Automatic quantification of REM sleep without atonia reliably identifies patients with REM sleep behavior disorder: a possible screening tool?

BACKGROUND: REM Sleep Behavior Disorder (RBD) is characterized by absence of physiological muscle atonia during REM sleep (REM sleep without atonia, RWA). Nigro-striatal dopaminergic impairment is a feature of Parkinson disease (PD) and can be identified in prodromal stages as well, such as idiopathic RBD (iRBD). Aims of this study are to explore the efficacy of an automatic RWA quantification in identifying RBD patients and the correlation between RWA and nigro-striatal dopaminergic function. METHODS: Forty-five iRBD, 46 PD with RBD, 24 PD without RBD patients and 11 healthy controls were enrolled in the Genoa Center (group A) and 25 patients with iRBD (group B) were enrolled in the Danish Center. Group A underwent brain [123I]FP-CIT-SPECT and group B underwent brain [18F]PE2I-PET as measures of nigro-striatal dopaminergic function. Chin muscle activity was recorded in all subjects and analyzed by applying a published automatic algorithm. Correlations between RWA and nigro-striatal dopaminergic function were explored. RESULTS: The automatic quantification of RWA significantly differentiated RBD from non-RBD subjects (AUC = 0.86), although with lower accuracy compared with conventional visual scoring (AUC = 0.99). No significant correlation was found between RWA and nigro-striatal dopaminergic function. CONCLUSION: The automatic quantification of RWA is a reliable tool to identify subjects with RBD and may be used as a first-line screening tool, but without correlations with nigro-striatal dopaminergic functioning.

The Ultra-Long-Term Sleep study: Design, rationale, data stability and user perspective.

Sleep deprivation and poor sleep quality are significant societal challenges that negatively impact individuals' health. The interaction between subjective sleep quality, objective sleep measures, physical and cognitive performance, and their day-to-day variations remains poorly understood. Our year-long study of 20 healthy individuals, using subcutaneous electroencephalography, aimed to elucidate these interactions, assessing data stability and participant satisfaction, usability, well-being and adherence. In the study, 25 participants were fitted with a minimally invasive subcutaneous electroencephalography lead, with 20 completing the year of subcutaneous electroencephalography recording. Signal stability was measured using covariance of variation. Participant satisfaction, usability and well-being were measured with questionnaires: Perceived Ease of Use questionnaire, System Usability Scale, Headache questionnaire, Major Depression Inventory, World Health Organization 5-item Well-Being Index, and interviews. The subcutaneous electroencephalography signals remained stable for the entire year, with an average participant adherence rate of 91%. Participants rated their satisfaction with the subcutaneous electroencephalography device as easy to use with minimal or no discomfort. The System Usability Scale score was high at 86.3 ± 10.1, and interviews highlighted that participants understood how to use the subcutaneous electroencephalography device and described a period of acclimatization to sleeping with the device. This study provides compelling evidence for the feasibility of longitudinal sleep monitoring during everyday life utilizing subcutaneous electroencephalography in healthy subjects, showcasing excellent signal stability, adherence and user experience. The amassed subcutaneous electroencephalography data constitutes the largest dataset of its kind, and is poised to significantly advance our understanding of day-to-day variations in normal sleep and provide key insights into subjective and objective sleep quality.

Real-world impact of continuous positive airway pressure on sleepiness in patients with obstructive sleep apnea in a national registry.

OBJECTIVE: Excessive daytime sleepiness (EDS) persists in some patients with obstructive sleep apnea (OSA) despite continuous positive airway pressure (CPAP) treatment. This study characterized response to CPAP and factors associated with residual EDS. METHODS: Danish National Patient Registry data were analyzed. Patients with OSA diagnosis (1994-2016), Epworth Sleepiness Scale (ESS) scores and apnea-hypopnea index recorded before beginning CPAP (baseline) and after 1-13 months of CPAP use, and CPAP adherence were included. Odds ratios (OR) for residual EDS after CPAP treatment were estimated using multivariate logistic regression. RESULTS: Of 1174 patients (mean age, 57 years; 75.5% male), 41.1% had baseline EDS (mild, 13.2%; moderate, 14.0%; severe, 13.9%); 58.9% did not. After CPAP treatment, follow-up mean ESS scores were normal (≤10) for all baseline EDS subgroups; however, 15.6% (n = 183) of patients had residual EDS (mild, 6.7%; moderate, 5.5%; severe, 3.4%). Odds of residual EDS were higher for patients with mild (OR, 5.2; 95% confidence interval [CI], 3.2-8.6), moderate (OR, 4.5; 95% CI, 2.7-7.4), and severe (OR, 13.0; 95% CI, 8.0-21.2) EDS at baseline compared with those with normal daytime sleepiness at baseline. Patients adherent with CPAP use were 38.2% less likely to have residual EDS compared with nonadherent patients (OR, 0.62; 95% CI, 0.43-0.88). CONCLUSIONS: EDS was common in this cohort of Danish patients with OSA. Baseline EDS severity predicted higher odds of residual EDS. After CPAP treatment, adherence was associated with reduced odds of residual EDS, but EDS persisted in a subgroup of patients.

