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Despite the availability of effective vaccines against COVID-19, booster vaccinations are needed to maintain vaccine-induced protection against variant strains and breakthrough infections. This study aimed to investigate the efficacy, safety, and immunogenicity of the Ad26.COV2.S vaccine (Janssen) as primary vaccination plus a booster dose.ENSEMBLE2 is a randomised, double-blind, placebo-controlled, phase 3 trial including crossover vaccination after emergency authorisation of COVID-19 vaccines. Adults aged at least 18 years without previous COVID-19 vaccination at public and private medical practices and hospitals in Belgium, Brazil, Colombia, France, Germany, the Philippines, South Africa, Spain, the UK, and the USA were randomly assigned 1:1 via a computer algorithm to receive intramuscularly administered Ad26.COV2.S as a primary dose plus a booster dose at 2 months or two placebo injections 2 months apart. The primary endpoint was vaccine efficacy against the first occurrence of molecularly confirmed moderate to severe-critical COVID-19 with onset at least 14 days after booster vaccination, which was assessed in participants who received two doses of vaccine or placebo, were negative for SARS-CoV-2 by PCR at baseline and on serology at baseline and day 71, had no major protocol deviations, and were at risk of COVID-19 (ie, had no PCR-positive result or discontinued the study before day 71). Safety was assessed in all participants; reactogenicity, in terms of solicited local and systemic adverse events, was assessed as a secondary endpoint in a safety subset (approximately 6000 randomly selected participants). The trial is registered with ClinicalTrials.gov, NCT04614948, and is ongoing.Enrolment began on Nov 16, 2020, and the primary analysis data cutoff was June 25, 2021. From 34 571 participants screened, the double-blind phase enrolled 31 300 participants, 14 492 of whom received two doses (7484 in the Ad26.COV2.S group and 7008 in the placebo group) and 11 639 of whom were eligible for inclusion in the assessment of the primary endpoint (6024 in the Ad26.COV2.S group and 5615 in the placebo group). The median (IQR) follow-up post-booster vaccination was 36·0 (15·0-62·0) days. Vaccine efficacy was 75·2% (adjusted 95% CI 54·6-87·3) against moderate to severe-critical COVID-19 (14 cases in the Ad26.COV2.S group and 52 cases in the placebo group). Most cases were due to the variants alpha (B.1.1.7) and mu (B.1.621); endpoints for the primary analysis accrued from Nov 16, 2020, to June 25, 2021, before the global dominance of delta (B.1.617.2) or omicron (B.1.1.529). The booster vaccine exhibited an acceptable safety profile. The overall frequencies of solicited local and systemic adverse events (evaluated in the safety subset, n=6067) were higher among vaccine recipients than placebo recipients after the primary and booster doses. The frequency of solicited adverse events in the Ad26.COV2.S group were similar following the primary and booster vaccinations (local adverse events, 1676 [55·6%] of 3015 vs 896 [57·5%] of 1559, respectively; systemic adverse events, 1764 [58·5%] of 3015 vs 821 [52·7%] of 1559, respectively). Solicited adverse events were transient and mostly grade 1-2 in severity.A homologous Ad26.COV2.S booster administered 2 months after primary single-dose vaccination in adults had an acceptable safety profile and was efficacious against moderate to severe-critical COVID-19. Studies assessing efficacy against newer variants and with longer follow-up are needed.Janssen ResearchDevelopment.

BackgroundMechanisms 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.MethodsA 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.ResultsThe 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 ConclusionThe 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.

International audience; No abstract available

Introduction Obstructive sleep apnea (OSA) and type 2 diabetes (T2Dia) is a frequent clinical association. Beyond OSA-related hypoxic burden, increased respiratory effort (RE) is one of the main features of OSA and contributes to sympathetic overactivity that in turn might participate to glucose homeostasis dysregulation. The independent contribution of RE to the OSA-T2Dia pathogenesis remains to be demonstrated. The study aims to determine the impact of metrics assessing sleep RE derived from the sleep mandibular jaw movements (MJM) signal on the prevalence of T2Dia in a large cohort of patients addressed for in-laboratory conventional polysomnography (PSG) with suspicion of OSA. Methods An interpretable machine learning model was built to predict T2Dia from clinical data, PSG indices, and MJM-derived parameters (including the time spent with increased RE, expressed in % of TST). The analysis included 1128 subjects, randomly assigned to training (n=853) and validation (n=275) subsets with equal T2Dia prevalence of 11%. Results The risk stratification model based on 19 input features including increased RE showed good performance for predicting prevalent T2Dia (sensitivity=0.81, specificity=0.89). Post-hoc interpretation using the Shapley additive explanation (SHAP) method revealed that increased RE was the most important risk factor of T2Dia after other clinical factors for T2Dia (i.e., sex, BMI and average SpO2), ahead of standard PSG metrics (including the apnea-hypopnea index and oxygen desaturation index). Conclusion These findings suggested that the proportion of sleep time spent with increased RE automatically derived from MJM is a potential new reliable metric to predict prevalent T2Dia in patients with OSA. Support (if any)

