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BACKGROUND: Obstructive sleep apnea is characterized by disordered breathing during sleep and is associated with major cardiovascular complications; excess adiposity is an etiologic risk factor. Tirzepatide may be a potential treatment. METHODS: We conducted two phase 3, double-blind, randomized, controlled trials involving adults with moderate-to-severe obstructive sleep apnea and obesity. Participants who were not receiving treatment with positive airway pressure (PAP) at baseline were enrolled in trial 1, and those who were receiving PAP therapy at baseline were enrolled in trial 2. The participants were assigned in a 1:1 ratio to receive either the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or placebo for 52 weeks. The primary end point was the change in the apnea-hypopnea index (AHI, the number of apneas and hypopneas during an hour of sleep) from baseline. Key multiplicity-controlled secondary end points included the percent change in AHI and body weight and changes in hypoxic burden, patient-reported sleep impairment and disturbance, high-sensitivity C-reactive protein (hsCRP) concentration, and systolic blood pressure. RESULTS: At baseline, the mean AHI was 51.5 events per hour in trial 1 and 49.5 events per hour in trial 2, and the mean body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) was 39.1 and 38.7, respectively. In trial 1, the mean change in AHI at week 52 was -25.3 events per hour (95% confidence interval [CI], -29.3 to -21.2) with tirzepatide and -5.3 events per hour (95% CI, -9.4 to -1.1) with placebo, for an estimated treatment difference of -20.0 events per hour (95% CI, -25.8 to -14.2) (P<0.001). In trial 2, the mean change in AHI at week 52 was -29.3 events per hour (95% CI, -33.2 to -25.4) with tirzepatide and -5.5 events per hour (95% CI, -9.9 to -1.2) with placebo, for an estimated treatment difference of -23.8 events per hour (95% CI, -29.6 to -17.9) (P<0.001). Significant improvements in the measurements for all prespecified key secondary end points were observed with tirzepatide as compared with placebo. The most frequently reported adverse events with tirzepatide were gastrointestinal in nature and mostly mild to moderate in severity. CONCLUSIONS: Among persons with moderate-to-severe obstructive sleep apnea and obesity, tirzepatide reduced the AHI, body weight, hypoxic burden, hsCRP concentration, and systolic blood pressure and improved sleep-related patient-reported outcomes. (Funded by Eli Lilly; SURMOUNT-OSA ClinicalTrials.gov number, NCT05412004.).
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Poor sleep quality or sleep deprivation may be related to decreased bone mineral density. We aimed to assess whether associations of sleep characteristics and bone turnover or strength are present in adults from the general population and whether these are independent of common risk factors such as sex, age, and obesity. A total of 1037 participants from the Study of Health in Pomerania-TREND underwent laboratory-based polysomnography and quantitative ultrasound measurements at the heel. Of these participants, 804 completed standardised questionnaires to assess daytime sleepiness, insomnia, and sleep quality. Serum concentrations of two bone turnover markers, intact amino-terminal propeptide of type 1 procollagen (P1NP) and carboxy-terminal telopeptide of type 1 collagen (CTX) were measured. Cross-sectional associations of polysomnography variables (total sleep time, sleep efficiency, time spent wake after sleep onset, oxygen desaturation index, apnea-hypopnea index, and obstructive sleep apnea [OSA]), as well as sleep questionnaire scores with the bone turnover markers and the ultrasound-based stiffness index were assessed in linear regression models. In adjusted models, higher insomnia scores and lower sleep quality scores were related to a higher bone turnover in women but not in men. However, associations between polysomnography variables or questionnaire scores and the stiffness index were absent. Our study provides limited evidence for relationships between sleep characteristics and bone turnover and strength independent of common risk factors for OSA and osteoporosis. Nevertheless, women reporting poor sleep or insomnia in combination with risk factors for osteoporosis might benefit from an evaluation of bone health.