Sleep disorders and sleep disturbances in persons with multiple sclerosis: A population-based matched case-control study in Denmark.

Introduction Adverse sleep is common in multiple sclerosis (MS). Population-based studies including adequate control groups are lacking. We hypothesized that the prevalence of sleep disorders and other sleep disturbances would be higher in persons with MS than in controls. Methods We conducted a population-based study linking individual-level data from the Danish MS Registry (n=21,943 persons with MS) and the Danish Population Registry (n=109,715 matched controls) with information on sleep disorders from the Danish National Patient Registry and other sleep disturbances assessed by dispensed prescription drugs from the Danish National Prescription Registry. Results Prevalence of diagnosed sleep disorders in terms of central hypersomnia (0.15% vs. 0.06%), sleep disturbances (1.05% vs. 0.70%), and sleep movements (0.22% vs. 0.13%) and other sleep disturbances identified by dispensed central acting (10.73% vs. 1.10%) and hypnotic use (30.65% vs. 20.13%) medication was statistically significantly higher among persons with MS when compared to controls. We found no statistically significant difference in the prevalence of sleep apnea and parasomnia between groups. Stratified by sex and age at MS diagnosis, results for differences between persons with MS and controls were similar. Conclusion In this registry-based study, we found that the prevalence of several diagnosed sleep disorders was higher persons with MS than in controls, that is those reflecting insomnia and daytime symptoms including hypersomnia. Other sleep disturbances identified by dispensed prescription medication was markedly higher in persons with MS than controls.

Lifestyle and demographic associations with 47 inflammatory and vascular stress biomarkers in 9876 blood donors.

BACKGROUND: The emerging use of biomarkers in research and tailored care introduces a need for information about the association between biomarkers and basic demographics and lifestyle factors revealing expectable concentrations in healthy individuals while considering general demographic differences. METHODS: A selection of 47 biomarkers, including markers of inflammation and vascular stress, were measured in plasma samples from 9876 Danish Blood Donor Study participants. Using regression models, we examined the association between biomarkers and sex, age, Body Mass Index (BMI), and smoking. RESULTS: Here we show that concentrations of inflammation and vascular stress biomarkers generally increase with higher age, BMI, and smoking. Sex-specific effects are observed for multiple biomarkers. CONCLUSION: This study provides comprehensive information on concentrations of 47 plasma biomarkers in healthy individuals. The study emphasizes that knowledge about biomarker concentrations in healthy individuals is critical for improved understanding of disease pathology and for tailored care and decision support tools.

Blood-based biomarkers are circulating molecules that can help to indicate health or disease. Biomarker levels may vary depending on demographic and lifestyle factors such as age, sex, smoking status, and body mass index. Here, we examine the effects of these demographic and lifestyle factors on levels of biomarkers related to activation of the immune system and cardiovascular stress. Measurements of 47 different proteins were performed on blood samples from nearly 10,000 healthy Danish blood donors. Measurement data were linked with questionnaire data to assess effects of lifestyle. We found that immune activation and vascular stress generally increased with age, BMI, and smoking. As these measurements are from healthy blood donors they can serve as a reference for expectable effects and inflammation levels in healthy individuals. Knowledge about the healthy state is important for understanding disease progression and optimizing care.

A deep transfer learning approach for sleep stage classification and sleep apnea detection using wrist-worn consumer sleep technologies.

