Prevalence of major depressive disorder and post-traumatic stress disorder among first-time sleep center attendees.

BACKGROUND: Sleep disorders and psychiatric disorders stand in a bidirectional relationship. Sleep complaints are prominent in populations with psychiatric disorders, especially amongst people with major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). Consultations at sleep clinics offer opportunities to screen psychiatric disorders and to propose primary psychiatric care. METHODS: This descriptive study was conducted on 755 patients making their first visit to sleep clinic, with 574 seeking consultation for suspected obstructive sleep apnoea-hypopnoea syndrome (OSAHS), 139 for complaints of insomnia, and 42 for complaints of hypersomnia. The results of 387 screening scales for MDD (BDI-II) and 403 for TSPT (PCL-5) were compared according to the reason given for the consultation. RESULTS: In the whole group, 12.1 % of patients presented a positive MDD screening and 4.9 % for PTSD. Among patients presenting with insomnia, 19.8 % had a positive screening for MDD, as compared to 9.3 % in patients presenting with suspected OSAHS (p = 0.02). Regarding PTSD, 9.7 % of patients seeking consultation because of insomnia had a positive screening, compared to 2.9 % among patients with suspected OSAHS (p = 0.03). Among patients with a positive screening for MDD, 40.5 % were not receiving antidepressant or mood stabilizer treatment. CONCLUSION: Positive screening for MDD and PTSD are frequent in patients who attend sleep centers, especially amongst those presenting with insomnia. Nearly half of the patients with positive screening for MDD or PTSD were not receiving a dedicated pharmacological treatment. These figures emphasize systematic screening for psychiatric disorders in sleep clinics.

Small Extracellular Vesicles Harboring PD-L1 in Obstructive Sleep Apnea.

Obstructive sleep apnea syndrome (OSA) has been associated with increased cancer incidence and aggressiveness. One hypothesis to support this association is the implication of immune response, particularly the programmed cell death pathway, formed by the receptor PD-1 and its ligand PD-L1. Recent studies have shown dysregulation of this pathway in severe OSA patients. It has also been shown that small extracellular vesicles (sEVs) carrying PD-L1 induce lymphocyte dysfunction. Thus, the aim of our study was to analyze the expression of PD-L1 on sEVs of OSA patients and to evaluate the role of sEVs on lymphocyte activation and cytotoxicity. Circulating sEVs were isolated from OSA patients and the control group. Lymphocytes were isolated from the control group. Circulating sEVs were characterized by western blot, nanotracking analysis, and flow cytometry and were incubated with lymphocytes. Our results show no differences in the quantity and composition of sEVs in OSA patients and no significant effects of sEVs in OSA patients on lymphocyte activation and cytotoxicity. These results suggest that OSA does not modify PD-L1 expression on sEVs, which does not contribute to dysregulation of cytotoxic lymphocytes.

Guidelines for the management of chronic cough in adults. Endorsed by the French speaking society of respiratory diseases (Société de Pneumologie de Langue Française, SPLF), the Société Française d'Oto-Rhino-Laryngologie et de Chirurgie de la Face et du Cou (SFORL), the Société Française de Phoniatrie et de Laryngologie (SFPL), the Société Nationale Française de Gastro-entérologie (SNFGE).

Patients with chronic cough experience a high alteration of quality of life. Moreover, chronic cough is a complex entity with numerous etiologies and treatments. In order to help clinicians involved in the management of patients with chronic cough, guidelines on chronic cough have been established by a group of French experts. These guidelines address the definitions of chronic cough and the initial management of patients with chronic cough. We present herein second-line tests that might be considered in patients with cough persistence despite initial management. Experts also propose a definition of unexplained or refractory chronic cough (URCC) in order to better identify patients whose cough persists despite optimal management. Finally, these guidelines address the pharmacological and non-pharmacological interventions useful in URCC. Thus, amitryptilline, pregabalin, gabapentin or morphine combined with speech and/or physical therapy are a mainstay of treatment strategies in URCC. Other treatment options, such as P2 × 3 antagonists, are being developed.

Sleep Apnea and Incident Unprovoked Venous Thromboembolism: Data from the Pays de la Loire Sleep Cohort.

