Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology and risk prediction.

Restless legs syndrome (RLS) affects up to 10% of older adults. Their healthcare is impeded by delayed diagnosis and insufficient treatment. To advance disease prediction and find new entry points for therapy, we performed meta-analyses of genome-wide association studies in 116,647 individuals with RLS (cases) and 1,546,466 controls of European ancestry. The pooled analysis increased the number of risk loci eightfold to 164, including three on chromosome X. Sex-specific meta-analyses revealed largely overlapping genetic predispositions of the sexes (rg = 0.96). Locus annotation prioritized druggable genes such as glutamate receptors 1 and 4, and Mendelian randomization indicated RLS as a causal risk factor for diabetes. Machine learning approaches combining genetic and nongenetic information performed best in risk prediction (area under the curve (AUC) = 0.82-0.91). In summary, we identified targets for drug development and repurposing, prioritized potential causal relationships between RLS and relevant comorbidities and risk factors for follow-up and provided evidence that nonlinear interactions are likely relevant to RLS risk prediction.

Post-COVID sequelae effect in chronic fatigue syndrome: SARS-CoV-2 triggers latent adenovirus in the oral mucosa.

The post-viral fatigue syndromes long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have multiple, potentially overlapping, pathological processes. These include persisting reservoirs of virus, e.g., SARS-CoV-2 in long COVID patient's tissues, immune dysregulation with or without reactivation of underlying pathogens, such as Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV6), as we recently described in ME/CFS, and possibly yet unidentified viruses. In the present study we tested saliva samples from two cohorts for IgG against human adenovirus (HAdV): patients with ME/CFS (n = 84) and healthy controls (n = 94), with either mild/asymptomatic SARS-CoV-2 infection or no infection. A significantly elevated anti-HAdV IgG response after SARS-CoV-2 infection was detected exclusively in the patient cohort. Longitudinal/time analysis, before and after COVID-19, in the very same individuals confirmed HAdV IgG elevation after. In plasma there was no HAdV IgG elevation. We conclude that COVID-19 triggered reactivation of dormant HAdV in the oral mucosa of chronic fatigue patients indicating an exhausted dysfunctional antiviral immune response in ME/CFS, allowing reactivation of adenovirus upon stress encounter such as COVID-19. These novel findings should be considered in clinical practice for identification of patients that may benefit from therapy that targets HAdV as well.

Evolution of sleep-disordered breathing and blood pressure during menopausal transition.

The purpose of this study was to investigate how the blood pressure increase observed during menopausal transition is affected by sleep-disordered breathing and the menopause itself. Further, we aimed to find new sleep-disordered breathing related markers that would predict the development of hypertension. Sixty-four community-dwelling premenopausal women aged 45-47 years were studied. Polysomnography, serum follicle stimulating hormone, forced expiratory volume in 1 s, and a physical examination were performed at baseline and again after 10 years of follow-up. Indices for sleep apnea/hypopnea and inspiratory flow-limitation were determined. Regression models were used to study the relationships between variables. Changes in the apnea-hypopnea index or serum follicle stimulating hormone were not significant for blood pressure change. An increase in morning blood pressure during the follow-up period was associated with a body mass-index increase. An increase in evening blood pressure was associated with an increase in inspiratory flow-limitation during non-rapid eye movement sleep. Incident hypertension during the follow-up was associated with hypopnea (median hypopnea index 7.6/h, p = 0.048) during rapid eye movement sleep at baseline. Users of menopausal hormone therapy had a lower rapid eye movement sleep apnea-hypopnea index (1.6/h vs. 6.9/h, p = 0.026) at baseline whereas at follow-up users and non-users did not differ in any way. The progression of menopause or the use of menopausal hormone therapy had a minimal effect on blood pressure in our population. The effects of inspiratory flow-limitation on blood pressure profile should be studied further.

Effect of menopause and age on vascular impairment.