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Osteoporose , Apneia Obstrutiva do Sono , Distúrbios do Início e da Manutenção do Sono , Masculino , Adulto , Humanos , Feminino , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Estudos Transversais , Sono , Remodelação ÓsseaRESUMO
Obstructive sleep apnea is a highly prevalent sleep-related breathing disorder, resulting in a disturbed breathing pattern, changes in blood gases, abnormal autonomic regulation, metabolic fluctuation, poor neurocognitive performance, and increased cardiovascular risk. With broad inter-individual differences recognised in risk factors, clinical symptoms, gene expression, physiological characteristics, and health outcomes, various obstructive sleep apnea subtypes have been identified. Therapeutic efficacy and its impact on outcomes, particularly for cardiovascular consequences, may also vary depending on these features in obstructive sleep apnea. A number of interventions such as positive airway pressure therapies, oral appliance, surgical treatment, and pharmaceutical options are available in clinical practice. Selecting an effective obstructive sleep apnea treatment and therapy is a challenging medical decision due to obstructive sleep apnea heterogeneity and numerous treatment modalities. Thus, an objective marker for clinical evaluation is warranted to estimate the treatment response in patients with obstructive sleep apnea. Currently, while the Apnea-Hypopnea Index is used for severity assessment of obstructive sleep apnea and still considered a major guide to diagnosis and managements of obstructive sleep apnea, the Apnea-Hypopnea Index is not a robust marker of symptoms, function, or outcome improvement. Abnormal cardiac autonomic modulation can provide additional insight to better understand obstructive sleep apnea phenotyping. Heart rate variability is a reliable neurocardiac tool to assess altered autonomic function and can also provide cardiovascular information in obstructive sleep apnea. Beyond the Apnea-Hypopnea Index, this review aims to discuss the role of heart rate variability as an indicator and predictor of therapeutic efficacy to different modalities in order to optimise tailored treatment for obstructive sleep apnea.
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Sistema Nervoso Autônomo , Apneia Obstrutiva do Sono , Humanos , Frequência Cardíaca/fisiologia , Resultado do Tratamento , Fatores de RiscoRESUMO
Sleeping problems are prevalent among children and adolescents, often leading to frequent consultations with pediatricians. While cognitive-behavioral therapy has shown effectiveness, especially in the short term, there is a lack of globally endorsed guidelines for the use of pharmaceuticals or over-the-counter remedies in managing sleep onset insomnia. An expert panel of pediatric sleep specialists and chronobiologists met in October 2023 to develop practical recommendations for pediatricians on the management of sleep onset insomnia in typically developing children. When sleep onset insomnia is present in otherwise healthy children, the management should follow a stepwise approach. Practical sleep hygiene indications and adaptive bedtime routine, followed by behavioral therapies, must be the first step. When these measures are not effective, low-dose melatonin, administered 30-60 min before bedtime, might be helpful in children over 2 years old. Melatonin use should be monitored by pediatricians to evaluate the efficacy as well as the presence of adverse effects. Conclusion: Low-dose melatonin is a useful strategy for managing sleep onset insomnia in healthy children who have not improved or have responded insufficiently to sleep hygiene and behavioral interventions.
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Melatonina , Distúrbios do Início e da Manutenção do Sono , Humanos , Melatonina/uso terapêutico , Melatonina/administração & dosagem , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Distúrbios do Início e da Manutenção do Sono/terapia , Criança , Adolescente , Depressores do Sistema Nervoso Central/uso terapêutico , Depressores do Sistema Nervoso Central/administração & dosagem , Pré-Escolar , Europa (Continente) , Higiene do SonoRESUMO
Obstructive sleep apnea is known to be an overall public health problem that, among other things, increases morbidity and mortality. Risk factors as well as symptoms of this multidimensional sleep-related breathing disorder negatively affect quality of life. With our study we aimed to expose the association between obstructive sleep apnea and quality of life in the population of Pomerania, Germany. We utilized data from the population-based Study of Health in Pomerania (SHIP). Information on health status and risk factors about 4420 participants (2275 women) were gathered within the cohort SHIP-TREND, of which 1209 (559 women) underwent an overnight polysomnography and completed sleep questionnaires. The quality of life of the participants was measured using the Short-Form 12 questionnaire. For our study, an ordinal regression analysis with age, sex, body mass index and the Short-Form 12 health survey as predictors for apnea-hypopnea index was computed. The potential factors affecting quality of life are different between physical and mental dimensions of quality of life. Significant effects were found regarding age, sex, body mass index and the Short-Form 12 Mental Component Score, but not the Physical Component Score.