BACKGROUND: Previous studies have reported inconsistent findings regarding the association between obstructive sleep apnea (OSA) and incident venous thromboembolism (VTE). More specifically, the association between OSA and unprovoked VTE was barely evaluated. We aimed to evaluate whether apnea hypopnea index (AHI) and nocturnal hypoxemia markers were associated with unprovoked VTE incidence in patients investigated for OSA. MATERIAL AND METHODS: Data from the Pays de la Loire Sleep Cohort were linked to the French health administrative data to identify incident unprovoked VTE in patients suspected for OSA and no previous VTE disease. Cox proportional hazards models were used to evaluate the association of unprovoked VTE incidence with AHI and nocturnal hypoxemia markers including the time spent under 90% of saturation (T90), oxygen desaturation index, and hypoxic burden (HB), a more specific marker of respiratory events related to hypoxia. The impact of continuous positive airway pressure (CPAP) was evaluated in the subgroup of patients who were proposed the treatment. RESULTS: After a median [interquartile range] follow-up of 6.3 [4.3-9.0] years, 104 of 7,355 patients developed unprovoked VTE, for an incidence rate of 10.8 per 1,000 patient-years. In a univariate analysis, T90 and HB predicted incident VTE. In the fully adjusted model, T90 was the only independent predictor (hazard ratio: 1.06; 95% confidence interval: [1.01-1.02]; p = 0.02). The CPAP treatment has no significant impact on VTE incidence. CONCLUSION: Patients with more severe nocturnal hypoxia are more likely to have incident unprovoked VTE.

Positive Airway Pressure Adherence, Mortality, and Cardiovascular Events in Patients with Sleep Apnea.

Rationale: Randomized controlled trials showed no effect of positive airway pressure (PAP) therapy for obstructive sleep apnea (OSA) on cardiovascular (CV) risk. However, patient selection and low PAP adherence preclude the generalization of their data to clinical samples. Objectives: To evaluate the association between hours of PAP use, mortality, and CV morbidity in real-life conditions. Methods: Data from the Pays de la Loire Cohort were linked to health administrative data to identify incident major adverse cardiovascular events (MACEs; a composite outcome of mortality, stroke, and cardiac diseases) in patients with OSA who were prescribed PAP. Cox proportional hazards analyses were conducted to evaluate the association between MACEs and quartiles of average daily PAP use over the study period. Measurements and Main Results: After a median follow-up of 6.6 years, 961 of 5,138 patients experienced MACEs. Considering nonadherent patients (0-4 h/night) as the reference group, adjusted hazard ratios (95% confidence intervals) for MACEs were 0.87 (0.73-1.04) for the 4-6 h/night group, 0.75 (0.62-0.92) for the 6-7 h/night group, and 0.78 (0.65-0.93) for the ⩾7 h/night group (P = 0.0130). Sensitivity analyses using causal inference approaches confirmed the association of PAP use with MACEs. The association was stronger in male patients (P value for interaction = 0.0004), patients without overt CV disease at diagnosis (P < 0.0001), and those belonging to the excessively sleepy symptom subtype (P = 0.060). Conclusions: These real-life clinical data demonstrate a dose-response relationship between PAP adherence and incident MACEs in OSA. Patient support programs may help improve PAP adherence and CV outcomes in patients with OSA.

Overnight pulse rate variability and risk of major neurocognitive disorder in older patients with obstructive sleep apnea.

BACKGROUND: Increasing evidence links obstructive sleep apnea (OSA) to cognitive decline. Autonomic dysfunction assessed by heart rate variability is a promising early biomarker of cognitive impairment in populations without major neurocognitive disorder (MND). We aimed to determine whether nocturnal pulse rate variability (PRV) extracted from oximetry signal and OSA severity could predict MND onset among older OSA patients. METHODS: This study relied on data collected within the multicenter longitudinal Pays de la Loire Sleep Cohort, linked to health administrative data to identify new-onset MND. We included patients ≥60 years with newly diagnosed OSA, and no history of MND or atrial fibrillation. Cox proportional-hazards models were used to evaluate the association of MND with indices of PRV and OSA severity generated from sleep recordings. RESULTS: After a median follow-up of 6.8 [4.7-9.4] years, 70 of 3283 patients (2.1%) had been diagnosed with MND. In multivariable Cox models, MND incidence was associated with age (p < 0.0001), depression (p = 0.013), and PRV assessed by the root mean square of the successive normal-to-normal (NN) beat interval differences (RMSSD; p = 0.008) and standard deviation of NN beat intervals (SDNN; p = 0.02). Patients with the highest quartile of RMSSD had a 2.3-fold [95%CI 1.11-4.92] higher risk of being diagnosed with MND. Indices of OSA and nocturnal hypoxia severity were not associated with MND. CONCLUSIONS: Within a large clinic-based cohort of older patients with OSA, we found an association between oximetry-based indices of PRV and the onset of MND. Nocturnal oximetry-derived PRV indices could allow the early identification of OSA patients at higher risk of MND.