Introduction Single night in-lab polysomnography (PSG) is still the conventional procedure for making obstructive sleep apnea (OSA) diagnosis, or alternatively a home sleep apnea test (HSAT) in patients free from comorbidity. Recent publications drew attention to considerable internight within-subject variability in OSA clinical status, notably but not only with HSAT. Taking benefit of multiple nights recording in home-based setting using measurements of mandibular jaw movement (MJM) combined with automated machine learning analysis, this study aimed to investigate the effect of change in sleep parameters on the internight variability of the apnea hypopnea index (VAHI). Methods 160 adults suspected of having OSA successfully completed 3 sleep tests at home with the Sunrise device (Sunrise, Namur, Belgium). Data analysis implied generalized estimating equation (GEE) regression. Results Even though the internight variability of AHI was not statistically significant at the population level with a mean VAHI of -1.1 ± 7.8 events/h, such variability could lead to misdiagnosis and wrong therapeutic decisions based on a single night. After adjusting for effects of gender, body mass index (BMI), age, total sleep time (TST) and time interval between sleep tests, regression models indicated that sleeping in supine position was positively and independently associated with VAHI, the AHI increased by 0.95 event/h for each 10% of increase in sleeping time in supine position. VAHI was negatively and significantly (p < 0.01) associated with sleep efficiency and deep sleep; VAHI decreased of 0.16 event/h (0.04 to 0.28) and 0.29 event/h (0.17 to 0.42) for each % of increase in sleep efficiency and proportion of deep sleep, respectively. Conclusion At the individual level, position, sleep efficiency and deep sleep are associated with short-term internight variability in AHI. Clinical decision based on a single-night testing may lead to errors in OSA diagnosis with delayed or wrong therapeutic decisions. Support (if any)

International audience; Bruxism is a heterogeneous condition related to various underlying mechanisms, including the presence of OSA. This case report illustrates that sleep mandibular movement monitoring and analysis could provide a useful opportunity for detection of both sleep bruxism and respiratory effort. The current case suggests that tracking of respiratory effort could enable evaluation of bruxism and its potential interactions. Successful treatment of sleep-related respiratory effort may lead to improved or resolution of bruxism in cases where such a causal relationship does exist.

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

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.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).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.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.Clover Biopharmaceuticals and the Coalition for Epidemic Preparedness Innovations.

Introduction 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 chin sensor (Sunrise, Namur, Belgium) is a reliable surrogate of PES in patients with suspected obstructive sleep apnea (OSA). 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 gyroscope MM signal amplitude differed significantly between event types: median (95% confidence interval) values of 0.60 (0.17–2.43) for CA, 0.83 (0.23–4.71) for CH, 1.93 (0.54–5.57) for MxA, 3.23 (0.72–18.09) for OH, and 6.42 (0.88–26.81) units for OA. Mixed regression indicated that crossing from NB to central events would decrease gyroscope MM signal amplitude by –1.23 (CH) and –2.04 (CA) units, while obstructive events would increase gyroscope MM signal amplitude by +3.27 (OH) and +6.79 (OA) units (all p 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. Support (If Any)

