Pulmonary function and atherosclerosis in the general population: causal associations and clinical implications.

Reduced lung function is associated with cardiovascular mortality, but the relationships with atherosclerosis are unclear. The population-based Swedish CArdioPulmonary BioImage study measured lung function, emphysema, coronary CT angiography, coronary calcium, carotid plaques and ankle-brachial index in 29,593 men and women aged 50-64 years. The results were confirmed using 2-sample Mendelian randomization. Lower lung function and emphysema were associated with more atherosclerosis, but these relationships were attenuated after adjustment for cardiovascular risk factors. Lung function was not associated with coronary atherosclerosis in 14,524 never-smokers. No potentially causal effect of lung function on atherosclerosis, or vice versa, was found in the 2-sample Mendelian randomization analysis. Here we show that reduced lung function and atherosclerosis are correlated in the population, but probably not causally related. Assessing lung function in addition to conventional cardiovascular risk factors to gauge risk of subclinical atherosclerosis is probably not meaningful, but low lung function found by chance should alert for atherosclerosis.

Hypertension treatment in patients with sleep apnea from the European Sleep Apnea Database (ESADA) cohort - towards precision medicine.

We recruited 5,970 hypertensive patients with obstructive sleep apnea (OSA) on current antihypertensive treatment from the European Sleep Apnea Database (ESADA) cohort. The group was subdivided into those receiving monotherapy (n = 3,594) and those receiving dual combined therapy (n = 2,376). We studied how major OSA confounders like age, gender, and body mass index as well as the degree of sleep apnea modified office systolic and diastolic blood pressure. Beta-blockers alone or in combination with a diuretic were compared with other antihypertensive drug classes. Monotherapy with beta-blocker was associated with lower systolic blood pressure, particularly in non-obese middle-aged males with hypertension. Conversely, the combination of a beta-blocker and a diuretic was associated with lower systolic and diastolic blood pressure in hypertensive patients with moderate-severe OSA. Systolic blood pressure was better controlled in female patients using this combined treatment. Our cross-sectional data suggest that specific clinical characteristics and type of antihypertensive medication influence the degree of blood pressure control in hypertensive OSA patients. Controlled trials are warranted.

A Randomized Controlled Clinical Trial Exploring Safety and Tolerability of Sulthiame in Sleep Apnea.

Rationale: Current therapies for obstructive sleep apnea (OSA) are limited by insufficient efficacy, compliance, or tolerability. An effective pharmacological treatment for OSA is warranted. Carbonic anhydrase inhibition has been shown to ameliorate OSA. Objectives: To explore safety and tolerability of the carbonic anhydrase inhibitor sulthiame (STM) in OSA. Methods: A 4-week double-blind, randomized, placebo-controlled dose-guiding trial was conducted in patients with moderate and/or severe OSA not tolerating positive airway pressure treatment. Measurements and Main Results: Intermittent paresthesia was reported by 79%, 67%, and 18% of patients receiving 400 mg STM (n = 34), 200 mg STM (n = 12), and placebo (n = 22), respectively. Dyspnea was reported after 400 mg STM (18%). Six patients in the higher dose group withdrew because of adverse events. There were no serious adverse events. STM reduced the apnea-hypopnea index from 55.2 to 33.0 events/h (-41.0%) in the 400-mg group and from 61.1 to 40.6 events/h (-32.1%) after 200 mg (P < 0.001 for both). Corresponding placebo values were 53.9 and 50.9 events/h (-5.4%). The apnea-hypopnea index reduction threshold of ⩾50% was reached in 40% of patients after 400 mg, 25% after 200 mg, and 5% after placebo. Mean overnight oxygen saturation improved by 1.1% after 400 and 200 mg (P < 0.001 and P = 0.034, respectively). Patient-related outcomes were unchanged. Conclusions: STM showed a satisfactory safety profile in moderate and/or severe OSA. STM reduced OSA, on average, by more than 20 events/h, one of the strongest reductions reported in a drug trial in OSA. Larger scale clinical studies of STM in OSA are justified. Clinical trial registered with www.clinicaltrialsregister.eu (2017-004767-13).