AIMS: The prevalence of cardiovascular diseases increases in women after menopause. The aim of the study was to determine the impact of conventional cardiovascular risk factors such as age, blood pressure, smoking, cholesterol, obesity, and glucose balance, but also menopausal state and sleep-disordered breathing on vascular impairment during menopausal transition. METHODS: 89 women initiated the study and 74 of them participated in the 10-year follow-up. Cardiovascular disease risk factor assessments, ultrasound measurements of brachial artery function, including nitroglycerin-mediated vasodilatation and flow-mediated endothelium-dependent vasodilation, and sleep studies were repeated at baseline and at 5-year and 10-year follow-ups. RESULTS: Over the study period, all the cardiovascular disease risk estimates increased. Both flow-mediated endothelium-dependent vasodilatation (decline 55 %) and nitroglycerin-mediated vasodilatation (decline 18 %) worsened over the 10 years (p < 0.001). Vascular function was not associated with menopausal state (determined with follicle stimulating hormone). Systolic blood pressure (p = 0.009) and smoking (p = 0.006) at baseline were negatively associated with nitroglycerin-mediated vasodilatation at 5-year follow-up and the use of hormonal therapy at 5-year follow-up was positively associated with concurrent nitroglycerin-mediated vasodilatation (p = 0.041). Intermittent nocturnal hypoxemia at baseline was associated with flow-mediated endothelium-dependent vasodilatation at 10-year follow-up (p = 0.043). High body mass index and impaired glucose balance at 5-year follow-up were associated with nitroglycerin-mediated vasodilatation decline at 10-year follow-up (p = 0.022 and p = 0.037, respectively). CONCLUSIONS: We demonstrate how cardiovascular risk factors and vascular function evolve during menopausal transition. Although menopause was not associated with vascular impairment, short-term improvement in vascular function was observed in those using menopausal hormonal therapy. Intermittent nocturnal hypoxemia, obesity and impaired glucose control are early predictors of vascular decline during postmenopause.

Saliva antibody-fingerprint of reactivated latent viruses after mild/asymptomatic COVID-19 is unique in patients with myalgic-encephalomyelitis/chronic fatigue syndrome.

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic disease considered to be triggered by viral infections in a majority of cases. Symptoms overlap largely with those of post-acute sequelae of COVID-19/long-COVID implying common pathogenetic mechanisms. SARS-CoV-2 infection is risk factor for sustained latent virus reactivation that may account for the symptoms of post-viral fatigue syndromes. The aim of this study was first to investigate whether patients with ME/CFS and healthy donors (HDs) differed in their antibody response to mild/asymptomatic SARS-CoV-2 infection. Secondly, to analyze whether COVID-19 imposes latent virus reactivation in the cohorts. Methods: Anti-SARS-CoV-2 antibodies were analyzed in plasma and saliva from non-vaccinated ME/CFS (n=95) and HDs (n=110) using soluble multiplex immunoassay. Reactivation of human herpesviruses 1-6 (HSV1, HSV2, VZV, EBV, CMV, HHV6), and human endogenous retrovirus K (HERV-K) was detected by anti-viral antibody fingerprints in saliva. Results: At 3-6 months after mild/asymptomatic SARS-CoV-2 infection, virus-specific antibodies in saliva were substantially induced signifying a strong reactivation of latent viruses (EBV, HHV6 and HERV-K) in both cohorts. In patients with ME/CFS, antibody responses were significantly stronger, in particular EBV-encoded nuclear antigen-1 (EBNA1) IgG were elevated in patients with ME/CFS, but not in HDs. EBV-VCA IgG was also elevated at baseline prior to SARS-infection in patients compared to HDs. Conclusion: Our results denote an altered and chronically aroused anti-viral profile against latent viruses in ME/CFS. SARS-CoV-2 infection even in its mild/asymptomatic form is a potent trigger for reactivation of latent herpesviruses (EBV, HHV6) and endogenous retroviruses (HERV-K), as detected by antibody fingerprints locally in the oral mucosa (saliva samples). This has not been shown before because the antibody elevation is not detected systemically in the circulation/plasma.

