-0.91) at PSG-RDIs of at least 5 events/h and at least 15 events/h, respectively, corresponding to positive likelihood ratios of 14.86 (95% CI, 9.86-30.12) and 5.63 (95% CI, 4.92-7.27), respectively., Conclusions and Relevance: Automatic analysis of MM patterns provided reliable performance in RDI calculation. The use of this index in OSA diagnosis appears to be promising.

Context: Accurate discrimination between obstructive and central hypopneas requires quantitative assessments of respiratory effort by esophageal pressure (OeP) measurements, which preclude widespread implementation in sleep medicine practice. Mandibular Movement (MM) signals are closely associated with diaphragmatic effort during sleep. Objective: We aimed at reliably detecting obstructive off central hypopneas events using MM statistical characteristics. Methods: A bio-signal learning approach was implemented whereby raw MM fragments corresponding to normal breathing (NPB; n = 501), central ( n = 263), and obstructive hypopneas ( n = 1861) were collected from 28 consecutive patients (mean age = 54 years, mean AHI = 34.7 n/h) undergoing in-lab polysomnography (PSG) coupled with a MM magnetometer, and OeP recordings. Twenty three input features were extracted from raw data fragments to explore distinctive changes in MM signals. A Random Forest model was built upon those input features to classify the central and obstructive hypopnea events. External validation and interpretive analysis were performed to evaluate the model's performance and the contribution of each feature to the model's output. Results: Obstructive hypopneas were characterized by a longer duration (21.9 vs. 17.8 s, p < 10 -6 ), more extreme low values ( p < 10 -6 ), a more negative trend reflecting mouth opening amplitude, wider variation, and the asymmetrical distribution of MM amplitude. External validation showed a reliable performance of the MM features-based classification rule (Kappa coefficient = 0.879 and a balanced accuracy of 0.872). The interpretive analysis revealed that event duration, lower percentiles, central tendency, and the trend of MM amplitude were the most important determinants of events. Conclusions: MM signals can be used as surrogate markers of OeP to differentiate obstructive from central hypopneas during sleep.

Rationale: The respiratory effort index derived from vertical mandibular movements (MM-REI) is a potential marker of increased respiratory effort during sleep. We evaluated the effectiveness of mandibular advancement splint therapy using MM-REI, in comparison with the apnea-hypopnea index (AHI) and oxygen desaturation index (ODI)., Methods: Fifty-six subjects (median age, 47 years) with OSA treated with a custom mandibular advancement splint (Herbst appliance) were evaluated at the end of the titration procedure when snoring was reported absent by the sleep partner. We employed a magnetometer to capture mandibular movements (Brizzy; Nomics). Mandibular advancement splint efficacy was assessed as the percent change from baseline, using Bayesian multilevel models., Results: At the end of titration, all indices of OSA severity decreased compared with baseline: AHI (-48.9% to -71.1%), ODI (-49.5% to -77.2%), with obstructive hypopnea index and MM-REI showing the largest responses (-70.6% to -88.5% and -69.5% to -96.3%, respectively). MM-REI normalization via reductions in both mandibular movement event rate and duration accurately reflected efficacy of the appliance., Conclusions: The reduction of vertical respiratory mandibular movements estimated by MM-REI and sleep respiratory effort duration accompanied the decrease in obstructive hypopneas, AHI, and ODI when snoring resolved in subjects with OSA treated with an optimally titrated mandibular advancement splint., (Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Nasal obstruction is frequently reported by patients with sleep apnea and complicates the choice of a nasal or oronasal mask for continuous positive airway pressure (CPAP) therapy. However, the type of interface used for the delivery of CPAP is crucial to ensure tolerance and compliance. The aim of this prospective pilot study was to identify whether the validated Nasal Obstruction Symptom Evaluation (NOSE) score rated at CPAP initiation was associated with the type of mask used after 4 months of treatment. Patients completed the NOSE questionnaire before initiation with automatic CPAP. The mask used (nasal/oronasal) after 4 months was documented. In total, 198 consecutive patients with sleep apnea were included. NOSE score (>50/100) was independently associated with the use of an oronasal mask at 4 months (sensitivity, 34.8%; specificity, 87.5%). The NOSE questionnaire could be a simple decision-making tool to guide the choice of mask during CPAP initiation.