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Qualidade de Vida , Apneia Obstrutiva do Sono , Humanos , Feminino , Inquéritos e Questionários , Inquéritos Epidemiológicos , Índice de Massa CorporalRESUMO
Obstructive sleep apnea is a common disorder that leads to sleep fragmentation and is potentially bidirectionally related to a variety of comorbidities, including an increased risk of heart failure and stroke. It is often considered a consequence of anatomical abnormalities, especially in the head and neck, but its pathophysiology is likely to be multifactorial in origin. With geometric morphometrics, and a large sample of adults from the Study for Health in Pomerania, we explore the association of craniofacial morphology to the apnea-hypopnea index used as an estimate of obstructive sleep apnea severity. We show that craniofacial size and asymmetry, an aspect of morphological variation seldom analysed in obstructive sleep apnea research, are both uncorrelated to apnea-hypopnea index. In contrast, as in previous analyses, we find evidence that brachycephaly and larger nasal proportions might be associated to obstructive sleep apnea severity. However, this correlational signal is weak and completely disappears when age-related shape variation is statistically controlled for. Our findings suggest that previous work might need to be re-evaluated, and urge researchers to take into account the role of confounders to avoid potentially spurious findings in association studies.
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Craniossinostoses , Insuficiência Cardíaca , Apneia Obstrutiva do Sono , Adulto , Humanos , Apneia Obstrutiva do Sono/epidemiologia , Apneia Obstrutiva do Sono/etiologia , Comorbidade , Insuficiência Cardíaca/complicações , Pescoço , Craniossinostoses/complicaçõesRESUMO
Obstructive sleep apnea increases morbidity and mortality risks. The most common treatment is continuous positive airway pressure, with nasal mask usage being important, but not always optimal. While most research on treatment adherence focuses on the patient, the bed partner's involvement may be detrimental. Our study aim is to obtain a European-wide picture of the bed partner's attitude and support towards continuous positive airway pressure therapy, including effects on relationship satisfaction and intimacy. The English translation of a German bed partner questionnaire, assessing relationship satisfaction and three major components (general attitude, perceived mask looks, intimacy effects) was distributed within the European Sleep Apnea Database Network and translated in participating countries' local language. Data were collected for 2 years. In total, 10 European countries (13 sleep centres) participated with 1546 questionnaires. Overall, 91% of bed partners had a positive attitude towards continuous positive airway pressure therapy, 86% perceived mask looks not negative, 64% stated no negative intimacy effects. More specifically, 71% mentioned improved sleep quality, 68% supported nightly device usage. For 41% of bed partners, relationship satisfaction increased (no change for 47%). These results were significantly more pronounced in Eastern/Southern Europe compared with Middle Europe, especially regarding intimacy effects. However, increased continuous positive airway pressure therapy length affected attitude negatively. These results provide necessary information to improve treatment strategies by including educational couple-focused approaches. Among others, we revealed that negative intimacy effects are not considered a barrier to continuous positive airway pressure adherence. These results may inspire more research identifying regional gaps with need for treatment adjustments.