Obstructive sleep apnea (OSA) is a common, underdiagnosed sleep-related breathing disorder with serious health implications Objective - We propose a deep transfer learning approach for sleep stage classification and sleep apnea (SA) detection using wrist-worn consumer sleep technologies (CST). Methods - Our model is based on a deep convolutional neural network (DNN) utilizing accelerometers and photo-plethysmography signals from nocturnal recordings. The DNN was trained and tested on internal datasets that include raw data from clinical and wrist-worn devices; external validation was performed on a hold-out test dataset containing raw data from a wrist-worn CST. Results - Training on clinical data improves performance significantly, and feature enrichment through a sleep stage stream gives only minor improvements. Raw data input outperforms feature-based input in CST datasets. The system generalizes well but performs slightly worse on wearable device data compared to clinical data. However, it excels in detecting events during REM sleep and is associated with arousal and oxygen desaturation. We found; cases that were significantly underestimated were characterized by fewer of such event associations. Conclusion - This study showcases the potential of using CSTs as alternate screening solution for undiagnosed cases of OSA. Significance - This work is significant for its development of a deep transfer learning approach using wrist-worn consumer sleep technologies, offering comprehensive validation for data utilization, and learning techniques, ultimately improving sleep apnea detection across diverse devices.

CD11c+ B cells in relapsing-remitting multiple sclerosis and effects of anti-CD20 therapy.

OBJECTIVES: B cells are important in the pathogenesis of multiple sclerosis. It is yet unknown which subsets may be involved, but atypical B cells have been proposed as mediators of autoimmunity. In this study, we investigated differences in B-cell subsets between controls and patients with untreated and anti-CD20-treated multiple sclerosis. METHODS: We recruited 155 participants for an exploratory cohort comprising peripheral blood and cerebrospinal fluid, and a validation cohort comprising peripheral blood. Flow cytometry was used to characterize B-cell phenotypes and effector functions of CD11c+ atypical B cells. RESULTS: There were no differences in circulating B cells between controls and untreated multiple sclerosis. As expected, anti-CD20-treated patients had a markedly lower B-cell count. Of B cells remaining after treatment, we observed higher proportions of CD11c+ B cells and plasmablasts. CD11c+ B cells were expanded in cerebrospinal fluid compared to peripheral blood in controls and untreated multiple sclerosis. Surprisingly, the proportion of CD11c+ cerebrospinal fluid B cells was higher in controls and after anti-CD20 therapy than in untreated multiple sclerosis. Apart from the presence of plasmablasts, the cerebrospinal fluid B-cell composition after anti-CD20 therapy resembled that of controls. CD11c+ B cells demonstrated a high potential for both proinflammatory and regulatory cytokine production. INTERPRETATION: The study demonstrates that CD11c+ B cells and plasmablasts are less efficiently depleted by anti-CD20 therapy, and that CD11c+ B cells comprise a phenotypically and functionally distinct, albeit heterogenous, B-cell subset with the capacity of exerting both proinflammatory and regulatory functions.

Fractional exhaled nitric oxide-a possible biomarker for risk of obstructive sleep apnea in snorers.

STUDY OBJECTIVES: Airway inflammation in patients with obstructive sleep apnea (OSA) has been described and can be assessed by measuring the biomarker fractional exhaled nitric oxide (FeNO). In this pilot study, we investigated FeNO measurements in identification of OSA among persons with snoring. METHODS: In this study we aimed to investigate (1) if FeNO could be used in screening for OSA, (2) if daytime sleepiness correlated to FeNO levels, and (3) whether asthma affected FeNO levels. Persons with snoring were prospectively included in three primary care ear, nose, and throat clinics. Patients underwent spirometry, FeNO tests, and partial polygraphy. They filled out questionnaires on sinonasal and asthma symptoms, daytime sleepiness, and quality of life. Current smokers, patients with upper airway inflammatory conditions, and patients treated with steroids were excluded. RESULTS: Forty-nine individuals were included. Median apnea-hypopnea index was 11.4, mean age was 50.9 years, and 29% were females. OSA was diagnosed in 73% of the patients of whom 53% had moderate-severe disease. Patients with moderate-severe OSA had significantly higher FeNO counts than patients with no or mild OSA (P = .024). Patients younger than 50 years with a FeNO below 15 had the lowest prevalence of moderate-severe OSA. No correlation was found between FeNO measurements and daytime sleepiness, and asthma did not affect FeNO levels. CONCLUSIONS: We found a low prevalence of moderate-severe OSA in persons with snoring when FeNO and age were low. This might be considered in a future screening model, though further studies testing the FeNO cutoff level and the diagnostic accuracy are warranted. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: NO Measurements in Screening for Asthma and OSA, in Patients With Severe Snoring; URL: https://clinicaltrials.gov/study/NCT03964324; Identifier: NCT03964324. CITATION: Kiaer E, Ravn A, Jennum P, et al. Fractional exhaled nitric oxide-a possible biomarker for risk of obstructive sleep apnea in snorers. J Clin Sleep Med. 2024;20(1):85-92.