Early signs of sleep-disordered breathing in healthy women predict carotid intima-media thickening after 10 years.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in women. The risk of CVD increases in women after menopause. The aim was to study how sleep parameters and cardiovascular risk factors in 46-year-old women predict future carotid intima-media thickness (IMT) 10 years after. METHODS: Prospective study of 92 healthy women, aged 46 years, were studied at baseline and at 10-year follow-up. Polysomnography for sleep and breathing; blood samples for cholesterol, glucose and follicle stimulating hormone; blood pressure (BP), weight and height measurements; questionnaires for background variables and vasomotor symptoms were carried out at both time points. Carotid ultrasound was scanned for IMT at 10-year follow-up. RESULTS: After adjusting for conventional risk factors, apnea-hypopnea index (AHI) during rapid-eye-movement (REM) sleep was the only parameter at baseline that predicted IMT 10 years after (IMT mean: ß 81.4 [95% CI, 14.0-148.8]; IMT max: ß 104.7 [95% CI, 15.4-194.1]). At 10-year follow-up, higher arousal index (IMT mean: ß 55.6 [95% CI, 19.5-91.8]; IMT max ß 59.9 [95% CI, 11.4-108.4]) and lower vasomotor symptoms (IMT max: ß -60.5 [95% CI, -119.0 to -2.0]) were associated with concurrent higher IMT. The conventional risk factors at baseline did not associate with future IMT but 10 years after higher concurrent HbA1c (IMT mean: ß 11.0 [95% CI, 3.4-18.5]; IMT max ß 14.0 [95% CI, 4.1-23.8]) and systolic BP (IMT mean: ß 2.4 [95% CI, 1.1-3.7]; IMT max: ß 2.7 [95% CI, 1.03 to 4.53]) were associated with higher IMT. CONCLUSIONS: In healthy 46-year-old women, AHI during REM sleep predicted IMT 10 years after. The conventional risk factors (HbA1c and BP) only associated with the concurrent IMT at 10-year follow-up.

European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE): Expert Consensus on the Diagnosis, Service Provision, and Care of People with ME/CFS in Europe.

Designed by a group of ME/CFS researchers and health professionals, the European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE) has received funding from the European Cooperation in Science and Technology (COST)-COST action 15111-from 2016 to 2020. The main goal of the Cost Action was to assess the existing knowledge and experience on health care delivery for people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in European countries, and to enhance coordinated research and health care provision in this field. We report our findings and make recommendations for clinical diagnosis, health services and care for people with ME/CFS in Europe, as prepared by the group of clinicians and researchers from 22 countries and 55 European health professionals and researchers, who have been informed by people with ME/CFS.

Mood, sleepiness, and weight gain after three years on CPAP therapy for sleep apnoea.

Background: The prevalence of obstructive sleep apnoea syndrome (OSAS) keeps on rising. Daytime sleepiness resulting from fragmented sleep is the prime symptom, and obesity the major risk factor for OSAS. Quality of life with OSAS is often affected by depressive symptoms and anxiety. Nasal continuous positive airway pressure (CPAP) therapy reduces daytime sleepiness, but the results on the effect on mood, physical activity, and weight are controversial especially on long-term therapy. Purpose of this study was to evaluate these factors and predictors of weight gain during long-term CPAP therapy. Methods: Consecutive patients (n = 223), referred to sleep study with suspected OSAS, were enrolled. Patients underwent a cardiorespiratory polygraphy at baseline and a battery of questionnaires was completed, both at baseline, and after three years of follow-up. Total of 149 (67%; M 65, F 84) patients completed the follow-up. Of the 149 patients, 76 (51.0%; M 32, F 44) used CPAP. Results: In this study, depressive symptoms, anxiety, and sleepiness were alleviated during CPAP therapy. However, therapy did not have an influence on cravings of different food categories, or exercise habits and exercise duration. From the various factors studied, solely higher adherence to CPAP therapy was associated with weight gain. Conclusions: This research provides further evidence that long-term CPAP therapy in patients with OSAS not only decreases sleepiness and improves sleep quality but could also alleviate depressive symptoms and anxiety. In addition, our study reinforces that CPAP therapy alone is not sufficient for weight management in patients with OSAS. Regardless of comprehensive battery of questionnaires, we were unable to establish markers predicting weight gain during therapy. We advise on life-style counselling and weight management program to all patients with obesity on CPAP therapy.