Background: ANDHI was done to assess the efficacy of benralizumab, including onset of effect and impact on health-related quality of life (HRQOL), exacerbation rate, lung function, and nasal polyposis symptoms. Methods: This phase 3b, randomised, double-blind, parallel-group, placebo-controlled ANDHI study was completed in adults (aged 18–75 years) with severe eosinophilic asthma with at least 2 exacerbations in the previous year, despite high-dose inhaled corticosteroid plus additional controllers, screening blood eosinophil counts of at least 150 cells per μL, and an Asthma Control Questionnaire 6 (ACQ-6) score of 1·5 or more. Patients who met eligibility criteria were randomly assigned (2:1; stratified by previous exacerbation count [two, or three or more], maintenance oral corticosteroid use, and region), using an integrated web-based response system, to receive benralizumab at 30 mg every 8 weeks (first three doses given 4 weeks apart) or matched placebo for 24 weeks. Primary efficacy measure was annualised asthma exacerbation rate, with rate ratio (RR) calculated over the approximate 24-week follow-up. Secondary efficacy measures included change from baseline to end of treatment (week 24) in St George's Respiratory Questionnaire (SGRQ) total score (key secondary endpoint), FEV1, peak expiratory flow (PEF), ACQ-6, Predominant Symptom and Impairment Assessment (PSIA), Clinician Global Impression of Change (CGI-C), Patient Global Impression of Change (PGI-C), and Sino-Nasal Outcome Test-22 (SNOT-22). All efficacy analyses, except for SNOT-22, were summarised and analysed using the full analysis set on an intention-to-treat population (all randomly assigned patients receiving investigational product, regardless of protocol adherence or continued participation in the study). SNOT-22 was summarised for the subgroup of patients with physician-diagnosed nasal polyposis with informed consent. This study is registered with ClinicalTrials.gov, NCT03170271. Findings: Between July 7, 2017, and Sept 25, 2019, 656 patients received benralizumab (n=427) or placebo (n=229). Baseline characteristics were consistent with severe eosinophilic asthma. Benralizumab significantly reduced exacerbation risk by 49% compared with placebo (RR estimate 0·51, 95% CI 0·39–0·65; p5%) were nasopharyngitis (30 [7%]), headache (37 [9%]), sinusitis (28 [7%]), bronchitis (22 [5%]), and pyrexia (26 [6%]). Fewer serious adverse events were reported for benralizumab (23 [5%]) versus placebo (25 [11%]), and the only common serious adverse event (experienced by >1% of patients) was worsening of asthma, which was reported for nine (2%) patients in the benralizumab group and nine (4%) patients in the placebo group. Interpretation: Our results extend the efficacy profile of benralizumab for patients with severe eosinophilic asthma, showing early clinical benefits in patient-reported outcomes, HRQOL, lung function, and nasal polyposis symptoms. Funding: AstraZeneca.

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 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.

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 Diagnostic 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_RDI), and Sunrise RDI (Sr_RDI). Performance of Sr_RDI was determined via ROC curves evaluating the device sensitivity and specificity at PSG_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_RDI and PSG_RDI. Areas under the ROC curves of Sr_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_OAHI ≥ 1, PSG_OAHI ≥ 5, or PSG_ OAHI ≥ 10, respectively. Conclusion MM automated analysis shows significant promise to diagnose moderate-to-severe pediatric OSA.

Context: Automated sleep stages scoring from surrogate signals is challenging. Mandibular movements (MM) are reliable markers of the neural respiratory drive, with activity patterns reflecting sleep stages. We introduce a new automated sleep stage scoring method using MM signal. Method: Study was conducted on 96 adults (18 to 58 yrs, AHI MM signals were split into 30 seconds epochs, from which 217 features were extracted to classify 3 labels: wake, nonREM and REM sleep. The model was trained on PSG data from 68 subjects consisting of 169 hrs of nonREM, 26 hrs of REM and 21 hrs of wake. The model was validated on unseen data from 28 subjects composed of 147 hrs of nonREM, 38 hrs of REM sleep and 33 hrs of wake. Results: Subjects had a mean total sleep time of 7.14 hrs (CI: 5.53 to 8.49), a mean AHI of 3.57 events/h (CI: 1.00 to 6.92) and a mean arousal index of 9.22 events/h (CI: 4.36 to 16.69). The model showed good global performances, with a balanced accuracy of 0.79 (CI: 0.78 to 0.80) and an area under the receiver operating curve of 0.94, 0.91 and 0.93 for wake, nonREM and REM. Conclusion: This study demonstrated for the first time that MM signals are suitable for automated sleep stage scoring, providing a promising solution for home monitoring of sleep architecture.

Objectif Le syndrome des apnees du sommeil (SAS) en pediatrie est frequent et co_morbide ; un diagnostic simplifie est necessaire en pratique clinique. Nous evaluons ici la performance d’une machine learning basee sur l’analyse de l’effort respiratoire a travers le signal du seul mouvement mandibulaire (MM) pour le diagnostic du SAS pediatrique (Sunrise, Namur, Belgium). Methodes L’etude prospective a ete realisee chez 140 enfants adresses pour une polysommographie au laboratoire de sommeil (PSG) avec enregistrement simultane des MMs. Le diagnostic et la severite sont definis en PSG par un index d’apnee/hypopnee (OAHI) ≥ 1/h (leger), ≥ 5/h (modere) et ≥ 10/h (severe). Resultats La concordance entre la PSG et Sunrise (Sr) est appreciee par un graphe de Bland-Altman comparant l’indice horaire des evenements obstructifs a type d’apnees/hypopnees et de micro-eveils lies a un effort respiratoire (ORDI). La performance de Sr-ORDI est determinee par une courbe ROC evaluant la sensibilite et la specificite aux 3 niveaux de severite de la PSG. Une difference mediane de 1,57 evenements/h (95 %CI : -2,49 ; 8,11) est mesuree entre Sr_ORDI et PSG_ORDI. Les aires (et leurs ecarts interquartiles) sous les courbes de ROC sont respectivement de 0,75 (0,72 ; 0,78), 0,90 (0,86 ; 0,92) et 0,95 (0,90 ; 0,99) aux seuils de severite en PSG de ≥ 1/h, ≥ 5/h et ≥ 10/h. Conclusion L’analyse automatisee de MM procure un diagnostic robuste du SAS pediatrique modere a severe.