Fully Automated Detection of Isolated Rapid-Eye-Movement Sleep Behavior Disorder Using Actigraphy.

Isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD) is caused by motor disinhibition during REM sleep and is a strong early predictor of Parkinson's disease. However, screening questionnaires for iRBD lack specificity due to other sleep disorders that mimic the symptoms. Nocturnal wrist actigraphy has shown promise in detecting iRBD by measuring sleep-related motor activity, but it relies on sleep diary-defined sleep periods, which are not always available. Our aim was to precisely detect iRBD using actigraphy alone by combining two actigraphy-based markers of iRBD - abnormal nighttime activity and 24-hour rhythm disruption. In a sample of 42 iRBD patients and 42 controls (21 clinical controls with other sleep disorders and 21 community controls) from the Stanford Sleep Clinic, the nighttime actigraphy model was optimized using automated detection of sleep periods. Using a subset of 38 iRBD patients with daytime data and 110 age-, sex-, and body-mass-index-matched controls from the UK Biobank, the 24-hour rhythm actigraphy model was optimized. Both nighttime and 24-hour rhythm features were found to distinguish iRBD from controls. To improve the accuracy of iRBD detection, we fused the nighttime and 24-hour rhythm disruption classifiers using logistic regression, which achieved a sensitivity of 78.9%, a specificity of 96.4%, and an AUC of 0.954. This study preliminarily validates a fully automated method for detecting iRBD using actigraphy in a general population.Clinical relevance- Actigraphy-based iRBD detection has potential for large-scale screening of iRBD in the general population.

The Role of Obstructive Sleep Apnea in Vision-Threatening Diabetic Retinopathy-A National Register-Based Study.

INTRODUCTION: we investigated the association between OSA and vision-threatening diabetic retinopathy (VTDR). METHODS: we used three nationwide registers to identify subjects with and without OSA and patients with type 1 (T1DM) or type 2 diabetes mellitus (T2DM). The Danish Civil Registration System was used to link OSA with diabetes diagnosis. The primary outcome was the occurrence of VTDR in diabetic patients with and without OSA. The secondary outcome was the prevalence of diabetes mellitus in patients with and without OSA. RESULTS: we included 532,828 diabetic subjects comprising 13,279 patients with OSA (2.5%) and 519,549 without OSA (97.5%). Diabetic patients with OSA had a 57% lower risk of VTDR compared to diabetic patients without OSA (OR 0.43, 95% CI 0.38-0.50, p < 0.0001). CONCLUSIONS: our findings indicate that OSA is associated with a lower risk of VTDR. Since we did not adjust our outcomes for diabetes duration, hypertension control and hemoglobin A1c, future studies are needed to confirm our findings.

Usage and impact of patient-reported outcomes in epilepsy.

BACKGROUND: The use of patient-reported outcomes (PRO) in clinical practice is gaining increasing attention. This study aimed to provide a critical assessment of the current state-of-the-art and beliefs about the use of PRO in the management of people with epilepsy across some European countries. METHODS: Structured interviews were conducted with European experts to collect insights about (I) the personal experience with PRO; (II) the value and impact of PRO in the decision-making process at the national level; and (III) the interest for and use of PRO by national health authorities. RESULTS: Nine neurologists (Austria, Belgium, Czechia, Denmark, France, Greece, Italy, Poland, and United Kingdom), three health economists (Portugal, Romania, and Sweden), and one epidemiologist (Slovakia) participated. They all stated that PRO are collected at their own countries in the context of clinical trials and/or specific projects. During everyday clinical practice, PRO are collected routinely/almost routinely in Austria and Sweden and only at the discretion of the treating physicians in Czechia, Denmark, France, Greece, and Portugal. There was complete consensus about the favorable impact that the PRO can have in terms of clinical outcomes, healthcare resources utilization, and general patient satisfaction. Only participants from Portugal and Sweden answered that the PRO are perceived as very important by the National Health Authorities of their respective countries. CONCLUSIONS: Differences exist in attitudes and perspectives about PRO in epilepsy across Europe. An active plan is warranted to harmonize the measurement of PRO and ensure they can be relevant to people with epilepsy and health services.

The European Insomnia Guideline: An update on the diagnosis and treatment of insomnia 2023.