Overuse of Short-Acting Beta-2 Agonists (SABAs) in Elite Athletes: Hypotheses to Explain It.

The use of short-acting beta-2 agonists (SABAs) is more common in elite athletes than in the general population, especially in endurance sports. The World Anti-Doping Code places some restrictions on prescribing inhaled ß2-agonists. These drugs are used in respiratory diseases (such as asthma) that might reduce athletes' performances. Recently, studies based on the results of the Olympic Games revealed that athletes with confirmed asthma/airway hyperresponsiveness (AHR) or exercise-induced bronchoconstriction (EIB) outperformed their non-asthmatic rivals. This overuse of SABA by high-level athletes, therefore, raises some questions, and many explanatory hypotheses are proposed. Asthma and EIB have a high prevalence in elite athletes, especially within endurance sports. It appears that many years of intensive endurance training can provoke airway injury, EIB, and asthma in athletes without any past history of respiratory diseases. Some sports lead to a higher risk of asthma than others due to the hyperventilation required over long periods of time and/or the high environmental exposure while performing the sport (for example swimming and the associated chlorine exposure). Inhaled corticosteroids (ICS) have a low efficacy in the treatment of asthma and EIB in elite athletes, leading to a much greater use of SABAs. A significant proportion of these high-level athletes suffer from non-allergic asthma, involving the th1-th17 pathway.

Sleep Apnea-Specific Hypoxic Burden, Symptom Subtypes, and Risk of Cardiovascular Events and All-Cause Mortality.

Rationale: Data from population-based cohorts suggest that symptom subtypes and obstructive sleep apnea (OSA)-specific hypoxic burden (HB) could help to better identify patients with OSA at high cardiovascular (CV) risk. Objectives: We aimed to evaluate whether those new markers are associated with the risk of major adverse CV events (MACE) in clinical setting. Methods: Data from the Pays de la Loire cohort were linked to health administrative data to identify the occurrence of MACE (a composite outcome including all-cause mortality, acute myocardial infarction, stroke, and unplanned coronary revascularization) in patients with newly diagnosed OSA and no overt CV disease. Latent class analysis was used to identify subtypes based on eight clinically relevant variables. HB was defined as the total area under the respiratory event-related desaturation curve. Cox proportional hazards models were used to evaluate the association of symptom subtypes and HB with MACE. Measurements and Main Results: Four symptom subtypes were identified (minimally symptomatic [22.0%], disturbed sleep [17.5%], excessively sleepy [49.8%], and moderately sleepy [10.6%]). After a median follow-up of 78 months (interquartile range, 52-109), 592 (11.05%) of 5,358 patients experienced MACE. In a fully adjusted model, HB and overall nocturnal hypoxemia assessed by sleep time with oxygen saturation <90% were the only predictors of MACE (hazard ratio, 1.21; 95% confidence interval, 1.07-1.38; and hazard ratio, 1.34; 95% confidence interval, 1.16-1.55, respectively). The association appeared stronger toward younger patients and women. Conclusion: In clinical setting, patients with OSA who demonstrate elevated OSA-specific HB are at higher risk of a CV event and all-cause mortality. Symptom subtypes were not associated with MACE after adjustment for confounders.

Cancer risk in patients with sleep apnoea following adherent 5-year CPAP therapy.

BACKGROUND: Increasing evidence suggests that obstructive sleep apnoea (OSA) contributes to cancer risk; however, limited data are available on the impact of continuous positive airway pressure (CPAP) therapy on cancer incidence. We aimed to determine whether adherence to CPAP therapy is associated with a reduction in all-cancer incidence compared with nonadherent patients with OSA. METHODS: The study relied on data collected by the multicentre Pays de la Loire Sleep Cohort study, linked to health administrative data, so as to identify new-onset cancer. We included patients who were prescribed CPAP for OSA, with no history of cancer before the diagnostic sleep study or during the first year of CPAP. Patients with documented CPAP use for ≥4 h per night were defined as adherent. Those who discontinued or used CPAP <4 h per night constituted the nonadherent group. A propensity score inverse probability of treatment weighting analysis was performed to assess the effect of CPAP adherence on cancer risk. RESULTS: After a median (interquartile range) follow-up of 5.4 (3.1-8.0) years, 437 (9.7%) out of 4499 patients developed cancer: 194 (10.7%) in the nonadherent group (n=1817) and 243 (9.1%) in adherent patients (n=2682). The final weighted model showed no significant impact of CPAP adherence on all-cause cancer risk (subdistribution hazard ratio 0.94, 95% CI 0.78-1.14). CONCLUSIONS: Adherence to CPAP therapy in OSA patients was not associated with a reduction in all-cancer incidence. Whether adherent CPAP therapy of OSA might reduce the risk of specific cancer sites should be further evaluated.