Objectives: Adenotonsillectomy (AT) markedly improves but does not necessarily normalize polysomnographic findings in children with adenotonsillar hypertrophy and related sleep-disordered breathing (SDB). Adenotonsillectomy efficacy should be evaluated by follow-up polysomnography (PSG), but this method may underestimate persistent respiratory effort (RE). Mandibular movement (MMas) monitoring is an innovative measurement that readily identifies RE during upper airway obstruction. We hypothesized that MMas indices would decrease in parallel of PSG indices and that children with persistent RE more reliably could be identified with MMas., Methods: Twenty-five children (3-12 years of age) with SDB were enrolled in this individual prospective-cohort study. Polysomnography was supplemented with a midsagittal movement magnetic sensor that measured MMas during each respiratory cycle before and > 3 months after AT., Results: Adenotonsillectomy significantly improved PSG indices, except for RE-related arousals (RERA). Mandibular movement index changes after AT significantly were correlated with corresponding decreases in sleep apnea-hypopnea index (AHI) and O 2 desaturation index (ODI) (Spearman's rho = 0.978 and 0.922, respectively), whereas changes in MMas duration significantly were associated with both RERA duration (rho = 0.475, P = 0.017) and index (rho = 0.564, P = 0.003). Conditional multivariate analysis showed that both AHI and RERA significantly contributed to the variance of MMas index after AT (P = 0.0003 and 0.0005, respectively), whereas MMas duration consistently was related to the duration of RERA regardless of AT., Conclusion: Adenotonsillectomy significantly reduced AHI. However, persistent RERA were apparent in a significant proportion of children, and this was reflected by the remaining abnormal MMas pattern. Follow-up of children after AT can be recommended and readily achieved by monitoring MMas to identify persistent RE., Level of Evidence: 4. Laryngoscope, 128:1230-1237, 2018., (© 2017 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Unintentional leakage from the mouth or around the mask may lead to cessation of CPAP treatment; however, the causes of unintentional leaks are poorly understood. The objectives of this study were (1) to identify determining factors of unintentional leakage and (2) to determine the effect of the type of mask (nasal/oronasal) used on unintentional leakage., Methods: Seventy-four polysomnograms from patients with OSA syndrome treated with auto-CPAP were analyzed (23 women; 56 ± 13 years; BMI, 32.9 kg/m 2 (range, 29.0-38.0 kg/m 2 ). Polysomnographic recordings were obtained under auto-CPAP, and mandibular behavior was measured with a magnetic sensor. After sleep and respiratory scoring, polysomnographic signals were computed as mean values over nonoverlapping 10-s intervals. The presence/absence of unintentional leakage was dichotomized for each 10-s interval (yes/no). Univariate and multivariate conditional regression models estimated the risk of unintentional leaks during an interval "T" based on the explanatory variables from the previous interval "T-1." A sensitivity analysis for the type of mask was then conducted., Results: The univariate analysis showed that mandibular lowering (mouth opening), a high level of CPAP, body position (other than supine), and rapid eye movement (REM) sleep increased the risk of unintentional leaks and microarousal decreased it. In the multivariate analysis, the same variables remained independently associated with an increased risk of unintentional leakage. The sensitivity analysis showed that oronasal masks reduced the risk of unintentional leaks in cases of mouth opening and REM sleep., Conclusions: Mouth opening, CPAP level, sleep position, and REM sleep independently contribute to unintentional leakage. These results provide a strong rationale for the definition of phenotypes and the individual management of leaks during CPAP treatment., (Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Patients with chronic obstructive pulmonary disease (COPD) with an eosinophilic phenotype may benefit from treatment with mepolizumab, a monoclonal antibody directed against interleukin-5., Methods: We performed two phase 3, randomized, placebo-controlled, double-blind, parallel-group trials comparing mepolizumab (100 mg in METREX, 100 or 300 mg in METREO) with placebo, given as a subcutaneous injection every 4 weeks for 52 weeks in patients with COPD who had a history of moderate or severe exacerbations while taking inhaled glucocorticoid-based triple maintenance therapy. In METREX, unselected patients in the modified intention-to-treat population with an eosinophilic phenotype were stratified according to blood eosinophil count (≥150 per cubic millimeter at screening or ≥300 per cubic millimeter during the previous year). In METREO, all patients had a blood eosinophil count of at least 150 per cubic millimeter at screening or at least 300 per cubic millimeter during the previous year. The primary end point was the annual rate of moderate or severe exacerbations. Safety was also assessed., Results: In METREX, the mean annual rate of