Progress in the field of insomnia since 2017 necessitated this update of the European Insomnia Guideline. Recommendations for the diagnostic procedure for insomnia and its comorbidities are: clinical interview (encompassing sleep and medical history); the use of sleep questionnaires and diaries (and physical examination and additional measures where indicated) (A). Actigraphy is not recommended for the routine evaluation of insomnia (C), but may be useful for differential-diagnostic purposes (A). Polysomnography should be used to evaluate other sleep disorders if suspected (i.e. periodic limb movement disorder, sleep-related breathing disorders, etc.), treatment-resistant insomnia (A) and for other indications (B). Cognitive-behavioural therapy for insomnia is recommended as the first-line treatment for chronic insomnia in adults of any age (including patients with comorbidities), either applied in-person or digitally (A). When cognitive-behavioural therapy for insomnia is not sufficiently effective, a pharmacological intervention can be offered (A). Benzodiazepines (A), benzodiazepine receptor agonists (A), daridorexant (A) and low-dose sedating antidepressants (B) can be used for the short-term treatment of insomnia (≤ 4 weeks). Longer-term treatment with these substances may be initiated in some cases, considering advantages and disadvantages (B). Orexin receptor antagonists can be used for periods of up to 3 months or longer in some cases (A). Prolonged-release melatonin can be used for up to 3 months in patients ≥ 55 years (B). Antihistaminergic drugs, antipsychotics, fast-release melatonin, ramelteon and phytotherapeutics are not recommended for insomnia treatment (A). Light therapy and exercise interventions may be useful as adjunct therapies to cognitive-behavioural therapy for insomnia (B).

Validation of the newly developed Sleep Screening Questionnaire Children and Adolescents (SSQ-CA) with objective sleep measures.

OBJECTIVES: Objectively validated pediatric sleep questionnaires covering a broader age range and different sleep disturbances are lacking, therefore we developed the Sleep Screening Questionnaire Children and Adolescents (SSQ-CA) and compared it with objective sleep parameters. METHODS: This child-reported questionnaire was developed by a multidisciplinary panel and face validated. In a cross-sectional prospective design, participants aged 6-17, answered the questionnaire twice with 21-28 days in between, wore actigraphy (AG) and kept a sleep diary for seven nights and home-polysomnography (PSG) for one of these nights. Exploratory factor analyses (EFA), reliability and validity assessments were performed. RESULTS: Of the 139 participants, 128 (F:47.7%, AG: n = 128, PSG: n = 59), were included in the analyses. Mean age: 11.3 years (SD: 2.9). EFA revealed 11 factors and 40 items loading above r = 0.4. Subscale internal consistency: 0.54-0.92. Subscale test-retest reliability: r = 0.71-0.87. Total sleep time (TST) from SSQ-CA on weekdays correlated with PSG (r = 0.48, p = 0.001) and with AG (r = 0.75, p < 0.001). The subscale total score for "Sleep duration and latency" correlated with TST from AG (r = -0.19, p = 0.03) and sleep latency (r = 0.31, p < 0.001), but not for PSG variables. The subscale "Awakenings" showed no correlation with objective measures whereas "Circadian rhythm" correlated to AG-derived mid-sleep time (r = 0.34, p < 0.001). CONCLUSIONS: The SSQ-CA shows adequate reliability for the 6-17-year-olds and acceptable criterion validity for two subscales. It appears to be a useful tool for screening for sleep disturbances in combination with objective tools as the subjective and objective parameters seem to uncover different aspects of sleep.

Transient intracranial pressure elevations (B waves) are associated with sleep apnea.

BACKGROUND: Repetitive transient intracranial pressure waveform elevations up to 50 mmHg (ICP B-waves) are often used to define pathological conditions and determine indications for ICP-reducing treatment. We recently showed that nocturnal transient ICP elevations are present in patients without structural brain lesions or hydrocephalus in whom they are associated with sleep apnea. However, whether this signifies a general association between ICP macropatterns and sleep apnea remains unknown. METHODS: We included 34 patients with hydrocephalus, or idiopathic intracranial hypertension (IIH), who were referred to the Neurosurgical Department, Copenhagen, Denmark, from 2017 to 2021. Every patient underwent diagnostic overnight ICP monitoring for clinical indications, with simultaneous polysomnography (PSG) sleep studies. All transient ICP elevations were objectively quantified in all patients. Three patients were monitored with continuous positive airway pressure (CPAP) treatment for an additional night. RESULTS: All patients had transient ICP elevations associated with sleep apnea. The mean temporal delay from sleep apnea to transient ICP elevations for all patients was 3.6 s (SEM 0.2 s). Ramp-type transient ICP elevations with a large increase in ICP were associated with rapid eye movement (REM) sleep and sinusoidal-type elevations with non-REM (NREM) sleep. In three patients treated with CPAP, the treatment reduced the number of transient ICP elevations with a mean of 37%. CPAP treatment resulted in insignificant changes in the average ICP in two patients but elevated the average ICP during sleep in one patient by 5.6 mmHg. CONCLUSION: The findings suggest that sleep apnea causes a significant proportion of transient ICP elevations, such as B-waves, and sleep apnea should be considered in ICP evaluation. Treatment of sleep apnea with CPAP can reduce the occurrence of transient ICP elevations. More research is needed on the impact of slow oscillating mechanisms on transient ICP elevations during high ICP and REM sleep.