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Existing neuroimaging studies have reported divergent structural alterations in insomnia disorder (ID). In the present study, we performed a large-scale coordinated meta-analysis by pooling structural brain measures from 1085 subjects (mean [SD] age 50.5 [13.9] years, 50.2% female, 17.4% with insomnia) across three international Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA)-Sleep cohorts. Two sites recruited patients with ID/controls: Freiburg (University of Freiburg Medical Center, Freiburg, Germany) 42/43 and KUMS (Kermanshah University of Medical Sciences, Kermanshah, Iran) 42/49, while the Study of Health in Pomerania (SHIP-Trend, University Medicine Greifswald, Greifswald, Germany) recruited population-based individuals with/without insomnia symptoms 75/662. The influence of insomnia on magnetic resonance imaging-based brain morphometry using an insomnia brain score was then assessed. Within each cohort, we used an ordinary least-squares linear regression to investigate the link between the individual regional cortical and subcortical volumes and the presence of insomnia symptoms. Then, we performed a fixed-effects meta-analysis across cohorts based on the first-level results. For the insomnia brain score, weighted logistic ridge regression was performed on one sample (Freiburg), which separated patients with ID from controls to train a model based on the segmentation measurements. Afterward, the insomnia brain scores were validated using the other two samples. The model was used to predict the log-odds of the subjects with insomnia given individual insomnia-related brain atrophy. After adjusting for multiple comparisons, we did not detect any significant associations between insomnia symptoms and cortical or subcortical volumes, nor could we identify a global insomnia-related brain atrophy pattern. Thus, we observed inconsistent brain morphology differences between individuals with and without insomnia across three independent cohorts. Further large-scale cross-sectional/longitudinal studies using both structural and functional neuroimaging are warranted to decipher the neurobiology of insomnia.
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Distúrbios do Início e da Manutenção do Sono , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Estudos Transversais , Imageamento por Ressonância Magnética/métodos , Neuroimagem/métodos , Sono , Distúrbios do Início e da Manutenção do Sono/complicações , Distúrbios do Início e da Manutenção do Sono/diagnóstico por imagem , AdultoRESUMO
PURPOSE: Despite polysomnography being the gold standard method of diagnosing obstructive sleep apnea (OSA), it is time-consuming and has long waiting lists. Alternative methods including questionnaires and portable sleep devices have been developed to increase the speed of diagnosis. However, most questionnaires such as the STOP-BANG questionnaire (SBQ) are limited due to low specificity. This study evaluated the value of SBQ to screen for OSA and compared it with the oxygen desaturation index (ODI) and their combination. METHODS: This retrospective study included patients who completed the SBQ and underwent a night at the sleep lab or home sleep testing. The ODI was extracted from these sleep study reports. The combination of SBQ with ODI and their individual scores were compared with apnea-hypopnea index (AHI) in terms of their accuracy in diagnosing OSA. Sensitivity, specificity, and area under the curve (AUC) for different severities of OSA were calculated and compared. RESULTS: Among 132 patients, SBQ showed a sensitivity of 0.9 and a specificity of 0.3 to screen for OSA. As the severity of OSA increased, the sensitivity increased whilst specificity decreased for both measurements. ODI achieved an increased specificity of 0.8 and could correctly diagnose OSA 86% of the time which was better than SBQ's 60%. For all severities of OSA, ODI alone displayed a larger AUC than SBQ and similar AUC to their combination. CONCLUSION: ODI produced a higher specificity and AUC than SBQ. Furthermore, ODI combined with SBQ failed to increase diagnostic value. Therefore, ODI may be the preferred way to initially screen patients for OSA as an easy-to-use alternative compared to SBQ.
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Oxigênio , Apneia Obstrutiva do Sono , Humanos , Estudos Retrospectivos , Apneia Obstrutiva do Sono/diagnóstico , Apneia Obstrutiva do Sono/epidemiologia , Alemanha , Inquéritos e Questionários , Programas de Rastreamento/métodosRESUMO
PURPOSE: Socioeconomic factors are known to modulate health. Concerning sleep apnea, influences of income, education, work, and living in a partnership are established. However, results differ between national and ethnic groups. Results also differ between various clinical studies and population-based approaches. The goal of our study was to determine if such factors can be verified in the population of Pomerania, Germany. METHODS: A subgroup from the participants of the population-based Study of Health in Pomerania volunteered for an overnight polysomnography. Their data were subjected to an ordinal regressions analysis with age, sex, body mass index (BMI), income, education, work, and life partner as predictors for the apnea-hypopnea index. RESULTS: Among the subgroup (N = 1209) from the population-based study (N = 4420), significant effects were found for age, sex, and BMI. There were no significant effects for any of the socioeconomic factors. CONCLUSION: Significant effects for well-established factors as age, sex, and BMI show that our study design has sufficient power to verify meaningful associations with sleep apnea. The lack of significant effects for the socioeconomic factors suggests their clinical irrelevance in the tested population.