Correlates of excessive daytime sleepiness in obstructive sleep apnea: Results from the nationwide SESAR cohort including 34,684 patients.

Excessive daytime sleepiness (EDS) is a hallmark symptom in obstructive sleep apnea (OSA). It is commonly eliminated by obstructive sleep apnea therapy and constitutes a major treatment indication. This study aimed to identify determinants of excessive daytime sleepiness by the Epworth Sleepiness Scale (ESS) scores in the large, representative national obstructive sleep apnea patient cohort of the Swedish Sleep Apnea Registry (SESAR, www.sesar.se). Data from 34,684 patients with obstructive sleep apnea recruited at 23 sites (33% females, mean age 55.7 ± 13.7 years, BMI 30.2 ± 6.3 kg/m2 , AHI 29.1 ± 22.3, and ODI 24.9 ± 21.4 events/h) had a mean ESS score in the mild to moderate excessive daytime sleepiness range (9.7 ± 4.9). The proportion of patients with excessive daytime sleepiness was 41.4% in men and 44.6% in women. Independent predictors of excessive daytime sleepiness included gender, age, and hypoxic markers (high ODI and low mean saturation). Univariate and multivariate analyses were used to identify significant predictors for the ESS score and for excessive daytime sleepiness (ESS ≥10) amongst anthropometric factors, sleep apnea frequency (apnea-hypopnea index (AHI)), markers of intermittent hypoxia (oxygen desaturation index (ODI), mean saturation (mSaO2 )), as well as prevalent comorbidities. Depression was associated with higher ESS scores and hypertension/atrial fibrillation with lower scores. The oxygen desaturation index provided a stronger predictor of excessive daytime sleepiness than the apnea-hypopnea index. The severity of obstructive sleep apnea, captured as the apnea-hypopnea index, was only weakly associated with daytime sleepiness in this representative obstructive sleep apnea patient cohort. Age had different effects in men and women.The impact of obstructive sleep apnea in a wider patient related perspective needs to be determined after the inclusion of factors other than the apnea-hypopnea index.

Ion concentrations in cerebrospinal fluid in wakefulness, sleep and sleep deprivation in healthy humans.

Sleep is controlled by a circadian rhythmicity, via a reduction of arousal-promoting neuromodulatory activity, and by accumulation of somnogenic factors in the interstitial fluid of the brain. Recent experiments in mice suggest that a reduced neuronal excitability caused by a reduced concentration of potassium in the brain, concomitant with an increased concentration of calcium and magnesium, constitutes an important mediator of sleep. In the present study, we examined whether such changes in ion concentrations could be detected in the cerebrospinal fluid of healthy humans. Each subject underwent cerebrospinal fluid collection at three occasions in a randomized order: at 15:00 hours-17:00 hours during waking, at 06:00 hours-07:00 hours immediately following 1 night of sleep, and at 06:00 hours-07:00 hours following 1 night of sleep deprivation. When compared with wakefulness, both sleep and sleep deprivation produced the same effect of a small (0.1 mm, about 3%), but robust and highly significant, reduction in potassium concentration. Calcium and magnesium concentrations were unchanged. Our results support a circadian modulation of neuronal excitability in the brain mediated via changes of the interstitial potassium concentration.

The Sleep Revolution project: the concept and objectives.

Obstructive sleep apnea is linked to severe health consequences such as hypertension, daytime sleepiness, and cardiovascular disease. Nearly a billion people are estimated to have obstructive sleep apnea with a substantial economic burden. However, the current diagnostic parameter of obstructive sleep apnea, the apnea-hypopnea index, correlates poorly with related comorbidities and symptoms. Obstructive sleep apnea severity is measured by counting respiratory events, while other physiologically relevant consequences are ignored. Furthermore, as the clinical methods for analysing polysomnographic signals are outdated, laborious, and expensive, most patients with obstructive sleep apnea remain undiagnosed. Therefore, more personalised diagnostic approaches are urgently needed. The Sleep Revolution, funded by the European Union's Horizon 2020 Research and Innovation Programme, aims to tackle these shortcomings by developing machine learning tools to better estimate obstructive sleep apnea severity and phenotypes. This allows for improved personalised treatment options, including increased patient participation. Also, implementing these tools will alleviate the costs and increase the availability of sleep studies by decreasing manual scoring labour. Finally, the project aims to design a digital platform that functions as a bridge between researchers, patients, and clinicians, with an electronic sleep diary, objective cognitive tests, and questionnaires in a mobile application. These ambitious goals will be achieved through extensive collaboration between 39 centres, including expertise from sleep medicine, computer science, and industry and by utilising tens of thousands of retrospectively and prospectively collected sleep recordings. With the commitment of the European Sleep Research Society and Assembly of National Sleep Societies, the Sleep Revolution has the unique possibility to create new standardised guidelines for sleep medicine.