Repeated polysomnography and multiple sleep latency test in narcolepsy type 1 and other hypersomnolence disorders.

BACKGROUND: The diagnosis of narcolepsy is based on clinical information, combined with polysomnography (PSG) and the Multiple Sleep Latency Test (MSLT). PSG and the MSLT are moderately reliable at diagnosing narcolepsy type 1 (NT1) but unreliable for diagnosing narcolepsy type 2 (NT2). This is a problem, especially given the increased risk of a false-positive MSLT in the context of circadian misalignment or sleep deprivation, both of which commonly occur in the general population. AIM: We aimed to clarify the accuracy of PSG/MSLT testing in diagnosing NT1 versus controls without sleep disorders. Repeatability and reliability of PSG/MSLT testing and temporal changes in clinical findings of patients with NT1 versus patients with hypersomnolence with normal hypocretin-1 were compared. METHOD: 84 patients with NT1 and 100 patients with non-NT1-hypersomnolence disorders, all with congruent cerebrospinal fluid hypocretin-1 (CSF-hcrt-1) levels, were included. Twenty-five of the 84 NT1 patients and all the hypersomnolence disorder patients underwent a follow-up evaluation consisting of clinical assessment, PSG, and a modified MSLT. An additional 68 controls with no sleep disorders were assessed at baseline. CONCLUSION: Confirming results from previous studies, we found that PSG and our modified MSLT accurately and reliably diagnosed hypocretin-deficient NT1 (accuracy = 0.88, reliability = 0.80). Patients with NT1 had stable clinical and electrophysiological presentations over time that suggested a stable phenotype. In contrast, the PSG/MSLT results of patients with hypersomnolence, and normal CSF-hcrt-1 had poor reliability (0.32) and low repeatability.

Prevalence of sleep apnea in unselected patients with atrial fibrillation by a home-monitoring device: The DAN-APNO study.

Background: Sleep apnea (SA), a modifiable risk factor in - atrial fibrillation (AF), is associated with worse outcomes in AF. We aimed to assess the prevalence and severity of SA in patients with AF, and, subsequently, to assess the positive predictive value (PPV) of moderate to severe SA by a home-monitoring device in comparison to cardio-respiratory monitoring (CRM) in consecutive patients with AF. Methods: This cross-sectional study recruited unselected patients with AF without known SA from an out-patient clinic at Department of Cardiology, Herlev-Gentofte University Hospital. Participants underwent four consecutive nights of sleep-recording with the home-monitoring device NightOwl™ (NO). Moderate SA was defined as an Apnea-Hypopnea Index (AHI) of 15-29 and severe SA as ≥ 30 AHI. Participants with moderate to severe SA was offered CRM for validation of the diagnosis. Results: We included 126 patients with AF with a median age of 68 (interquartile range: 60-75) years, 42 (33 %) women, 70 (56 %) hypertension, 61 (48 %) hyperlipidemia and 49 (39 %) heart failure. NO detected severe SA in 36 (29 %) of patients with AF, moderate SA in 35 (28 %), mild SA in 45 (36 %) and no SA in 10 (8 %). Of 71 patients with moderate to severe SA by NO, 38 patients underwent CRM and the PPV of NO was 0.82 (31/38) to diagnose moderate SA and 0.92 (22/24) to diagnose severe SA by CRM. Conclusion: Moderate to severe SA by NO was highly prevalent in patients with AF without known SA. A home-monitoring device such as NO could be an easy and feasible SA screening tool in patients with AF.

The short-term and long-term adverse effects of melatonin treatment in children and adolescents: a systematic review and GRADE assessment.