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Síndromes da Apneia do Sono , Apneia Obstrutiva do Sono , Humanos , Apneia Obstrutiva do Sono/diagnóstico , Apneia Obstrutiva do Sono/epidemiologia , Apneia Obstrutiva do Sono/complicações , Síndromes da Apneia do Sono/diagnóstico , Síndromes da Apneia do Sono/epidemiologia , Síndromes da Apneia do Sono/complicações , Fatores Socioeconômicos , Polissonografia/métodos , Alemanha , Índice de Massa CorporalRESUMO
PURPOSE: To analyze sleep characteristics as measured with polysomnography (PSG) in adults from the general population with and without physician-diagnosed atopic dermatitis (AD). METHODS: We analyzed data from participants from the German population-based Study of Health in Pomerania (SHIP) TREND-0. AD was diagnosed in a standardized skin examination. The following polysomnographic parameters were measured: total sleep duration (min), sleep latency (min), wake after sleep onset (WASO; min), rapid eye movement (REM) latency (min), sleep efficiency (%), total number of wakefulness and movement episodes, stages of sleep (%), and apnea-hypopnea index (AHI). Additionally, the subjective sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). We compared sleep characteristics of participants with and without AD. RESULTS: Among 1187 participants, 47 (4.0%) had AD. We found no differences between participants with and without AD in any of the analyzed PSG parameters except for the total number of wakefulness and movement episodes and the percentage of REM sleep. Participants with AD had a higher number of wakefulness and movement episodes, and a lower proportion of REM sleep compared to those without AD. Regarding subjective sleep parameters, no significant differences were found between participants with and without AD. CONCLUSION: Our data do not provide evidence for poor sleep quality in individuals with AD. Major limitations of the study include the unavailability of data on AD severity and the small number of participants with AD. Larger-scaled longitudinal studies considering disease severity and specific AD symptoms with an effect on sleep are required.
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PURPOSE: Diagnosis and treatment of obstructive sleep apnea are traditionally performed in sleep laboratories with polysomnography (PSG) and are associated with significant waiting times for patients and high cost. We investigated if initiation of auto-titrating CPAP (APAP) treatment at home in patients with obstructive sleep apnea (OSA) and subsequent telemonitoring by a homecare provider would be non-inferior to in-lab management with diagnostic PSG, subsequent in-lab APAP initiation, and standard follow-up regarding compliance and disease-specific quality of life. METHODS: This randomized, open-label, single-center study was conducted in Germany. Screening occurred between December 2013 and November 2015. Eligible patients with moderate-to-severe OSA documented by polygraphy (PG) were randomized to home management or standard care. All patients were managed by certified sleep physicians. The home management group received APAP therapy at home, followed by telemonitoring. The control group received a diagnostic PSG, followed by therapy initiation in the sleep laboratory. The primary endpoint was therapy compliance, measured as average APAP usage after 6 months. RESULTS: The intention-to-treat population (ITT) included 224 patients (110 home therapy, 114 controls); the per-protocol population (PP) included 182 patients with 6-month device usage data (89 home therapy, 93 controls). In the PP analysis, mean APAP usage at 6 months was not different in the home therapy and control groups (4.38 ± 2.04 vs. 4.32 ± 2.28, p = 0.845). The pre-specified non-inferiority margin (NIM) of 0.3 h/day was not achieved (p = 0.130); statistical significance was achieved in a post hoc analysis when NIM was set at 0.5 h/day (p < 0.05). Time to APAP initiation was significantly shorter in the home therapy group (7.6 ± 7.2 vs. 46.1 ± 23.8 days; p < 0.0001). CONCLUSION: Use of a home-based telemonitoring strategy for initiation of APAP in selected patients with OSA managed by sleep physicians is feasible, appears to be non-inferior to standard sleep laboratory procedures, and facilitates faster access to therapy.