New pharmacologic agents for obstructive sleep apnoea: what do we know and what can we expect?

PURPOSE OF REVIEW: This review provides a condensed description of pharmacological remedies explored in patients with obstructive sleep apnoea (OSA) as well as projections of what we might expect in terms of clinical performance of these drugs. RECENT FINDINGS: Conventional drug therapies explored in OSA have generally produced disappointing results and there is a shortage of pharmacological treatment alternatives in this disorder. Recent insights into pathophysiological mechanisms potentially involved in OSA suggest that the condition may be divided into distinct subgroups based on clusters or defined by means of unique functional endotypic criteria. In fact, positive outcomes in clinical trials have now resulted in several drug candidates that show a convincing reduction of sleep disordered breathing in both short and intermediate term. Such drugs may be particularly useful in certain variants of OSA but not in others. These insights have also raised the ambition to create personalized therapies in OSA. Another recent development is the insight that OSA-linked conditions such as obesity, daytime somnolence and various forms of cardiovascular/metabolic disease may provide drug-based targets. For instance, pharmacological obesity therapy may provide not only positive metabolic effects but may also be a way to eliminate the anatomic component in obese OSA patients. SUMMARY: Recent insights into the pathophysiology of OSA have opened possibilities to develop personalized therapy. Drugs addressing fundamental aspects of the sleep and breathing disorder provide a particularly promising avenue for development of novel forms of treatment in OSA.

Daridorexant, a New Dual Orexin Receptor Antagonist to Treat Insomnia Disorder.

OBJECTIVE: To evaluate the dose-response relationship of daridorexant, a new dual orexin receptor antagonist, on sleep variables in subjects with insomnia disorder. METHODS: Adults (≤64 years) with insomnia disorder were randomized (1:1:1:1:1:1) to receive daily oral placebo, daridorexant (5, 10, 25, or 50mg), or 10mg zolpidem for 30 days. The primary efficacy outcome was the change in wake time after sleep onset from baseline to days 1 and 2. Secondary outcome measures were change in latency to persistent sleep from baseline to days 1 and 2, change in subjective wake time after sleep onset, and subjective latency to sleep onset from baseline to week 4. Safety was also assessed. RESULTS: Of 1,005 subjects screened, 359 (64% female) were randomized and received ≥1 dose. A significant dose-response relationship (multiple comparison procedure-modeling, 2-sided p < 0.001) was found in the reduction of wake after sleep onset and latency to persistent sleep from baseline to days 1 and 2 with daridorexant. These reductions were sustained through to days 28 and 29 (p = 0.050 and p = 0.042, respectively). Similar dose-dependent relationships were observed for subjective wake after sleep onset and subjective latency to sleep onset. The incidence of treatment-emergent adverse events was 35%, 38%, 38%, and 34% in subjects treated with 5, 10, 25, and 50mg daridorexant, respectively, compared with 30% for placebo, and 40% for 10mg zolpidem. There were no clinically relevant treatment-related serious adverse events. Four subjects withdrew due to adverse events. INTERPRETATION: Daridorexant induced a dose-dependent reduction in wake time after sleep onset in subjects with insomnia disorder (Clinicaltrials.gov NCT02839200). Ann Neurol 2020;87:347-356.

Beyond the AHI-pulse wave analysis during sleep for recognition of cardiovascular risk in sleep apnea patients.