Background: Currently, melatonin is used to treat children and adolescents with insomnia without knowing the full extent of the short-term and long-term consequences. Our aim was to provide clinicians and guideline panels with a systematic assessment of serious-and non-serious adverse events seen in continuation of melatonin treatment and the impact on pubertal development and bone health following long-term administration in children and adolescents with chronic insomnia. Methods: We searched PubMed, Embase, Cinahl and PsycINFO via Ovid, up to March 17, 2023, for studies on melatonin treatment among children and adolescents (aged 5-20 years) with chronic insomnia. The language was restricted to English, Danish, Norwegian, and Swedish. Outcomes were non-serious adverse events and serious adverse events assessed 2-4 weeks after initiating treatment and pubertal development and bone health, with no restriction on definition or time of measurement. Observational studies were included for the assessment of long-term outcomes, and serious and non-serious adverse events were assessed via randomised studies. The certainty of the evidence was assessed using Grades of Recommendation, Assessment, Development and Evaluation (GRADE). The protocol is registered with the Danish Health Authority. Findings: We identified 22 randomised studies with 1350 patients reporting on serious-and non-serious adverse events and four observational studies with a total of 105 patients reporting on pubertal development. Melatonin was not associated with serious adverse events, yet the number of patients experiencing non-serious adverse events was increased (Relative risk 1.56, 95% CI 1.01-2.43, 17 studies, I2 = 47%). Three studies reported little or no influence on pubertal development following 2-4 years of treatment, whereas one study registered a potential delay following longer treatment durations (>7 years). These findings need further evaluation due to several methodological limitations. Interpretation: Children who use melatonin are likely to experience non-serious adverse events, yet the actual extent to which melatonin leads to non-serious adverse events and the long-term consequences remain uncertain. This major gap of knowledge on safety calls for caution against complacent use of melatonin in children and adolescents with chronic insomnia and for more research to inform clinicians and guideline panels on this key issue. Funding: The Danish Health Authority. The Parker Institute, Bispebjerg and Frederiksberg Hospital, supported by the Oak Foundation.

Use of melatonin for children and adolescents with chronic insomnia attributable to disorders beyond indication: a systematic review, meta-analysis and clinical recommendation.

Background: Melatonin has become a widely used sleeping aid for young individuals currently not included in existing guidelines. The aim was to develop a recommendation on the use of melatonin in children and adolescents aged 2-20 years, with chronic insomnia due to disorders beyond indication. Methods: We performed a systematic search for guidelines, systematic reviews, and randomised trials (RCTs) in Medline, Embase, Cochrane Library, PsycInfo, Cinahl, Guidelines International Network, Trip Database, Canadian Agency for Drugs and Technologies in Health, American Academy of Sleep Medicine, European Sleep Research Society and Scandinavian Health Authorities databases. A separate search for adverse events was also performed. The latest search for guidelines, systematic reviews, and adverse events was performed on March 17, 2023. The latest search for RCTs was performed on to February 6, 2023. The language was restricted to English, Danish, Norwegian, and Swedish. Eligible participants were children and adolescents (2-20 years of age) with chronic insomnia due to underlying disorders, in whom sleep hygiene practices have been inadequate and melatonin was tested. Studies exclusively on autism spectrum disorders or attention deficit hyperactive disorder were excluded. There were no restrictions on dosage, duration of treatment, time of consumption or release formula. Primary outcomes were quality of sleep, daytime functioning and serious adverse events, assessed at 2-4 weeks post-treatment. Secondary outcomes included total sleep time, sleep latency, awakenings, drowsiness, quality of life, non-serious adverse events, and all-cause dropouts (assessed at 2-4 weeks post-treatment), plus quality of sleep and daytime functioning (assessed at 3-6 months post-treatment). Pooled estimates were calculated using inverse variance random effects model. Statistical heterogeneity was calculated using I2 statistics. Risk of bias was assessed using Cochrane risk of bias tool. Publication bias was assessed using funnel plots. A multidisciplinary guideline panel constructed the recommendation using Grades of Recommendation, Assessment, Development and Evaluation (GRADE). The certainty of evidence was considered either high, moderate, low or very low depending on the extent of risk of bias, inconsistency, imprecision, indirectness, or publication bias. The evidence-to-decision framework was used to discuss the feasibility and acceptance of the constructed recommendation and its impact on resources and equity. The protocol is registered with the Danish Health Authority. Findings: We identified 13 RCTs, including 403 patients with a wide range of conditions. Melatonin reduced sleep latency by 14.88 min (95% CI 23.42-6.34, 9 studies, I2 = 60%) and increased total sleep time by 18.97 min (95% CI 0.37-37.57, 10 studies, I2 = 57%). The funnel plot for total sleep time showed no apparent indication of publication bias. No other clinical benefits were found. The number of patients experiencing adverse events was not statistically increased however, safety data was scarce. Certainty of evidence was low. Interpretation: Low certainty evidence supports a moderate effect of melatonin in treating sleep continuity parameters in children and adolescents with chronic insomnia due to primarily medical disorders beyond indication. The off-label use of melatonin for these patients should never be the first choice of treatment, but may be considered by medical specialists with knowledge of the underlying disorder and if non-pharmacological interventions are inadequate. If treatment with melatonin is initiated, adequate follow-up to evaluate treatment effect and adverse events is essential. Funding: The Danish Health Authority. The Parker Institute, Bispebjerg and Frederiksberg Hospital, supported by the Oak Foundation.