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 O2 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, 2017

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.

Background: Sleep mandibular movements (MM) patterns inform about sleep/wake phases, micro-arousals and respiratory efforts; providing a robust bio-signal for the detection of obstructive apnea/hypopneas and respiratory efforts-related arousals (RERAs). Objective: To validate a new MM recording sensor and machine learning algorithm (Sunrise, Belgium) in computing total sleep time (TST), arousal index (ArI) and respiratory disturbances index (RDI). The usefulness of the indices derived by the algorithm will be validated against reference polysomnography. Methods: 400 subjects with suspected OSA underwent in-lab polysomnography (PSG) supplemented with concomitant MM recording with the sensor. Scoring was conducted independently for the two methods. PSG were scored by experienced investigators. PSG_TST, PSG_ArI and PSG_RDI were derived to guide OSA diagnosis using ICSD-3 rules (5, 15 events/h). MM data were processed in a cloud-based platform without human intervention. Machine learning identification of sleep/wake, micro-arousals and respiratory efforts allowed the computation of Sunrise Sr_TST, Sr_ArI and Sr_RDI. Bland-Altman agreement analysis and ROC curves analysis were conducted to compare the two methods. Results: Mean difference between the two methods was -2.6 min (95%CI: ± 35.2) and -1.7 e/h (95%CI: ± 7.3) for TST and ArI, respectively. OSA detection reached a sensitivity - specificity of 0.90 - 0.94 at RDI cutoffs of 5 e/h and 0.92 - 0.85 at 15 e/h. Conclusion: Automatic machine learning diagnosis using MM patterns showed reliable performances in detecting sleep/wake, arousals and RDI, demonstrating a promising value as a standalone OSA diagnosis tool.

Objective: We explored the causal relationship between Head-Body positions (HBp) and Sleep obstructive apnea/hypopnea (OAH) to fill the evidence gap in this topic. Methods: Rotations (pitch/yaw) and directions (prone, supine, up/left, supine, right) of HBp were captured by two miniaturized sensors under 45° segments during type1 PSG in 20 consecutive OSA patients. Sequential categorical data of Arousals (A, n=559) and OAH events (n=630) (accordingly to AASM2012) associated with HBp status (n=1633) were built. A timestamps-based algorithm was applied to extract every possible combinations between changes in HBp and events. The association between HBp and events risk was evaluated with Lasso-logistic and RandomForest models Results: Head and body prone pitching (PP) and right yawing (RY) were found significantly associated to either A or OAH events. Head position played the most important role (OR=2.2 for PP and 3.9 for RY), compared to that of body postural changes (OR=1.2 for RY and OR=1.1 for PP). Chronological order analysis showed that HBp changes occurred after A (73.7%) or OAH (72.6%) episodes. A and OAH events were triggered by HBp in only 23% observations. Rarely, A and OAH events occurred during a long and stable HBp (2.5%). Conclusion: Prone pitching and right yawing were the most important positions contributing to the classification of A and OAH events. HBp seemed here more likely consequences than causes of A or OAH risk.

Objectif Les mouvements de la mandibule associes a l’effort respiratoire sont soumis a des variations conditionnees par les changements de stade de sommeil. Nous presentons les resultats d’une analyse de machine learning basee sur le seul signal mandibulaire pour le scoring des stades de sommeil. Methodes Le signal est acquis via un dispositif connecte Sunrise (Sunrise, Namur, Belgium) au cours d’une polysomnographie au laboratoire (PSG). Le modele decrit 4 etats : la veille (V), le sommeil lent leger (SLL), lent profond (SLP) et le sommeil paradoxal (SP). Il est entraine sur 707 417 segments de 30 sec. collectes chez 800 sujets suspects de SAS correspondant a 1134 heures de V, 2806 h. de SLL, 1052 h. de SLP et 902 h. de SP. Il est valide sur les donnees ulterieures chez 226 autres sujets. Resultats Le modele montre un niveau eleve de concordance segment par segment avec la PSG (Kappa = 0,71 (95 %CI : 0,59 to 0,80). Il fournit un niveau de concordance acceptable avec les variables de qualite de sommeil de la PSG : la mediane [95 %CI] de la mesure des biais est respectivement de −10,25 min. [−52,87 ; +19,00], de 0 min. [−23,37 ; +6,50], de −2,22 % [−11,06 ; +3,80] et de +7,20 % [−2,41 ; +21,26] pour le temps en SP, pour le temps total de sommeil (TST), pour le delai d’endormissement, pour l’efficience du sommeil et pour SP en % de TST. Conclusion L’analyse par intelligence artificielle du signal mandibulaire se prete bien a la stadification automatique du sommeil. Elle offre une solution ambulatoire peu onereuse pour apprecier sa qualite.