moderate or severe exacerbations in the modified intention-to-treat population with an eosinophilic phenotype (462 patients) was 1.40 per year in the mepolizumab group versus 1.71 per year in the placebo group (rate ratio, 0.82; 95% confidence interval [CI], 0.68 to 0.98; adjusted P=0.04); no significant between-group differences were found in the overall modified intention-to-treat population (836 patients) (rate ratio, 0.98; 95% CI, 0.85 to 1.12; adjusted P>0.99). In METREO, the mean annual rate of moderate or severe exacerbations was 1.19 per year in the 100-mg mepolizumab group, 1.27 per year in the 300-mg mepolizumab group, and 1.49 per year in the placebo group. The rate ratios for exacerbations in the 100-mg and 300-mg mepolizumab groups versus the placebo group were 0.80 (95% CI, 0.65 to 0.98; adjusted P=0.07) and 0.86 (95% CI, 0.70 to 1.05; adjusted P=0.14), respectively. A greater effect of mepolizumab, as compared with placebo, on the annual rate of moderate or severe exacerbations was found among patients with higher blood eosinophil counts at screening. The safety profile of mepolizumab was similar to that of placebo., Conclusions: Mepolizumab at a dose of 100 mg was associated with a lower annual rate of moderate or severe exacerbations than placebo among patients with COPD and an eosinophilic phenotype. This finding suggests that eosinophilic airway inflammation contributes to COPD exacerbations. (Funded by GlaxoSmithKline; METREX and METREO ClinicalTrials.gov numbers, NCT02105948 and NCT02105961 .).

Context: Mandibular movements (MM) are considered as reliable reporters of respiratory effort (RE) during sleep and sleep disordered breathing (SDB), but MM accuracy has never been validated against the gold standard diaphragmatic electromyography (EMG-d)., Objectives: To assess the degree of agreement between MM and EMG-d signals during different sleep stages and abnormal respiratory events., Methods: Twenty-five consecutive adult patients with SDB were studied by polysomnography (PSG) that also included multipair esophageal diaphragm electromyography and a magnetometer to record MM. EMG-d activity (microvolt) and MM (millimeter) amplitudes were extracted by envelope processing. Agreement between signals amplitudes was evaluated by mixed linear regression and cross-correlation function and in segments of PSG including event-free and SDB periods., Results: The average total sleep time was 370 ± 18 min and the apnea hypopnea index was 24.8 ± 5.2 events/h. MM and EMG-d amplitudes were significantly cross-correlated: median r (95% CI): 0.67 (0.23-0.96). A mixed linear model showed that for each 10 µV of increase in EMG-d activity, MM amplitude increased by 0.28 mm. The variations in MM amplitudes (median range: 0.11-0.84 mm) between normal breathing, respiratory effort-related arousal, obstructive, mixed, and central apnea periods closely corresponded to those observed with EMG-d activity (median range: 2.11-8.23 µV)., Conclusion: MM amplitudes change proportionally to diaphragmatic EMG activity and accurately identify variations of RE during normal sleep and SDB.

The simultaneous measurement of the lung transfer factor for carbon monoxide (DLCO) and nitric oxide (DLNO) is now available as a powerful method for studying the alveolar-capillary gas exchange. However, application of the DLNO-CO technique in daily settings is still limited by some technical drawbacks. This paper provides a manufacturer's overview of the measuring principles, technical challenges and current available solutions for implementing the DLNO-CO measurement in to a marketed device. This includes the recent developments in technology for NO sensors, latest findings on NO uptake and new statistical methods., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Just a few clinicians routinely measure the subcomponents of the lung diffusing capacity for Carbone monoxide (DL CO ). This is because the measurement of membrane and blood conductances for CO (Dm CO and Db CO  = θ CO  × V c , respectively) by the classic Roughton and Forster method is complicated and time consuming. In addition, it mistakenly assumes a close relationship between alveolar oxygen partial pressure (PAO 2 ) and mean intracapillary oxygen partial pressure (PcapO 2 ) which is the true determinant of specific conductance of haemoglobin for CO (θ CO ). Besides that, the critical multistep oxygenation method along with different linear equations relating 1/θ CO to PcapO 2 gave highly scattered Dm CO and V c values. The Dm and V c can also be derived from a simultaneous measurement of DL NO and DL CO with the blood resistance for NO assumed to be negligible. However, recent in vitro and in vivo experiments point towards a finite value of θ NO (about 4·5 ml NO  × ml blood -1  × min -1  × mmHg -1 ). Putting together the arguments and our clinical data allows us to report here the state of the art in partitioning the CO diffusing capacity into its constitutive components, with the goal to encourage further studies examining the sensitivity of Dm CO and V c to alterations observed in parenchymal diseases., (© 2015 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.)