Use of melatonin in children and adolescents with idiopathic chronic insomnia: a systematic review, meta-analysis, and clinical recommendation.

Background: Melatonin prescriptions for children and adolescents have increased substantially during the last decade. Existing clinical recommendations focus on melatonin as a treatment for insomnia related to neurodevelopmental disorders. To help guide clinical decision-making, we aimed to construct a recommendation on the use of melatonin in children and adolescents aged 5-20 years with idiopathic chronic insomnia. Methods: A systematic search for guidelines, systematic reviews and randomised controlled trials (RCT) were performed in Medline, Embase, Cochrane Library, PsycInfo, Cinahl, Guidelines International Network, Trip Database, Canadian Agency for Drugs and Technologies in Health, American Academy of Sleep Medicine, European Sleep Research Society and Scandinavian Health Authorities databases. A search for adverse events in otherwise healthy children and adolescents was also performed. The latest search for guidelines, systematic reviews, and adverse events was performed on March 18, 2023. The latest search for RCTs was performed on to February 6, 2023. The language was restricted to English, Danish, Norwegian, and Swedish. Eligible participants were children and adolescents (5-20 years of age) with idiopathic chronic insomnia, in whom sleep hygiene practices have been inadequate and melatonin was tested. There were no restrictions on dosage, duration of treatment, time of consumption, or release formula. Primary outcomes were quality of sleep, daytime functioning and serious adverse events. Secondary outcomes included total sleep time, sleep latency, awakenings, drowsiness, quality of life, all-cause dropouts, and non-serious adverse events. Outcomes were assessed at different time points to assess short-term and long-term effects. Meta-analysis was performed using inverse variance random-effects model and risk of bias was assessed using Cochrane risk of bias tool. If possible, funnel plots would be constructed to investigate publication bias. Heterogeneity was calculated via I2 statistics. A multidisciplinary guideline panel formulated the recommendation according to Grading of Recommendations Assessment, Development and Evaluation (GRADE). The certainty of evidence was considered either high, moderate, low or very low depending on the extent of risk of bias, inconsistency, imprecision, indirectness, or publication bias. The evidence-to-decision framework was subsequently used to discuss the feasibility and acceptance of the constructed recommendation alongside the impact on resources and equity. The protocol is registered with the Danish Health Authority. Findings: We included eight RCTs with 419 children and adolescents with idiopathic chronic insomnia. Melatonin led to a moderate increase in total sleep time by 30.33 min (95% confidence interval (CI) 18.96-41.70, 4 studies, I2 = 0%) and a moderate reduction in sleep latency by 18.03 min (95% CI -26.61 to -9.44, 3 studies, I2 = 0%), both as assessed by sleep diary. No other beneficial effects were found. None of the studies provided information on serious adverse events, yet the number of participants experiencing non-serious adverse events was increased (Relative risk 3.44, 95% CI 1.25-9.42, 4 studies, I2 = 0%). Funnel plots were not constructed due to the low number of studies. The certainty of evidence was very low on the quality of sleep and low for daytime functioning. Interpretation: Evidence of very low certainty shows that benefits are limited and unwanted events are likely when melatonin is used to treat otherwise healthy children and adolescents with chronic insomnia. Melatonin should never be the first choice of treatment for this particular population, yet carefully monitored short-term use may be considered if sleep hygiene practices and non-pharmacological interventions have proven inadequate, and only if daytime function is compromised. Funding: The Danish Health Authority and the Parker Institute, Bispebjerg and Frederiksberg Hospital supported by the Oak Foundation.