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 (R2 = 0.906; P

BACKGROUNDPatients with chronic obstructive pulmonary disease (COPD) with an eosinophilic phenotype may benefit from treatment with mepolizumab, a monoclonal antibody directed against interleukin-5.METHODSWe 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.RESULTSIn 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.CONCLUSIONSMepolizumab 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.

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.

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.

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/m2; 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

Context: Mandibular movements (MM) during sleep disordered breathing (SDB) are considered as related to the intensity of respiratory effort (RE). However this relationship has never been objectively documented by assessing RE with crural diaphragmatic EMG activity (EMGd). Objective: To assess the link between the MM and EMGd signals during sleep. Methods: 25 consecutive patients with SDB were explored during a type 2 PSG including a magnetometer (Brizzy®Nomics, BE) and an Edi-catheter (Getinge, SWE) to record MM and EMGd, respectively. The PSG scoring was performed according to AASM-2012 rules. Peak to peak distance of MM (MMd, expressed in 1/10mm) and EMGd (in mV) were extracted by envelope processing. Preliminary analysis showed a strong cross-correlation between both signals. A dataset of 14000 randomized, equal segments were used for fitting mixed linear model. Results: Patients characteristics were: Age= 49.8±12.5 yrs; BMI =30.2±6.6 kg/m2; TST=370±61.6min and AHI=24.8 ± 27.5 events/hour. There was a significant strong relationship between MMd and EMGd (MMd ~ 0.01 EMGd; p Pairwise comparisons indicated significant differences in MMd between Normal breathing and RE events, including RERA, Obstructive, Mixed and Central Apneas. Conclusion: Peak to peak Mandibular Movements change in proportion to crural diaphragmatic EMG, and allow identifying RE during sleep.

Chest surface EMG at diaphragmatic insertions (IC-EMG) is an alternative way for capturing respiratory effort (RE) during SAHOS.IC-EMG wasn9t investigated with regards to oesophageal crural diaphragmatic EMG (DI-EMG). Our study aimed to assess the similarity between IC and DI-EMG and the ability of IC-EMG to classify RE episodes. Methods 14 adults SAHOS underwent a lab-based PSG study with IC-EMG and DI-EMG. 70 periods of normal breathing (NB),309 RE events (including 135 RERA,70 OH and104 OA) were randomly selected for analysis in R-studio. After noise reduction, AUC and peak-to-peak distance (d) were calculated for both signals. Similarity between 2 signals was evaluated by cross-correlation as a function of the lag of one relative to the other. Correlation and d-value were compared among 4 groups of RE levels. Ability of each signal to detect RE was evaluated by multiclass CART algorithm. Results Patients have a mean age of 42.8±10.7 yrs and BMI of 31.1±8.6 kg/m2.Their averaged TST and AHI were 347±51.9 min and 35.3±25.1 n/h respectively. IC and DI-EMG signals are cross-correlated in either NB or RE events (r=0.6 to 0.86) by a lag of 0.5-0.9 second. AUC was also correlated (r=0.96). IC showed a significant difference in d-value among 4 groups (NB:14.6 vs RERA:21.9, OH:19.8 and OA:44.2). Using cut-offs at 17.8 and 31.5, IC distance allows classifying RERA, OAH and NB with accuracy, inter-class agreement and specificity of 0.8, 0.63 and 0.91, respectively. Conclusions IC-EMG is a useful method to assess RE and the obstructive nature of AH .