Recent evidence supports the use of pulse wave analysis during sleep for assessing functional aspects of the cardiovascular system. The current study compared the influence of pulse wave and sleep study-derived parameters on cardiovascular risk assessment. In a multi-centric study design, 358 sleep apnea patients (age 55 ± 13 years, 64% male, body mass index 30 ± 6 kg m-2 , apnea-hypopnea index 13 [5-26] events per hr) underwent a standard overnight sleep recording. A novel cardiac risk index was computed based on pulse wave signals derived from pulse oximetry, reflecting vascular stiffness, cardiac variability, vascular autonomic tone and nocturnal hypoxia. Cardiovascular risk was determined using the ESC/ESH cardiovascular risk matrix, and categorized to high/low added cardiovascular risk. Comparisons between cardiac risk index and sleep parameters were performed for cardiovascular risk prediction. Apnea-hypopnea index, oxygen desaturation index and cardiac risk index were associated with high cardiovascular risk after adjustment for confounders (p = .002, .001, < .001, respectively). In a nested reference model consisting of age, gender and body mass index, adding cardiac risk index but not apnea-hypopnea index or oxygen desaturation index significantly increased the area under the receiver operating characteristic curve (p = .012, .22 and .16, respectively). In a direct comparison of oxygen desaturation index and cardiac risk index, only the novel risk index had an independent effect on cardiovascular risk prediction (pCRI  < .001, pODI  = .71). These results emphasize the association between nocturnal pulse wave and overall cardiovascular risk determined by an established risk matrix. Thus, pulse wave analysis during sleep provides a powerful approach for cardiovascular risk assessment in addition to conventional sleep study parameters.

Impact of temperature on obstructive sleep apnoea in three different climate zones of Europe: Data from the European Sleep Apnoea Database (ESADA).

Recent studies indicate that ambient temperature may modulate obstructive sleep apnoea (OSA) severity. However, study results are contradictory warranting more investigation in this field. We analysed 19,293 patients of the European Sleep Apnoea Database (ESADA) cohort with restriction to the three predominant climate zones according to the Köppen-Geiger climate classification: Cfb (warm temperature, fully humid, warm summer), Csa (warm temperature, summer dry, hot summer), and Dfb (snow, fully humid, warm summer). Average outside temperature values were obtained and several hierarchical regression analyses were performed to investigate the impact of temperature on the apnea-hypopnea index (AHI), oxygen desaturation index (ODI), time of oxygen saturation <90% (T90) and minimum oxygen saturation (MinSpO2 ) after controlling for confounders including age, body mass index, gender, and air conditioning (A/C) use. AHI and ODI increased with higher temperatures with a standardised coefficient beta (ß) of 0.28 for AHI and 0.25 for ODI, while MinSpO2 decreased with a ß of -0.13 (all results p < .001). When adjusting for climate zones, the temperature effect was only significant in Cfb (AHI: ß = 0.11) and Dfb (AHI: ß = 0.08) (Model 1: p < .001). The presence of A/C (3.9% and 69.3% in Cfab and Csa, respectively) demonstrated only a minor increase in the prediction of the variation (Cfb: AHI, R2 +0.003; and Csa: AHI, R2 +0.007; both p < .001). Our present study indicates a limited but consistent influence of environmental temperature on OSA severity and this effect is modulated by climate zones.

Positive airway pressure (PAP) treatment reduces glycated hemoglobin (HbA1c) levels in obstructive sleep apnea patients with concomitant weight loss: Longitudinal data from the ESADA.