Long-term dentoskeletal side effects of mandibular advancement therapy in patients with obstructive sleep apnea: data from the Pays de la Loire sleep cohort.

OBJECTIVES: Mandibular advancement devices (MADs) are the main therapeutic alternative to continuous positive airway pressure for obstructive sleep apnea. Our aim was to evaluate the long-term dentoskeletal side effects of MADs and to identify the predictive factors for these side effects. MATERIALS AND METHODS: Patients from the Pays de la Loire cohort treated with a custom-made MAD for at least 1 year were included in this retrospective study. Digital cephalometric analyses were performed at baseline and at follow-up. RESULTS: We included a total of 117 patients, treated with a MAD for a median [interquartile range] of 4.6 [2.6-6.6] years. The main significant side effects were a decrease in overbite (- 0.5 ± 1 mm), overjet (- 0.7 ± 1 mm) and maxillary incisor inclination (- 2.5 ± 2.8°) and an increase in mandibular incisor inclination (+ 2.2 ± 2.7°). Subjective side effects were not linked to the observed dentoskeletal changes. Current smokers were at higher risk of overjet modifications. A pre-existing anterior open-bite was associated with a greater decrease in overbite. Treatment duration was associated with a more pronounced mandibular incisor proclination. Propulsion was negatively associated with maxillary incisor retroclination. CONCLUSIONS: Long-term dentoskeletal side effects were mainly moderate dental side effects. Some predictive factors were shown to be associated with more pronounced changes. Subjective side effects did not appear to be reliable tools to detect dentoskeletal side effects. CLINICAL RELEVANCE: Regular follow-up with clinical examination and regular radiographs is mandatory. The predictive factors could be of interest for a better selection of patients and to individualize follow-up.

European Respiratory Society guideline on non-CPAP therapies for obstructive sleep apnoea.

Treatment of obstructive sleep apnoea (OSA) in adults is evolving, as new therapies have been explored and introduced in clinical practice, while other approaches have been refined or reconsidered. In this European Respiratory Society (ERS) guideline on non-continuous positive airway pressure (CPAP) therapies for OSA, we present recommendations determined by a systematic review of the literature. It is an update of the 2011 ERS statement on non-CPAP therapies, advanced into a clinical guideline. A multidisciplinary group of experts, including pulmonary, surgical, dentistry and ear-nose-throat specialists, methodologists and patient representatives considered the most relevant clinical questions (for both clinicians and patients) relating to the management of OSA. Eight key clinical questions were generated and a systematic review was conducted to identify published randomised clinical trials that answered these questions. We used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to assess the quality of the evidence and the strength of recommendations. The resulting guideline addresses gastric bypass surgery, custom-made dual-block mandibular advancement devices, hypoglossal nerve stimulation, myofunctional therapy, maxillo-mandibular osteotomy, carbonic anhydrase inhibitors and positional therapy. These recommendations can be used to benchmark quality of care for people with OSA across Europe and to improve outcomes.

Heterogeneity of Melanoma Cell Responses to Sleep Apnea-Derived Plasma Exosomes and to Intermittent Hypoxia.

Obstructive sleep apnea (OSA) is associated with increased cutaneous melanoma incidence and adverse outcomes. Exosomes are secreted by most cells, and play a role in OSA-associated tumor progression and metastasis. We aimed to study the effects of plasma exosomes from OSA patients before and after adherent treatment with continuous positive airway pressure (CPAP) on melanoma cells lines, and also to identify exosomal miRNAs from melanoma cells exposed to intermittent hypoxia (IH) or normoxia. Plasma-derived exosomes were isolated from moderate-to-severe OSA patients before (V1) and after (V2) adherent CPAP treatment for one year. Exosomes were co-incubated with three3 different melanoma cell lines (CRL 1424; CRL 1619; CRL 1675) that are characterized by genotypes involving different mutations in BRAF, STK11, CDKN2A, and PTEN genes to assess the effect of exosomes on cell proliferation and migration, as well as on pAMK activity in the presence or absence of a chemical activator. Subsequently, CRL-1424 and CRL-1675 cells were exposed to intermittent hypoxia (IH) and normoxia, and exosomal miRNAs were identified followed by GO and KEG pathways and gene networks. The exosomes from these IH-exposed melanoma cells were also administered to THP1 macrophages to examine changes in M1 and M2 polarity markers. Plasma exosomes from V1 increased CRL-1424 melanoma cell proliferation and migration compared to V2, but not the other two cell lines. Exposure to CRL-1424 exosomes reduced pAMPK/tAMPK in V1 compared to V2, and treatment with AMPK activator reversed the effects. Unique exosomal miRNAs profiles were identified for CRL-1424 and CRL-1675 in IH compared to normoxia, with six miRNAs being regulated and several KEGG pathways were identified. Two M1 markers (CXCL10 and IL6) were significantly increased in monocytes when treated with exosomes from IH-exposed CRL-1424 and CRL-1625 cells. Our findings suggest that exosomes from untreated OSA patients increase CRL-1424 melanoma malignant properties, an effect that is not observed in two other melanoma cell lines. Exosomal cargo from CRL-1424 cells showed a unique miRNA signature compared to CRL-1675 cells after IH exposures, suggesting that melanoma cells are differentially susceptible to IH, even if they retain similar effects on immune cell polarity. It is postulated that mutations in STK-11 gene encoding for the serine/threonine kinase family that acts as a tumor suppressor may underlie susceptibility to IH-induced metabolic dysfunction, as illustrated by CRL-1424 cells.