Objectives i) To identify determining factors of UL under CPAP during sleep ii) to determine if these factors are modulated by the type of mask. Methods This study is an analysis of in-lab PSG recordings: PSG were supplemented with a movement magnetic sensor that measured mandibular behavior (mouth opening and mandibular oscillations-a surrogate marker of respiratory effort). Continuous variables (mouth opening, mandibular oscillations, pressure) were computed as mean values over non-overlapping 10 seconds intervals. Categorical data (sleep position, sleep stage) and dichotomous data (presence of respiratory events, micro-arousals (µA) and UL (>0 L/sec): yes vs no) were also reported by 10-second intervals. Univariate and multivariate conditional regression models estimated the risk of UL during an interval T according to the variables at the previous interval (T-1). A sensitivity analysis for nasal and oronasal masks (ONM) was conducted. Results 74 PSG were analyzed (51 males; 56±13years; BMI=34±6kg/m2; baseline AHI=47±23/h). In univariate analysis mouth opening (≥median/patient), CPAP pressure (≥median/patient), position (other vs supine), and REM sleep increased the risk of UL; µA decreased it. In multivariate analysis, the same variables plus mandibular oscillations (>0,3mm) remained independently associated with the risk of UL; in contrast, a respiratory event or a µA at T-1 reduced the risk of UL. In the sensitivity analysis, ONM reduced the risk of UL in case of mouth opening, mandibular oscillation or REM sleep. Conclusion Mouth opening, respiratory effort, CPAP pressure, sleep position and REM sleep are determining factors of UL. ONM may decrease this risk.

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.

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

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.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).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.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.

Adenotonsillar hypertrophy is a major cause of obstructive sleep apnea (OSAS) in childhood. Increased respiratory effort associated with OSAS is accompanied by an increase in pulse transit time (PTT) but also mandibular movements (MMs) amplify with increased upper airway resistance. We compared dynamic changes in PTT and MMs using a magnetic distance sensor during polysomnography (PSG) in a pre-school child with severe OSAS before and after adenotonsillectomy. The results show that repetitive respiratory effort to overcome upper airway obstruction can be identified in children using MMs.

It has been suggested that increased pulmonary vascular reserve, as defined by reduced pulmonary vascular resistance (PVR) and increased pulmonary transit of agitated contrast measured by echocardiography, might be associated with increased exercise capacity. Thus, at altitude, where PVR is increased because of hypoxic vasoconstriction, a reduced pulmonary vascular reserve could contribute to reduced exercise capacity. Furthermore, a lower PVR could be associated with higher capillary blood volume and an increased lung diffusing capacity. We reviewed echocardiographic estimates of PVR and measurements of lung diffusing capacity for nitric oxide (DL(NO)) and for carbon monoxide (DL(CO)) at rest, and incremental cardiopulmonary exercise tests in 64 healthy subjects at sea level and during 4 different medical expeditions at altitudes around 5000 m. Altitude exposure was associated with a decrease in maximum oxygen uptake (VO2max), from 42±10 to 32±8 mL/min/kg and increases in PVR, ventilatory equivalents for CO2 (V(E)/VCO2), DL(NO), and DL(CO). By univariate linear regression VO2max at sea level and at altitude was associated with V(E)/VCO2 (p0.001), mean pulmonary artery pressure (mPpa, p0.05), stroke volume index (SVI, p0.05), DL(NO) (p0.02), and DL(CO) (p=0.05). By multivariable analysis, VO2max at sea level and at altitude was associated with V(E)/VCO2, mPpa, SVI, and DL(NO). The multivariable analysis also showed that the altitude-related decrease in VO2max was associated with increased PVR and V(E)/VCO2. These results suggest that pulmonary vascular reserve, defined by a combination of decreased PVR and increased DL(NO), allows for superior aerobic exercise capacity at a lower ventilatory cost, at sea level and at high altitude.

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.

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); arte rial 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.

Lung diffusing capacity has been reported variably in high-altitude newcomers and may be in relation to different pulmonary vascular resistance (PVR). Twenty-two healthy volunteers were investigated at sea level and at 5,050 m before and after random double-blind intake of the endothelin A receptor blocker sitaxsentan (100 mg/day) vs. a placebo during 1 wk. PVR was estimated by Doppler echocardiography, and exercise capacity by maximal oxygen uptake (V̇o2 max). The diffusing capacities for nitric oxide (DLNO) and carbon monoxide (DLCO) were measured using a single-breath method before and 30 min after maximal exercise. The membrane component of DLCO (Dm) and capillary volume (Vc) was calculated with corrections for hemoglobin, alveolar volume, and barometric pressure. Altitude exposure was associated with unchanged DLCO, DLNO, and Dm but a slight decrease in Vc. Exercise at altitude decreased DLNO and Dm. Sitaxsentan intake improved V̇o2 max together with an increase in resting and postexercise DLNO and Dm. Sitaxsentan-induced decrease in PVR was inversely correlated to DLNO. Both DLCO and DLNO were correlated to V̇o2 max at sea level ( r = 0.41–0.42, P < 0.1) and more so at altitude ( r = 0.56–0.59, P < 0.05). Pharmacological pulmonary vasodilation improves the membrane component of lung diffusion in high-altitude newcomers, which may contribute to exercise capacity.