Patients with obstructive sleep apnea (OSA) are at increased risk of developing metabolic disease such as diabetes. The effects of positive airway pressure on glycemic control are contradictory. We therefore evaluated the change in glycated hemoglobin (HbA1c) in a large cohort of OSA patients after long-term treatment with positive airway pressure. HbA1c levels were assessed in a subsample of the European Sleep Apnea Database [n=1608] at baseline and at long-term follow up with positive airway pressure therapy (mean 378.9±423.0 days). In a regression analysis, treatment response was controlled for important confounders. Overall, HbA1c decreased from 5.98±1.01% to 5.93±0.98% (p=0.001). Patient subgroups with a more pronounced HbA1c response included patients with diabetes (-0.15±1.02, p=0.019), those with severe OSA baseline (-0.10±0.68, p=0.005), those with morbid obesity (-0.20±0.81, p<0.001). The strongest HbA1c reduction was observed in patients with a concomitant weight reduction >5 kilos (-0.38±0.99, p<0.001). In robust regression analysis, severe OSA (p=0.038) and morbid obesity (p=0.005) at baseline, and weight reduction >5 kilos (p<0.001) during follow up were independently associated with a reduction of HbA1c following PAP treatment. In contrast, PAP treatment alone without weight reduction was not associated with significant Hb1Ac reduction. In conclusion, positive airway pressure therapy is associated with HbA1c reduction in patients with severe OSA, in morbidly obese patients. and most obviously in those with significant weight lost during the follow-up. Our study underlines the importance to combine positive airway pressure use with adjustments in lifestyle to substantially modify metabolic complications in OSA.

Clusters of sleep apnoea phenotypes: A large pan-European study from the European Sleep Apnoea Database (ESADA).

BACKGROUND AND OBJECTIVE: To personalize OSA management, several studies have attempted to better capture disease heterogeneity by clustering methods. The aim of this study was to conduct a cluster analysis of 23 000 OSA patients at diagnosis using the multinational ESADA. METHODS: Data from 34 centres contributing to ESADA were used. An LCA was applied to identify OSA phenotypes in this European population representing broad geographical variations. Many variables, including symptoms, comorbidities and polysomnographic data, were included. Prescribed medications were classified according to the ATC classification and this information was used for comorbidity confirmation. RESULTS: Eight clusters were identified. Four clusters were gender-based corresponding to 54% of patients, with two clusters consisting only of men and two clusters only of women. The remaining four clusters were mainly men with various combinations of age range, BMI, AHI and comorbidities. The preferred type of OSA treatment (PAP or mandibular advancement) varied between clusters. CONCLUSION: Eight distinct clinical OSA phenotypes were identified in a large pan-European database highlighting the importance of gender-based phenotypes and the impact of these subtypes on treatment prescription. The impact of cluster on long-term treatment adherence and prognosis remains to be studied using the ESADA follow-up data set.

Pitolisant for Daytime Sleepiness in Patients with Obstructive Sleep Apnea Who Refuse Continuous Positive Airway Pressure Treatment. A Randomized Trial.

Rationale: Excessive daytime sleepiness is a common disabling symptom in obstructive sleep apnea syndrome.Objectives: To evaluate the efficacy and safety of pitolisant, a selective histamine H3 receptor antagonist with wake-promoting effects, for the treatment of daytime sleepiness in patients with moderate to severe obstructive sleep apnea refusing continuous positive airway pressure treatment.Methods: In an international, multicenter, double-blind, randomized (3:1), placebo-controlled, parallel-design trial, pitolisant was individually titrated at up to 20 mg/d over 12 weeks. The primary endpoint was the change in the Epworth Sleepiness Scale score. Key secondary endpoints were maintenance of wakefulness assessed on the basis of the Oxford Sleep Resistance test, safety, Clinical Global Impression of severity, patient's global opinion, EuroQol quality-of-life questionnaire, and Pichot fatigue questionnaire.Measurements and Main Results: A total of 268 patients with obstructive sleep apnea (75% male; mean age, 52 yr; apnea-hypopnea index, 49/h; baseline sleepiness score, 15.7) were randomized (200 to pitolisant and 68 to placebo) and analyzed on an intention-to-treat basis. The Epworth Sleepiness Scale score was reduced more with pitolisant than with placebo (-2.8; 95% confidence interval, -4.0 to -1.5; P < 0.001). Wake maintenance tests were not improved. The Pichot fatigue score was reduced with pitolisant. The overall impact of pitolisant was confirmed by both physicians' and patients' questionnaires. Adverse event incidence, mainly headache, insomnia, nausea, and vertigo, was similar in the pitolisant and placebo groups (29.5% and 25.4%, respectively), with no cardiovascular or other significant safety concerns.Conclusions: Pitolisant significantly reduced self-reported daytime sleepiness and fatigue and improved patient-reported outcomes and physician disease severity assessment in sleepy patients with obstructive sleep apnea refusing or nonadherent to continuous positive airway pressure.Clinical trial registered with www.clinicaltrials.gov (NCT01072968) and EU Clinical Trials Register (EudraCT 2009-017251-94).