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Apneia Obstrutiva do Sono/terapia , Telemetria , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Serviços de Assistência Domiciliar , Humanos , Laboratórios , Masculino , Pessoa de Meia-Idade , Sono , Resultado do Tratamento , Adulto JovemRESUMO
The novel coronavirus disease-2019 (COVID-19) and the ensuing pandemic have greatly impacted the global healthcare system due to its high infectiousness, associated high mortality, and a complete lack of immunity in the population. Globally, the COVID-19 pandemic has unleashed a health crisis that has not only seriously disrupted people's lives but also affected their normal sleep, along with physical and mental health; this situation is especially exacerbated in people suffering from pre-existing conditions, such as sleep apnea. A recent meta-analysis of 18 studies by Miller et al. (September 2020) showed that obstructive sleep apnea (OSA) is related to higher mortality and morbidity in patients with COVID-19 and is most likely independent of other risk factors. A recent meta-analysis indicated that COVID-19 patients with OSA are more severely affected than those without OSA, thereby providing further evidence that concurrent OSA may elevate the severity of COVID-19 infection, along with the risk of mortality. The COVID-19 pandemic has significantly impacted the diagnosis and therapeutic management of patients with OSA. Thus, it is necessary to identify and develop new diagnostic and therapeutic avenues in the future. In this context, the current study summarizes known associations between COVID-19 and OSA and the regular diagnostic and therapeutic strategies for OSA in the light of COVID-19 pandemic prevention and control.
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COVID-19 , Síndromes da Apneia do Sono , Apneia Obstrutiva do Sono , COVID-19/complicações , Humanos , Pandemias , Fatores de Risco , Síndromes da Apneia do Sono/epidemiologia , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/diagnóstico , Apneia Obstrutiva do Sono/epidemiologiaRESUMO
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.
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Benzimidazóis/administração & dosagem , Pirrolidinas/administração & dosagem , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Triazóis/administração & dosagem , Adulto , Benzimidazóis/efeitos adversos , Benzimidazóis/uso terapêutico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Imidazóis , Pessoa de Meia-Idade , Antagonistas dos Receptores de Orexina/efeitos adversos , Antagonistas dos Receptores de Orexina/uso terapêutico , Pirrolidinas/efeitos adversos , Pirrolidinas/uso terapêutico , Resultado do Tratamento , Triazóis/efeitos adversos , Triazóis/uso terapêutico , Zolpidem/uso terapêuticoRESUMO
OBJECTIVE: Restless legs syndrome is a frequent neurological disorder with substantial burden on individual well-being and public health. Genetic risk loci have been identified, but the causatives genes at these loci are largely unknown, so that functional investigation and clinical translation of molecular research data are still inhibited. To identify putatively causative genes, we searched for highly significant mutational burden in candidate genes. METHODS: We analyzed 84 candidate genes in 4,649 patients and 4,982 controls by next generation sequencing using molecular inversion probes that targeted mainly coding regions. The burden of low-frequency and rare variants was assessed, and in addition, an algorithm (binomial performance deviation analysis) was established to estimate independently the sequence variation in the probe binding regions from the variation in sequencing depth. RESULTS: Highly significant results (considering the number of genes in the genome) of the conventional burden test and the binomial performance deviation analysis overlapped significantly. Fourteen genes were highly significant by one method and confirmed with Bonferroni-corrected significance by the other to show a differential burden of low-frequency and rare variants in restless legs syndrome. Nine of them (AAGAB, ATP2C1, CNTN4, COL6A6, CRBN, GLO1, NTNG1, STEAP4, VAV3) resided in the vicinity of known restless legs syndrome loci, whereas 5 (BBS7, CADM1, CREB5, NRG3, SUN1) have not previously been associated with restless legs syndrome. Burden test and binomial performance deviation analysis also converged significantly in fine-mapping potentially causative domains within these genes. INTERPRETATION: Differential burden with intragenic low-frequency variants reveals putatively causative genes in restless legs syndrome. ANN NEUROL 2020;87:184-193.