Sleep during menopausal transition: a 10-year follow-up.

STUDY OBJECTIVES: A 10-year observational follow-up study to evaluate the changes in sleep architecture during the menopausal transition. METHODS: Fifty-seven premenopausal women (mean age 46 years, SD 0.9) were studied at baseline and after a 10-year follow-up. At both time points, polysomnography (PSG) was performed, and the serum follicle-stimulating hormone (S-FSH) concentration was measured. Linear regression models were used to study the effects of aging and menopause (assessed as change in S-FSH) on sleep. RESULTS: After controlling for body mass index, vasomotor, and depressive symptoms, higher S-FSH level was associated with longer sleep latency (B 0.45, 95% confidence interval [CI]: 0.07 to 0.83). Aging of 10 years was associated with shorter sleep latency (B -46.8, 95% CI: -77.2 to -16.4), shorter latency to stage 2 sleep (B -50.6, 95% CI: -85.3 to -15.9), decreased stage 2 sleep (B -12.4, 95% CI: -21.4 to -3.4), and increased slow-wave sleep (B 12.8, 95% CI: 2.32 to 23.3) after controlling for confounding factors. CONCLUSIONS: This study suggests that PSG measured sleep of middle-aged women does not worsen over a 10-year time span due to the menopausal transition. The observed changes seem to be rather age- than menopause-dependent.

Gender-specific change in leptin concentrations during long-term CPAP therapy.

PURPOSE: Nasal continuous positive airway pressure (CPAP) alleviates sleepiness in patients with obstructive sleep apnoea syndrome (OSAS), but part of OSAS patients keep gaining weight. Leptin and insulin-like growth factor-1 (IGF-1) interact with energy balance, and CPAP therapy has been suggested to influence these endocrine factors. We hypothesised that leptin would decrease during long-term CPAP therapy, and weight gain would associate with OSAS severity, lower CPAP adherence, lower IGF-1, and leptin concentrations. METHODS: Consecutive patients (n = 223) referred to sleep study with suspected OSAS were enrolled. Patients underwent cardiorespiratory polygraphy at baseline. Questionnaires were completed, and blood samples were drawn both at baseline and after 3 years. A total of 149 (67%; M 65, F 84) patients completed the follow-up. Plasma samples were available from 114 patients, 109 of which with CPAP adherence data (49 CPAP users, 60 non-users). RESULTS: At baseline, the CPAP users were more obese and had more severe OSAS than the non-users. Leptin concentrations did not differ. After follow-up, leptin concentrations were higher in CPAP users (30.2 ng/ml vs. 16.8 ng/ml; p = 0.001). In regression analysis, increase in leptin concentrations was independent of age, baseline body mass index (BMI), or the change in BMI. Leptin concentrations increased among females (- 8.9 vs. 12.7 ng/ml; p < 0.001); whereas in men, CPAP did not have an effect, if not opposed the natural decrease in leptin observed in men not using CPAP. Change in IGF-1 levels did not differ. CONCLUSIONS: Our results suggest increase in leptin concentrations during long-term CPAP therapy among females.

Alterations in heart rate variability in patients with peripheral arterial disease requiring surgical revascularization have limited association with postoperative major adverse cardiovascular and cerebrovascular events.