Background: The patterns of mandibular movements (MM) during sleep can be used to identify increased respiratory effort periodic large-amplitude MM (LPM), and cortical arousals associated with "sharp" large-amplitude MM (SPM). We hypothesized that Cheyne Stokes breathing (CSB) may be identified by periodic abnormal MM patterns. The present study aims to evaluate prospectively the concordance between CSB detected by periodic MM and polysomnography (PSG) as gold-standard. The present study aims to evaluate prospectively the concordance between CSB detected by periodic MM and polysomnography (PSG) as gold-standard., Methods: In 573 consecutive patients attending an in-laboratory PSG for suspected sleep disordered breathing (SDB), MM signals were acquired using magnetometry and scored manually while blinded from the PSG signal. Data analysis aimed to verify the concordance between the CSB identified by PSG and the presence of LPM or SPM. The data were randomly divided into training and validation sets (985 5-min segments/set) and concordance was evaluated using 2 classification models., Results: In PSG, 22 patients (mean age ± SD: 65.9 ± 15.0 with a sex ratio M/F of 17/5) had CSB (mean central apnea hourly indice ± SD: 17.5 ± 6.2) from a total of 573 patients with suspected SDB. When tested on independent subset, the classification of CSB based on LPM and SPM is highly accurate (Balanced-accuracy = 0.922, sensitivity = 0.922, specificity = 0.921 and error-rate = 0.078). Logistic models based odds-ratios for CSB in presence of SPM or LPM were 172.43 (95% CI: 88.23-365.04; p < 0.001) and 186.79 (95% CI: 100.48-379.93; p < 0.001), respectively., Conclusion: CSB in patients with sleep disordered breathing could be accurately identified by a simple magnetometer device recording mandibular movements.

Background and Objective: Mandibular movements (MMs) and position during sleep reflect respiratory efforts related to increases in upper airway resistance and micro-arousals. The study objective was to assess whether MM identifies sleep-disordered breathing (SDB) in patients with moderate to high pre-test probability., Methods: This was a prospective study of 87 consecutive patients referred for an in-laboratory sleep test. Magnetometer-derived MM signals were incorporated into standard polysomnography (PSG). Respiratory events detected with MM analysis were compared with PSG for respiratory disturbance index (RDI) with a blinded scoring. All records were scored manually according to American Academy of Sleep Medicine rules. Primary outcome was to rule-in obstructive sleep apnoea syndrome (OSAS) defined as RDI cut-off value ≥5 or 15/h total sleep time (TST)., Results: High concordance emerged between MM and PSG-derived RDI with high temporal coincidence between events (R 2  = 0.906; P < 0.001). The mean diagnostic accuracy of MM for OSAS using RDI MM cut-off values of 5.9 and 13.5 was 0.935 (0.86-0.97) and 0.913 (0.84-0.95), with a mean positive likelihood ratio (LLR+) of 3.73 (2.7-20.4) and 8.46 (2.3-31.5), respectively. Receiver operating characteristic (ROC) curves at PSG cut-off values of 5 and 15/h TST had areas under the curve (AUC) of 0.96 (95% CI: 0.89-0.99) and 0.97 (95% CI: 0.91-0.99) (P < 0.001), respectively. MM analysis accurately identified SDB at different levels of severity., Conclusion: RDI assessed by MM is highly concordant with PSG, suggesting a role of ambulatory MM recordings to screen for SDB in patients with moderate to high pre-test probability., (© 2016 Asian Pacific Society of Respirology.)