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Análise Mutacional de DNA , Predisposição Genética para Doença/genética , Síndrome das Pernas Inquietas/genética , Estudos de Casos e Controles , Mapeamento Cromossômico/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
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 kgâ 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, <â .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.
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Doenças Cardiovasculares , Síndromes da Apneia do Sono , Adulto , Idoso , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Masculino , Pessoa de Meia-Idade , Oximetria , Análise de Onda de Pulso , Fatores de Risco , Sono , Síndromes da Apneia do Sono/diagnósticoRESUMO
In patients with chronic obstructive pulmonary disease (COPD), sleep is often fragmented while, conversely, the use of sleep medications is of concern in these patients due to potential impairment of nocturnal breathing. This randomised, double-blind, placebo-controlled, two-period crossover study was conducted to evaluate the effect of the new dual orexin receptor antagonist daridorexant on night-time respiratory function and sleep in patients with moderate COPD. In each period, the highest Phase-III dose of 50 mg daridorexant or placebo was administered once daily in the evening for 5 consecutive days. The primary endpoint was peripheral oxygen saturation (SpO2 ) during total sleep time (TST) after last dosing. Night-time respiratory function and sleep were further evaluated based on the apnea-hypopnea index (AHI), sleep duration, and objective sleep parameters. Pharmacokinetics, safety, and tolerability were also assessed. Primary endpoint analysis revealed no significant mean treatment difference (i.e. daridorexant - placebo) for SpO2 during TST as it was 0.18% (90% confidence interval: -0.21 to 0.57). There was also no difference from placebo for SpO2 during non-rapid eye movement (REM) and REM sleep at Night 5 and after first dosing. The AHI was slightly increased compared to placebo, but not to a clinically meaningful extent. In addition, daridorexant improved objective sleep parameters (i.e. prolonged TST, increased sleep efficiency, and decreased wake after sleep onset), reached expected plasma concentrations, and was safe and well tolerated. In conclusion, single and multiple doses of 50 mg daridorexant do not impair night-time respiratory function and improves sleep in patients with moderate COPD.
Assuntos
Imidazóis/uso terapêutico , Antagonistas dos Receptores de Orexina/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Pirrolidinas/uso terapêutico , Respiração/efeitos dos fármacos , Sono/efeitos dos fármacos , Adolescente , Adulto , Idoso , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Imidazóis/farmacologia , Masculino , Pessoa de Meia-Idade , Antagonistas dos Receptores de Orexina/administração & dosagem , Antagonistas dos Receptores de Orexina/farmacologia , Doença Pulmonar Obstrutiva Crônica/complicações , Pirrolidinas/farmacologia , Adulto JovemRESUMO
PURPOSE: Since 2001, hypoglossal nerve stimulators have been implanted in patients with obstructive sleep apnea around the world, initially in trial situations but more recently also in regular care settings. Medium term data indicate effectiveness and tolerability of treatment. However, when assessing the safety of the procedure, the safe feasibility of explantation or reimplantation must also be considered. PATIENTS AND METHODS: Nine patients with an implanted respiratory-driven hypoglossal nerve stimulator. We have evaluated the feasibility and safety of explantation or re-implantation with another stimulation system. RESULTS: In 2012, nine patients were implanted with a respiratory-driven hypoglossal nerve stimulator as part of the Apnex Medical Pivotal Study. The study was ended in 2013. For a variety of reasons, the system was explanted from all nine patients by the year 2019. Three of these patients were re-implanted with a different system with respiratory sensing during the same session (mean incision to closure time for explantation 88.2 ± 35.01 min., mean incision to closure time for re-implantation 221.75 ± 52.73 min.). Due to extensive scar tissue formation, all procedures were technically challenging. Complication rate was significantly higher when re-implantation was performed or attempted in the same surgical session (0 of 5 patients with explantation versus 3 of 4 patients with attempted re-implantation; p = 0.018). There was no significant difference between the AHI values before and after implantation in patients with re-implantation. CONCLUSION: Explantation and re-implantation are technically challenging though possible procedures. The single-staged equilateral reimplantation of another hypoglossal nerve stimulation system can, but need not, be successful.