Objectif Evaluer l’auto-correlation entre les signaux issus de l’EMG de surface thoracique (intercostal EMG-IC) et l’EMG diaphragmatique (crural EMG - DIA) endo-œsophagien pour capter l’effort respiratoire au cours du SAS. Methodes EMG-IC a ete enregistre (8eme espace intercostal) chez 10 adultes adresses consecutivement avec la suspicion de SAS pour PSG type 1 (Somnoscreen, Somnomedics, Germany) equipee d’une sonde œsophagienne (Edi catheter, Getinge Group, Sweden) pour la capture de l’EMG DIA. L’analyse auto-correlative (ACF) a ete effectuee sur des fragments de duree equivalente tires au sort. La meilleure auto-correlation et le decalage entre EMG-IC et EMG-DIA ont ete compares parmi les episodes d’apnees (n = 45) ou hypopnees obstructives (n = 113) et de respiration normale (n = 52). Resultats L’âge moyen ± DS du groupe est de 42,8 ± 10,7 ans, IMC de 31,1 ± 8,6 kg/m2, TTS de 347 ± 51,9 min et IAH de 35,3 ± 35,1. Le signal EMG-IC a ete correctement acquis chez 9/10 patients. La meilleure ACF entre EMG-IC et EMG-DIA est observee au cours HO (0,84 ± 0,01) et AO (0,85 ± 0,01) pour un decalage (s) de −1,80 ± 0,33 et 1,88 ± 0,02, respectivement -EMG-DIA avant EMG-IC- versus en respiration normale de 0,48 ± 0,13 (p Wilkoxon 0,017) pour un decalage de −1,32 ± 0,13 (p Wilkoxon 0,085 [NS]). Conclusion EMG-IC fournit un signal tres bien correle avec l’EMG-DIA endo-œsophagien pendant le sommeil en presence AH obstructives. EMG-IC pour caracteriser la nature de l’evenement respiratoire pendant le sommeil merite d’etre analyse dans de larges cohortes.

Lung carbon monoxide (CO) transfer and pulmonary capillary blood volume (Vc) at high altitudes have been reported as being higher in native highlanders compared to acclimatised lowlanders but large discrepancies appears between the studies. This finding raises the question of whether hypoxia induces pulmonary angiogenesis. Eighteen highlanders living in Bolivia and 16 European lowlander volunteers were studied. The latter were studied both at sea level and after acclimatisation to high altitude. Membrane conductance (Dm(CO)) and Vc, corrected for the haemoglobin concentration (Vc(cor)), were calculated using the NO/CO transfer technique. Pulmonary arterial pressure and left atrial pressures were estimated using echocardiography. Highlanders exhibited significantly higher NO and CO transfer than acclimatised lowlanders, with Vc(cor)/VA and Dm(CO)/VA being 49 and 17% greater (VA: alveolar volume) in highlanders, respectively. In acclimatised lowlanders, Dm(CO) and Dm(CO)/VA values were lower at high altitudes than at sea level. Echocardiographic estimates of cardiac output and pulmonary arterial pressure were significantly elevated at high altitudes as compared to sea level. The decrease in Dm(CO) in lowlanders might be due to altered gas transport in the airways due to the low density of air at high altitudes. The disproportionate increase in Vc in Andeans compared to the change in Dm(CO) suggests that the recruitment of capillaries is associated with a thickening of the blood capillary sheet. Since there was no correlation between the increase in Vc and the slight alterations in haemodynamics, this data suggests that chronic hypoxia might stimulate pulmonary angiogenesis in Andeans who live at high altitudes.

In patients with chronic obstructive pulmonary disease (COPD) classified as moderate onwards, Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guidelines recommend regular treatment with one or more long-acting bronchodilators, such as beta(2)-agonists or anticholinergics. In contrast to currently available long-acting beta(2)-agonists, which have a duration of action of 12 h, indacaterol has demonstrated effective 24-h bronchodilation on once-daily dosing. A double-blind, randomised, placebo-controlled study was conducted to compare the safety, tolerability and efficacy of indacaterol with that of placebo, over a 28-day period, in patients with moderate COPD (as defined by GOLD 2001 criteria; equivalent to moderate-to-severe COPD in the GOLD 2005 criteria). Patients were randomised 2:2:1 to receive indacaterol 400 microg or 800 microg or placebo once-daily (between 07:00 and 11:00 h) via a single-dose dry-powder inhaler for 28 days. Assessments included monitoring of adverse events (AEs), blood chemistry (including serum potassium and blood glucose), vital signs (blood pressure and heart rate), electrocardiograms and spirometry. One hundred and sixty-three patients were randomised, with 155 (95%) completing the study. There were no statistically significant differences between treatment groups in the overall incidence of AEs, with AEs reported by 35%, 51% and 25% of patients in the indacaterol 400 microg, 800 microg and placebo groups, respectively. The majority of AEs were mild or moderate in severity, and there were no study-drug related serious AEs. There were no statistically significant differences between indacaterol groups and placebo in mean pulse rate and QTc interval, and isolated statistically significant (p