CPAP is the first-line treatment for moderate to severe OSA syndrome. Up to 25% of patients with OSA syndrome discontinue CPAP treatment due to side effects. Unintentional leakage and its associated annoying consequences are the most frequently reported adverse effects of CPAP. Successive technological improvements have not succeeded in addressing this issue. A systematic review was conducted (1) to assess the impact of different technological advances on unintentional leaks and (2) to determine if any patient characteristics have already been identified as determinants of unintentional leakage. No CPAP modality was superior to another in reducing unintentional leaks and, surprisingly, oronasal masks were associated with higher unintentional leaks. Nasal obstruction, older age, higher BMI, central fat distribution, and male sex might be associated with an increased risk of unintentional leakage. Such leaks remain an important problem. Further studies are needed to improve the understanding of underlying clinical factors so that patients at risk of unintentional leaks may be identified and individualized solutions applied., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Membrane conductance (Dm) and capillary lung volume (Vc) derived from NO and CO lung transfer measurements in humans depend on the blood conductance (θ) values of both gases. Many θ values have been proposed in the literature. In the present study, measurements of CO and NO transfer while breathing 15% or 21% O2 allowed the estimation of θNO and the calculation of the optimal equation relating 1/θCO to pulmonary capillary oxygen pressure (PcapO2). In 10 healthy subjects, the mean calculated θNO value was similar to the θNO value previously reported in the literature (4.5mmHgmin(-1)) provided that one among three θCO equations from the literature was chosen. Setting 1/θCO=a·PcapO2+b, optimal values of a and b could be chosen using two methods: 1) by minimizing the difference between Dm/Vc ratios for any PcapO2, 2) by establishing a linear equation relating a and b. Using these methods, we are proposing the equation 1/θCO=0.0062·PcapO2+1.16, which is similar to two equations previously reported in the literature. With this set of θ values, DmCO reached the morphometric range., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background and Objective: During continuous positive airway pressure (CPAP) treatment, some patients with obstructive sleep apnoea syndrome (OSAS) require an oronasal mask (ONM) to prevent excessive mouth leakage. Factors contributing to sleep-related mouth opening under CPAP treatment remain known. We compared mouth opening during sleep in patients treated with CPAP by nasal mask (NM) versus ONM., Methods: Cross-sectional prospective study: patients treated with CPAP for at least 4 months underwent a sleep recording using a type 4 monitoring device (Brizzy-Nomics) that records mouth opening via a magnetometric distance meter. Clinical assessment included anthropometry, smoking status and the Mallampati score. Nasal obstruction was assessed by the Nasal Obstruction Symptom Evaluation questionnaire., Results: Thirty-eight patients were included, 34 analysed (22 men; age = 57.4 (53; 62) years; body mass index = 32.6 (29.1; 35.2) kg/m(2) ; median (25th; 75th)). Twenty-seven patients were treated with NM and seven with ONM. Patients with ONM were more often active smokers and trended to have greater nasal obstruction and lower forced expiratory volume in 1 s. They also exhibited a greater mouth opening during sleep (median (25th;75th) = 13.0 (11.0; 15.0) vs 6.0 (5.0; 10.0) mm, P < 0.001) and a higher oxygen desaturation index (9.5 (6.2; 15.5) vs 2.9 (1.0; 6.1) events/h, P = 0.009). In multivariate analysis, male gender and nasal obstruction were independently associated with mouth opening under ONM CPAP treatment., Conclusions: After several months of CPAP treatment, some patients using ONM persist in keeping their mouths open at night. Nasal obstruction and male gender contribute to this phenomenon., (© 2015 Asian Pacific Society of Respirology.)