Risk Factors for Sleepiness at the Wheel and Sleep-Related Car Accidents Among Patients with Obstructive Sleep Apnea: Data from the French Pays de la Loire Sleep Cohort.

PURPOSE: We aimed to determine the risk factors of sleepiness at the wheel among patients with obstructive sleep apnea (OSA) and to determine factors that were independently associated with reported sleep-related near-miss accidents or car accidents. PATIENTS AND METHODS: This retrospective study was conducted on 843 OSA patients from the French Pays de la Loire sleep cohort database. Each patient completed surveys including anthropometric data, medical history, professional status, and data on alcohol and tobacco use. Epworth sleepiness scale (ESS) and sleep quality questionnaires were administered. Regarding driving, data were collected on occurrence of sleepiness-related near-misses or car accidents, and on distance driven per year. The primary dependent variable of interest was reported sleepiness at the wheel. RESULTS: On multivariable regression analysis, reported sleepiness at the wheel (n=298) was independently associated with younger age (p=0.02), male gender (p=0.009), marked nocturnal hypoxemia (p=0.006), lower BMI (p=0.03), absence of cardiovascular disease (p=0.022), executives or high degree jobs (p=0.003) and reported difficulty-maintaining sleep (p=0.03). Only past experience of sleepiness at the wheel (OR 12.18, [6.38-23.25]) and an ESS ≥11 (OR 4.75 [2.73-8.27]) were independently associated with reported car accidents (n=30) or near-miss accidents (n=137). CONCLUSION: In patients newly diagnosed with OSA, the risk of car accident seems multifactorial, and its evaluation should include multiple parameters such as patient self-reported sleepiness at the wheel, occurrence of sleepiness-related accidents, anthropometry, professional status, and insomnia complaints. Thus, it is possible to evaluate this risk and advise patients as early as the first visit at the sleep medicine clinic without waiting for the results of the sleep study.

Cardiovascular risk and mortality prediction in patients suspected of sleep apnea: a model based on an artificial intelligence system.

Objective. Cardiovascular disease (CVD) is one of the leading causes of death worldwide. There are many CVD risk estimators but very few take into account sleep features. Moreover, they are rarely tested on patients investigated for obstructive sleep apnea (OSA). However, numerous studies have demonstrated that OSA index or sleep features are associated with CVD and mortality. The aim of this study is to propose a new simple CVD and mortality risk estimator for use in routine sleep testing.Approach. Data from a large multicenter cohort of CVD-free patients investigated for OSA were linked to the French Health System to identify new-onset CVD. Clinical features were collected and sleep features were extracted from sleep recordings. A machine-learning model based on trees, AdaBoost, was applied to estimate the CVD and mortality risk score.Main results. After a median [inter-quartile range] follow-up of 6.0 [3.5-8.5] years, 685 of 5234 patients had received a diagnosis of CVD or had died. Following a selection of features, from the original 30 features, 9 were selected, including five clinical and four sleep oximetry features. The final model included age, gender, hypertension, diabetes, systolic blood pressure, oxygen saturation and pulse rate variability (PRV) features. An area under the receiver operating characteristic curve (AUC) of 0.78 was reached.Significance. AdaBoost, an interpretable machine-learning model, was applied to predict 6 year CVD and mortality in patients investigated for clinical suspicion of OSA. A mixed set of simple clinical features, nocturnal hypoxemia and PRV features derived from single channel pulse oximetry were used.