Carbonic anhydrase, obstructive sleep apnea and hypertension: Effects of intervention.

Whole blood carbonic anhydrase activity (CAa) is increased in patients with obstructive sleep apnea (OSA). Our study investigated the influence of positive airway pressure (PAP) or CA inhibitor acetazolamide (ACT) therapy on CAa, OSA and blood pressure. Thirty-three OSA patients (21 hypertensive, body mass index (BMI) 37 ± 7 kg/m2 and apnea-hypopnea index (AHI) of 47 ± 31 events/hr) were followed-up after PAP treatment (compliance, 4.7 ± 1.5 hr/day; duration, median 6 [IQR 6,6] months) (Cohort A). A second OSA Cohort (B) contained nine hypertensive patients (BMI, 29 ± 4 kg/m2 ; AHI, 39 ± 20 events/hr) with 2-week treatment of ACT, PAP or ACT + PAP in an open crossover study. CAa was assessed at baseline and at the end of each treatment period. In Cohort A, baseline CAa was higher in hypertensive, compared with normotensive, patients (1,033 ± 204 versus 861 ± 201 units, p = .028). PAP treatment reduced systolic/diastolic blood pressure but not CAa (-9 ± 11/-5 ± 7 mmHg and -20 ± 289 units, p < .001, <.001 and .70). In Cohort B, blood pressure was reduced in both ACT-treated groups (-10 ± 10/-5 ± 7 mmHg, p = .043 and .019; and -5 ± 5/-13 ± 13 mmHg, p < .001 and .009). AHI was reduced in both groups: ACT only, -17 ± 9 events/hr p = .001; and ACT + PAP, -39 ± 19 events/hr, p < .001. PAP did not change CAa (p = .98) but activity tended to decrease after ACT with or without PAP (p = .081 and .056). CAa is elevated in hypertensive OSA patients. Long-term PAP reduced blood pressure without affecting CAa. ACT reduced blood pressure and CAa. Increased CAa may constitute a physiological characteristic in OSA, contributing to comorbid hypertension.

Periodic limb movements during sleep and blood pressure changes in sleep apnoea: Data from the European Sleep Apnoea Database.

BACKGROUND AND OBJECTIVE: OSA and PLMS are known to induce acute BP swings during sleep. Our current study aimed to address the independent effect of PLMS on BP in an unselected OSA patient cohort. METHODS: This cross-sectional analysis included 1487 patients (1110 males, no previous hypertension diagnosis or treatment, mean age: 52.5 years, mean BMI: 30.5 kg/m2 ) with significant OSA (defined as AHI ≥ 10) recruited from the European Sleep Apnoea Cohort. Patients underwent overnight PSG. Patients were stratified into two groups: patients with significant PLMS (PLMSI > 25 events/hour of sleep) and patients without significant PLMS (PLMSI < 25 events/hour of sleep). SBP, DBP and PP were the variables of interest. For each of these, a multivariate regression linear model was fitted to evaluate the relationship between PLMS and outcome adjusting for sociodemographic and clinical covariates (gender, age, BMI, AHI, ESS, diabetes, smoking and sleep efficiency). RESULTS: The univariate analysis of SBP showed an increment of BP equal to 4.70 mm Hg (P < 0.001) in patients with significant PLMS compared to patients without significant PLMS. This increment remained significant after implementing a multivariate regression model (2.64 mm Hg, P = 0.044). No significant increment of BP was observed for DBP and PP. CONCLUSION: PLMS is associated with a rise in SBP regardless of AHI, independent of clinical and sociodemographic confounders. A PLMS phenotype may carry an increased risk for cardiovascular disease in OSA patients.

Chronic pulmonary disease is associated with pain spreading and restless legs syndrome in middle-aged women-a population-based study.