OBJECTIVE: Obstructive sleep apnea (OSA) is common in peripheral arterial disease (PAD) and associates with high mortality after surgery. Since abnormal heart rate variability (HRV) is predictive of postoperative complications, we investigated the relations of HRV with PAD, OSA and major adverse cardiovascular and cerebrovascular events (MACCE). MATERIALS AND METHODS: Seventy-five patients (67±9 years) scheduled for sub-inguinal revascularization and 15 controls (63±6 years) underwent polysomnography and HRV analyses. OSA with an apnea-hypopnea index (AHI) ≥20/hour was considered significant. HRV was measured during wakefulness, S2, S3-4 and rapid eye movement (REM) sleep with time and frequency domain methods including beat-to-beat variability, low frequency (LF) and high frequency (HF) power, and detrended fluctuation analysis (DFA). MACCE was defined as cardiac death, myocardial infarction, coronary revascularization, hospitalized angina pectoris and stroke. RESULTS: Thirty-six patients (48%) had AHI≥20/hour. During follow-up (median 52 months), 22 patients (29%) suffered a MACCE. Compared to controls, fractal correlation of HRV (scaling exponent alpha 1 measured with DFA) was weaker during S2 and evening wakefulness in all subgroups (+/-AHI≥20/hour, +/-MACCE) but only in patients with AHI≥20/hour during morning wakefulness. The LF/HF ratio was lower in all subgroups during S2 but only in patients with AHI ≥20/hour during evening or morning wake. In the covariance analysis adjusted for age, body mass index, coronary artery disease and PAD duration, the alpha 1 during morning wakefulness remained significantly lower in patients with AHI≥20/hour than in those without (1.12 vs. 1.45; p = 0.03). Decreased HF during REM (p = 0.04) and S3-4 sleep (p = 0.03) were predictive of MACCE. In analyses with all sleep stages combined, mean heart rate as well as very low frequency, LF, HF and total power were associated with OSA of mild-to-moderate severity (AHI 10-20/hour). CONCLUSIONS: HRV is altered in patients with PAD. These alterations have a limited association with OSA and MACCE.

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.

Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis.

BACKGROUND: Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets. METHODS: In the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15 126 cases and 95 725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p≤5 × 10-8) were tested for replication in an independent GWAS of 30 770 cases and 286 913 controls, followed by a joint analysis of the discovery and replication stages. We did gene annotation, pathway, and gene-set-enrichment analyses and studied the genetic correlations between restless legs syndrome and traits of interest. FINDINGS: We identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. MEIS1 was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1·92, 95% CI 1·85-1·99). Gene prioritisation, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1). INTERPRETATION: Identification of new candidate genes and associated pathways will inform future functional research. Advances in understanding of the molecular mechanisms that underlie restless legs syndrome could lead to new treatment options. We focused on common variants; thus, additional studies are needed to dissect the roles of rare and structural variations. FUNDING: Deutsche Forschungsgemeinschaft, Helmholtz Zentrum München-Deutsches Forschungszentrum für Gesundheit und Umwelt, National Research Institutions, NHS Blood and Transplant, National Institute for Health Research, British Heart Foundation, European Commission, European Research Council, National Institutes of Health, National Institute of Neurological Disorders and Stroke, NIH Research Cambridge Biomedical Research Centre, and UK Medical Research Council.

QT interval variability index and QT interval duration during different sleep stages in patients with obstructive sleep apnea.