Assuntos
Terapia por Estimulação Elétrica , Apneia Obstrutiva do Sono , Remoção de Dispositivo , Terapia por Estimulação Elétrica/efeitos adversos , Humanos , Nervo Hipoglosso , Reimplante , Apneia Obstrutiva do Sono/terapiaRESUMO
In obstructive sleep apnea, patients' sleep is fragmented leading to excessive daytime sleepiness and co-morbidities like arterial hypertension. However, traditional metrics are not always directly correlated with daytime sleepiness, and the association between traditional sleep quality metrics like sleep duration and arterial hypertension is still ambiguous. In a development cohort, we analysed hypnograms from mild (n = 209), moderate (n = 222) and severe (n = 272) obstructive sleep apnea patients as well as healthy controls (n = 105) from the European Sleep Apnea Database. We assessed sleep by the analysis of two-step transitions depending on obstructive sleep apnea severity and anthropometric factors. Two-step transition patterns were examined for an association to arterial hypertension or daytime sleepiness. We also tested cumulative distributions of wake as well as sleep-states for power-laws (exponent α) and exponential distributions (decay time τ) in dependency on obstructive sleep apnea severity and potential confounders. Independent of obstructive sleep apnea severity and potential confounders, wake-state durations followed a power-law distribution, while sleep-state durations were characterized by an exponential distribution. Sleep-stage transitions are influenced by obstructive sleep apnea severity, age and gender. N2 â N3 â wake transitions were associated with high diastolic blood pressure. We observed higher frequencies of alternating (symmetric) patterns (e.g. N2 â N1 â N2, N2 â wake â N2) in sleepy patients both in the development cohort and in a validation cohort (n = 425). In conclusion, effects of obstructive sleep apnea severity and potential confounders on sleep architecture are small, but transition patterns still link sleep fragmentation directly to obstructive sleep apnea-related clinical outcomes like arterial hypertension and daytime sleepiness.
Assuntos
Apneia Obstrutiva do Sono/fisiopatologia , Sono/fisiologia , Adulto , Fatores Etários , Feminino , Identidade de Gênero , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
PURPOSE OF REVIEW: Diagnosis of sleep apnoea was performed in sleep laboratories with polysomnography. This requires a room with supervision and presence of technologists and trained sleep experts. Today, clinical guidelines in most countries recommend home sleep apnoea testing with simple systems using six signals only. If criteria for signal quality, recording conditions, and patient selection are considered, then this is a reliable test with high accuracy. RECENT FINDINGS: Recently diagnostic tools for sleep apnoea diagnosis become even more simple: smartwatches and wearables with smart apps claim to diagnose sleep apnoea when these devices are tracking sleep and sleep quality as part of new consumer health checking. Alternative and new devices range from excellent diagnostic tools with high accuracy and full validation studies down to very low-quality tools which only result in random diagnostic reports. Due to the high prevalence of sleep apnoea, even a random diagnosis may match a real disorder sometimes. SUMMARY: Until now, there are no metrics established how to evaluate these alternative algorithms and simple devices. Proposals for evaluating smartwatches, smartphones, single-use sensors, and new algorithms are presented. New assessments may help to overcome current limitations in sleep apnoea severity metrics. VIDEO ABSTRACT: http://links.lww.com/COPM/A28.