INTRODUCTION: Recent studies suggest an increased prevalence of chronic pain conditions and restless legs syndrome (RLS) in patients with chronic pulmonary disease (CPD). We analyzed the prevalence and risk factors for pain and RLS in a population-based sample of females with comorbid CPD. METHOD: Questionnaire-based data from 2745 women aged 18-64 years were analyzed regarding comorbid CPD status (severe bronchitis, emphysema, asthma). Pain status was assessed according to symptoms reflecting severity (Visual Analogue Scale, VAS rating 0-10) and duration and spreading (limited spread or widespread) of pain. A diagnosis of RLS was defined by four validated diagnostic criteria. Anthropometrics and co-morbidities were assessed as covariates in univariate and multivariate analyses. RESULTS: Widespread pain was overrepresented in women with CPD (44.6 vs. 24.6%, p < 0.001). The odds ratio for widespread pain in women with CPD was 1.6 (95% confidence interval (CI) 1.2-2.2, p < 0.001) in the fully adjusted model. Severe pain (VAS rating ≥ 7) was more prevalent in females with known CPD (28.8 vs. 15.4%, p < 0.001, odd ratio 1.4 (95% CI 1.0-1.9, p = 0.029)). The prevalence of RLS was 37.4 and 23.8% in subjects with or without CPD, respectively (p < 0.001). In multivariate analysis, CPD was associated with a 30% risk increase for RLS (odds ratio 1.3 (95% CI 1.0-1.7, p = 0.04)). CONCLUSION: This population-based study identified CPD as an independent risk factor for severe and widespread pain as well as for RLS. Further research addressing pathophysiological mechanisms linking CPD and chronic pain conditions/RLS is warranted.

Insomnia and cardiorespiratory fitness in a middle-aged population: the SCAPIS pilot study.

BACKGROUND: The relationship between insomnia and cardiorespiratory fitness (CRF), a well-established risk factor for cardiovascular disease, has not been extensively studied. We aimed to assess the independent association between insomnia and CRF in a population-based cohort of subjects aged 50 to 64 years. METHODS: Subjects participating in the Swedish CArdioPulmonary bioImaging Study (SCAPIS) pilot cohort (n = 603, men 47.9%) underwent a submaximal cycle ergometer test for estimation of maximal oxygen consumption (VO2max). Data on physical activity and sedentary time were collected via waist-worn accelerometers. An insomnia severity index score ≥ 10 was used to define insomnia. RESULTS: Insomnia was identified in 31.8% of the population. The VO2max was significantly lower in insomnia subjects compared with the non-insomnia group (31.2 ± 6.3 vs. 32.4 ± 6.5 ml* kg-1 *min-1, p = 0.028). There was no difference in objectively assessed physical activity or time spent sedentary between the groups. In a multivariate generalized linear model adjusting for confounders, an independent association between insomnia status and lower VO2max was found in men, but not in women (ß = - 1.15 [95% CI - 2.23-- 0.06] and - 0.09 [- 1.09-0.92], p = 0.038 and 0.866, respectively). CONCLUSIONS: We found a modest, but significant, association between insomnia and lower CRF in middle-aged men, but not in women. Our results suggest that insomnia may link to cardiovascular disease via reduced CRF. Insomnia may require a specific focus in the context of health campaigns addressing CRF.

Challenges and perspectives in obstructive sleep apnoea: Report by an ad hoc working group of the Sleep Disordered Breathing Group of the European Respiratory Society and the European Sleep Research Society.

Obstructive sleep apnoea (OSA) is a major challenge for physicians and healthcare systems throughout the world. The high prevalence and the impact on daily life of OSA oblige clinicians to offer effective and acceptable treatment options. However, recent evidence has raised questions about the benefits of positive airway pressure therapy in ameliorating comorbidities.An international expert group considered the current state of knowledge based on the most relevant publications in the previous 5 years, discussed the current challenges in the field, and proposed topics for future research on epidemiology, phenotyping, underlying mechanisms, prognostic implications and optimal treatment of patients with OSA.The group concluded that a revision to the diagnostic criteria for OSA is required to include factors that reflect different clinical and pathophysiological phenotypes and relevant comorbidities (e.g. nondipping nocturnal blood pressure). Furthermore, current severity thresholds require revision to reflect factors such as the disparity in the apnoea-hypopnoea index (AHI) between polysomnography and sleep studies that do not include sleep stage measurements, in addition to the poor correlation between AHI and daytime symptoms such as sleepiness. Management decisions should be linked to the underlying phenotype and consider outcomes beyond AHI.