OBJECTIVES: The aim of the study was to investigate the impact of obstructive sleep apnea (OSA) on the QT interval variability and duration in patients during different sleep stages. METHODS: Polysomnographic recordings of 28 (13 male, 15 female) patients with OSA and 30 (15 male, 15 female) patients without OSA were analyzed. The QT interval variability index (QTVI) and the corrected QT interval (QTc) analyses were performed using two awake, 3-4 non-rapid eye movement (NREM) and three rapid eye movement (REM) sleep episodes (each 300 s). The Bazett formula, linear, and parabolic heart rate correction formulas with two separate α values were used. RESULTS: QTVI was statistically higher in OSA than in non-OSA patients for males while awake (awake -0.7 ± 0.3 vs -1.2 ± 0.2, p = 0.001; NREM ‒0.9 ± 0.4 vs -1.1 ± 0.3, p = 0.110; REM ‒1.1 ± 0.3 vs -1.3 ± 0.2, p = 0.667) and for females in all wake-sleep stages (awake -0.3 ± 0.7 vs -0.9 ± 0.5, p = 0.001; NREM ‒0.3 ± 0.5 vs -0.8 ± 0.4, p = 0.002; REM -0.3 ± 0.5 vs -1.0 ± 0.4, p < 0.001). QTVI was significantly higher during awake compared to sleep stages in OSA males (p < 0.05); no difference between wake-sleep stages was found in females (p > 0.05). Significant gender differences in QTVI existed in OSA patients during sleep (p < 0.05) but not while awake. No significant differences in QTc between patients groups were observed. CONCLUSIONS: OSA is associated with increased QT variability. REM sleep per se does not increase QTVI. In OSA patients, QTVI might be a more useful measure to detect ventricular repolarization abnormality than measures of QTc.

Upper-airway flow limitation and transcutaneous carbon dioxide during sleep in normal pregnancy.

OBJECTIVE: Sleep during pregnancy involves a physiological challenge to provide sufficient gas exchange to the fetus. Enhanced ventilatory responses to hypercapnia and hypoxia may protect from deficient gas exchange, but sleep-disordered breathing (SDB) may predispose to adverse events. The aim of this study was to analyze sleep and breathing in healthy pregnant women compared to non-pregnant controls, with a focus on CO2 changes and upper-airway flow limitation. METHODS: Healthy women in the third trimester and healthy non-pregnant women with normal body mass index (BMI) were recruited for polysomnography. Conventional analysis of sleep and breathing was performed. Transcutaneous carbon dioxide (TcCO2) was determined for each sleep stage. Flow-limitation was analyzed using the flattening index and TcCO2 values were recorded for every inspiration. RESULTS: Eighteen pregnant women and 12 controls were studied. Pregnancy was associated with shorter sleep duration and more superficial sleep. Apnea-hypopnea index, arterial oxyhemoglobin desaturation, flow-limitation, snoring or periodic leg movements were similar in the two groups. Mean SaO2 and minimum SaO2 were lower and average heart rate was higher in the pregnant group. TcCO2 levels did not differ between groups but variance of TcCO2 was smaller in pregnant women during non-rapid eye movement (NREM). TcCO2 profiles showed transient TcCO2 peaks, which seem specific to pregnancy. CONCLUSIONS: Healthy pregnancy does not predispose to SDB. Enhanced ventilatory control manifests as narrowing threshold of TcCO2 between wakefulness and sleep. Pregnant women have a tendency for rapid CO2 increases during sleep which might have harmful consequences if not properly compensated.

Efficacy and safety of almorexant in adult chronic insomnia: a randomized placebo-controlled trial with an active reference.

BACKGROUND AND OBJECTIVES: The orally active dual OX1R and OX2R antagonist, almorexant, targets the orexin system for the treatment of primary insomnia. This clinical trial assessed the effect of almorexant on sleep maintenance and other sleep endpoints, and its safety and tolerability in adults. PATIENTS AND METHODS: Prospective, randomized, double-blind, placebo-controlled, active referenced trial in male and female adults aged 18-64 years with chronic, primary insomnia. Patients were randomized 1:1:1:1 to receive placebo, almorexant 100 mg, almorexant 200 mg, or zolpidem 10 mg (active reference) for 16 days. Primary efficacy assessments were objective (polysomnography-measured) and subjective (patient-recorded) wake time after sleep onset (WASO). Further sleep variables were also evaluated. RESULTS: From 709 randomized patients, 707 (mean age 45.4 years; 61.7% female) received treatment and 663 (93.8%) completed the study. A significant decrease versus placebo in median objective WASO was observed with almorexant 200 mg at the start and end of randomized treatment (-26.8 min and -19.5 min, respectively; both p < 0.0001); subjective WASO also decreased over the two-week treatment period (p = 0.0006). Objective and subjective total sleep time (TST) were increased with almorexant 200 mg (p < 0.0001). Almorexant 200 mg significantly reduced objective and subjective latency to persistent sleep and latency to sleep onset at initiation of therapy, and provided longer duration of sleep stages with no suppression of slow-wave sleep. No impaired next-day performance, rebound insomnia, or withdrawal effects were observed. Adverse events were similar with almorexant and placebo. CONCLUSION: Almorexant reduced time to sleep onset and maintained sleep without residual effects on next-day performance or safety concerns. This study provides further support for the role of the endogenous orexin system in insomnia disorder. CLINICALTRIALS. GOV REGISTRATION: NCT00608985.