Study Objectives: Obstructive sleep apnea-hypopnea (OAH) diagnosis in children is based on the quantification of flow and respiratory effort (RE). Pulse transit time (PTT) is one validated tool to recognize RE. Pattern analysis of mandibular movements (MM) might be an alternative method to detect RE. We compared several patterns of MM to concomittant changes in PTT during OAH in children with adenotonsillar hypertrophy., Participants: 33 consecutive children with snoring and symptoms/signs of OAH., Measurements: MMs were measured during polysomnography with a magnetometer device (Brizzy Nomics, Liege, Belgium) placed on the chin and forehead. Patterns of MM were evaluated representing peak to peak fluctuations > 0.3 mm in mandibular excursion (MML), mandibular opening (MMO), and sharp MM (MMS), which closed the mouth on cortical arousal (CAr)., Results: The median (95% CI) hourly rate of at least 1 MM (MML, or MMO, or MMS) was 18.1 (13.2-36.3) and strongly correlated with OAHI (p = 0.003) but not with central apnea-hypopnea index (CAHI; p = 0.292). The durations when the MM amplitude was > 0.4 mm and PTT > 15 ms were strongly correlated (p < 0.001). The mean (SD) of MM peak to peak amplitude was larger during OAH than CAH (0.9 ± 0.7 mm and 0.2 ± 0.3 mm; p < 0.001, respectively). MMS at the termination of OAH had larger amplitude compared to MMS with CAH (1.5 ± 0.9 mm and 0.5 ± 0.7 mm, respectively, p < 0.001)., Conclusions: MM > 0.4 mm occurred frequently during periods of OAH and were frequently terminated by MMS corresponding to mouth closure on CAr. The MM findings strongly correlated with changes in PTT. MM analysis could be a simple and accurate promising tool for RE characterization and optimization of OAH diagnosis in children., (© 2015 American Academy of Sleep Medicine.)

Background: Evaluation of novel compounds for COPD often relies on FEV1 for signal detection. Partial forced exhalations from end-tidal inspiration (PEFV) might complement FEV1 in identifying such a signal. We examined the prevalence of bronchodilator response (BDR) using PEFV and FEV1 in patients with COPD., Methods: 110 consecutive COPD patients were tested prospectively with PEFV and maximal expiratory flow before and after inhalation of a short-acting β2 agonist (salbutamol, 400 μg). Partial flow at 800 ml above residual volume was derived from the PEFV (PF800). Significant changes in PF800 and/or FEV1 were set at the upper 95% confidence interval after placebo (n = 28)., Results: Four groups were identified by the presence (+) or absence (-) of a BDR: Group 1 [PF800 (-)FEV1(-)] when no change was observed (n = 31), Group 2 [PF800(+)FEV1(-)] when PF800 alone improved (n = 31), Group 3 [PF800(-)FEV1(+)] when FEV1 alone improved (n = 26), and Group 4 [PF800(+)FEV1(+)] when both variables improved (n = 18). There were 35 non-responders in any parameter, and 75/110 subjects who showed a response in at least one parameter. The changes in PF800 and FEV1 were not correlated suggesting these assess different airway generations., Conclusions: The use of PF800 increased detection of a BDR in COPD compared to FEV1 alone and may reflect small airway responses. The PEFV maneuver is simple, repeatable and may avoid some of the theoretical disadvantages of FEV1. The role of PF800 for evaluating novel anti-inflammatory agents remains to be determined., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Tibetans have been reported to present with a unique phenotypic adaptation to high altitude characterized by higher resting ventilation and arterial oxygen saturation, no excessive polycythemia, and lower pulmonary arterial pressures (Ppa) compared with other high-altitude populations. How this affects exercise capacity is not exactly known. We measured aerobic exercise capacity during an incremental cardiopulmonary exercise test, lung diffusing capacity for carbon monoxide (DL(CO)) and nitric oxide (DL(NO)) at rest, and mean Ppa (mPpa) and cardiac output by echocardiography at rest and at exercise in 13 Sherpas and in 13 acclimatized lowlander controls at the altitude of 5,050 m in Nepal. In Sherpas vs. lowlanders, arterial oxygen saturation was 86 ± 1 vs. 83 ± 2% (mean ± SE; P = nonsignificant), mPpa at rest 19 ± 1 vs. 23 ± 1 mmHg (P < 0.05), DL(CO) corrected for hemoglobin 61 ± 4 vs. 37 ± 2 ml · min(-1) · mmHg(-1) (P < 0.001), DL(NO) 226 ± 18 vs. 153 ± 9 ml · min(-1) · mmHg(-1) (P < 0.001), maximum oxygen uptake 32 ± 3 vs. 28 ± 1 ml · kg(-1) · min(-1) (P = nonsignificant), and ventilatory equivalent for carbon dioxide at anaerobic threshold 40 ± 2 vs. 48 ± 2 (P < 0.001). Maximum oxygen uptake was correlated directly to DL(CO) and inversely to the slope of mPpa-cardiac index relationships in both Sherpas and acclimatized lowlanders. We conclude that Sherpas compared with acclimatized lowlanders have an unremarkable aerobic exercise capacity, but with less pronounced pulmonary hypertension, lower ventilatory responses, and higher lung diffusing capacity.