Certification of fitness to drive in sleep apnea patients: Are we doing the right thing?

New European Union (EU) regulations state that untreated moderate to severe obstructive sleep apnea (OSA) coincident with excessive daytime sleepiness (EDS) constitutes a medical disorder leading to unfitness to drive. However, fitness to drive can be re-established by successful treatment of OSA and EDS. The aim of the current study was to compare patients undergoing the certification process with those of an unselected OSA patient cohort. The study compared consecutive patients in the certification group (n = 132) with a representative group of OSA patients with a current driving license and an Apnea Hypopnea Index (AHI) ≥ 15 n/h (n = 790). The adherence to positive airway pressure (PAP) therapy and the change in EDS (Epworth Sleepiness Scale [ESS] score) with treatment were analysed. Patient characteristics and severity of sleep apnea did not differ significantly between groups (certification/reference group: BMI 30 ± 5/31 ± 5 kg/m2 , AHI 33 ± 20/36 ± 20 n/hr, ESS 12 ± 6/11 ± 5). However, the certification group was oversampled with elderly drivers (70-85 years: 22% vs. 9%, p = 0.001). PAP compliance was higher in the certification group than in the reference group (PAP use ≥ 4 hr/night in 96% vs. 53%, p = 0.001) and mean ESS reduction was -8.0 (-8.9 - -7.1) versus -4.0 (-4.4 - -3.5), respectively (p < 0.001). Patients attending the fitness to drive evaluation reported almost complete adherence to continuous positive airway pressure (CPAP) and elimination of EDS symptoms. Besides possible baseline differences, this strong response may be explained by factors such as a selection process of elderly patients, a self-rating component in the assessment of the treatment response and the threat of a driving license suspension. Our data suggest that an improved certification process with objective rather than subjective components, along with a reduced selection bias, is warranted.

Change in weight and central obesity by positive airway pressure treatment in obstructive sleep apnea patients: longitudinal data from the ESADA cohort.

The effect of positive airway pressure treatment on weight and markers of central obesity in patients with obstructive sleep apnea remains unclear. We studied the change in body weight and anthropometric measures following positive airway pressure treatment in a large clinical cohort. Patients with obstructive sleep apnea with positive airway pressure treatment from the European Sleep Apnea Database registry (n = 1,415, 77% male, age 54 ± 11 [mean ± SD] years, body mass index 31.7 ± 6.4 kg/m2 , apnea-hypopnea index 37 ± 24 n per hr, Epworth Sleepiness Scale 10.2 ± 5.0) were selected. Changes in body mass index and neck/waist/hip circumferences at baseline and at follow-up visit were analysed. Overall, body mass index (0.0 [95% confidence interval, -0.1 to 0.2] kg/m2 ) and neck circumference (0.0 (95% confidence interval, -0.1 to 0.1] cm) were unchanged after positive airway pressure treatment compared with baseline (follow-up duration 1.1 ± 1.0 years and compliance 5.2 ± 2.1 hr per day). However, in non-obese (body mass index <30 kg/m2 ) patients, positive airway pressure treatment was associated with an increased body mass index and waist circumference (0.4 [0.3-0.5] kg/m2 and 0.8 [0.4-1.2] cm, respectively, all p < 0.05), and weight gain was significantly associated with higher positive airway pressure compliance and longer positive airway pressure treatment duration. In the obese subgroup, body mass index was reduced after positive airway pressure treatment (-0.3 [-0.5 to -0.1] kg/m2 , p < 0.05) mainly in patients with a strong reduction in Epworth Sleepiness Scale. In conclusion, positive airway pressure therapy was not found to systematically change body mass index in the European Sleep Apnea Database cohort, but the response was heterogeneous. Our findings suggest that weight gain may be restricted to an obstructive sleep apnea phenotype without established obesity. Lifestyle intervention needs to be considered in both lean and obese patients with obstructive sleep apnea receiving positive airway pressure treatment.