An Official American Thoracic Society Workshop Report: Noninvasive Identification of Inspiratory Flow Limitation in Sleep Studies.

This report summarizes the proceedings of the American Thoracic Society Workshop on the Noninvasive Identification of Inspiratory Flow Limitation in Sleep Studies held on May 16, 2015, in Denver, Colorado. The goal of the workshop was to discuss methods for standardizing the scoring of flow limitation from nasal cannula pressure tracings. The workshop began with presentations on the physiology underlying flow limitation, existing methods of scoring flow limitation, the effects of signal acquisition and filtering on flow shapes, and a review of the literature examining the adverse outcomes related to flow limitation. After these presentations, the results from online scoring exercises, which were crowdsourced to workshop participants in advance of the workshop, were reviewed and discussed. Break-out sessions were then held to discuss potential algorithms for scoring flow limitation. Based on these discussions, subsequent online scoring exercises, and webinars after the workshop, a consensus-based set of recommendations for a scoring algorithm for flow limitation was developed. Key conclusions from the workshop were: (1) a standardized and automated approach to scoring flow limitation is needed to provide a metric of nonepisodic elevated upper airway resistance, which can then be related to clinical outcomes in large cohorts and patient groups; (2) at this time, the most feasible method for standardization is by proposing a consensus-based framework, which includes scoring rules, developed by experts (3) hardware and software settings of acquisition devices, including filter settings, affect the shape of the flow curve, and should be clearly specified; and (4) a priority for future research is the generation of an open-source, expert-derived training set to encourage and support validation of automated flow limitation scoring algorithms.

Sleep During Menopausal Transition: A 6-Year Follow-Up.

Study Objectives: Menopausal transition is associated with increased dissatisfaction with sleep, but the effects on sleep architecture are conflicting. This prospective 6-year follow-up study was designed to evaluate the changes in sleep stages and sleep continuity that occur in women during menopausal transition. Methods: Sixty women (mean age 46.0 years, SD 0.9) participated. All women were premenopausal at baseline, and at the 6-year follow-up, women were in different stages of menopausal transition. Polysomnography was used to study sleep architecture at baseline and follow-up. The effects of aging and menopause (assessed as change in serum follicle-stimulating hormone [S-FSH]) on sleep architecture were evaluated using linear regression models. Results: After controlling for body mass index, vasomotor, and depressive symptoms, aging of 6 years resulted in shorter total sleep time (B -37.4, 95% confidence interval [CI] -71.5 to (-3.3)), lower sleep efficiency (B -6.5, 95%CI -12.7 to (-0.2)), as well as in increased transitions from slow-wave sleep (SWS) to wakefulness (B 1.0, 95%CI 0.1 to 1.9), wake after sleep onset (B 37.7, 95%CI 12.5 to 63.0), awakenings per hour (B 1.8, 95%CI 0.8 to 2.8), and arousal index (B 2.3, 95%CI 0.1 to 4.4). Higher S-FSH concentration in menopausal transition was associated with increased SWS (B 0.09, 95%CI 0.01 to 0.16) after controlling for confounding factors. Conclusions: A significant deterioration in sleep continuity occurs when women age from 46 to 52 years, but change from premenopausal to menopausal state restores some SWS.