Aerobic exercise capacity is decreased at altitude because of combined decreases in arterial oxygenation and in cardiac output. Hypoxic pulmonary vasoconstriction could limit cardiac output in hypoxia. We tested the hypothesis that acetazolamide could improve exercise capacity at altitude by an increased arterial oxygenation and an inhibition of hypoxic pulmonary vasoconstriction. Resting and exercise pulmonary artery pressure (Ppa) and flow (Q) (Doppler echocardiography) and exercise capacity (cardiopulmonary exercise test) were determined at sea level, 10 days after arrival on the Bolivian altiplano, at Huayna Potosi (4,700 m), and again after the intake of 250 mg acetazolamide vs. a placebo three times a day for 24 h. Acetazolamide and placebo were administered double-blind and in a random sequence. Altitude shifted Ppa/Q plots to higher pressures and decreased maximum O(2) consumption ((.)Vo(2max)). Acetazolamide had no effect on Ppa/Q plots but increased arterial O(2) saturation at rest from 84 +/- 5 to 90 +/- 3% (P < 0.05) and at exercise from 79 +/- 6 to 83 +/- 4% (P < 0.05), and O(2) consumption at the anaerobic threshold (V-slope method) from 21 +/- 5 to 25 +/- 5 ml.min(-1).kg(-1) (P < 0.01). However, acetazolamide did not affect (.)Vo(2max) (from 31 +/- 6 to 29 +/- 7 ml.kg(-1).min(-1)), and the maximum respiratory exchange ratio decreased from 1.2 +/- 0.06 to 1.05 +/- 0.03 (P < 0.001). We conclude that acetazolamide does not affect maximum exercise capacity or pulmonary hemodynamics at high altitudes. Associated changes in the respiratory exchange ratio may be due to altered CO(2) production kinetics., SCOPUS: ar.j, info:eu-repo/semantics/published

The phosphodiesterase-5 inhibitor sildenafil has been reported to improve hypoxic exercise capacity, but the mechanisms accounting for this observation remain incompletely understood. Sixteen healthy subjects were included in a randomized, double-blind, placebo-controlled, cross-over study on the effects of 50-mg sildenafil on echocardiographic indexes of the pulmonary circulation and on cardiopulmonary cycle exercise in normoxia, in acute normobaric hypoxia (fraction of inspired O2, 0.1), and then again after 2 weeks of acclimatization at 5000 m on Mount Chimborazo (Ecuador). In normoxia, sildenafil had no effect on maximum VO2 or O2 saturation. In acute hypoxia, sildenafil increased maximum VO2 from 27 +/- 5 to 32 +/- 6 mL/min/kg and O2 saturation from 62% +/- 6% to 68% +/- 9%. In chronic hypoxia, sildenafil did not affect maximum VO2 or O2 saturation. Resting mean pulmonary artery pressure increased from 16 +/- 3 mmHg in normoxia to 28 +/- 5 mmHg in normobaric hypoxia and 32 +/- 6 mmHg in hypobaric hypoxia. Sildenafil decreased pulmonary vascular resistance by 30% to 50% in these different conditions. We conclude that sildenafil increases exercise capacity in acute normobaric hypoxia and that this is explained by improved arterial oxygenation, rather than by a decrease in right ventricular afterload.

International audience; 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.

Just a few clinicians routinely measure the subcomponents of the lung diffusing capacity for Carbone monoxide (DLCO ). This is because the measurement of membrane and blood conductances for CO (DmCO and DbCO = θCO × Vc , 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 (PAO2 ) and mean intracapillary oxygen partial pressure (PcapO2 ) which is the true determinant of specific conductance of haemoglobin for CO (θCO ). Besides that, the critical multistep oxygenation method along with different linear equations relating 1/θCO to PcapO2 gave highly scattered DmCO and Vc values. The Dm and Vc can also be derived from a simultaneous measurement of DLNO and DLCO with the blood resistance for NO assumed to be negligible. However, recent in vitro and in vivo experiments point towards a finite value of θNO (about 4·5 mlNO × mlblood-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 DmCO and Vc to alterations observed in parenchymal diseases.