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Sleep-disordered breathing (SDB) is often accompanied by noncommunicable diseases (NCDs), including gout. However, the association between serum uric acid (sUA) levels and NCDs is complicated in patients with SDB. We aimed to clarify this issue utilizing large-scale epidemiological data. This community-based study included 9850 inhabitants. SDB and its severity were assessed by a 3% oxygen desaturation index (3% ODI) corrected for sleep duration using wrist actigraphy. The associations between sUA and moderate to severe SDB (MS-SDB) and sUA and NCDs in patients with MS-SDB were analyzed. A total of 7895 subjects were eligible. In females, the prevalence of MS-SDB increased according to an elevation in sUA levels even after adjusting for confounders, and sUA ≥ 5 mg/dL was the threshold. These were not found in males. There was a positive interaction between sUA ≥ 5 mg/dL and female sex for MS-SDB. In females with MS-SDB, the prevalence of diabetes mellitus (DM) increased according to an elevation in sUA levels, and those with sUA ≥ 5 mg/dL showed a higher prevalence of DM than their counterparts. There is a clear correlation between sUA levels and the severity of SDB, and elevated sUA poses a risk for DM in females with MS-SDB.

Sleep disordered breathing (SDB), mainly obstructive sleep apnea (OSA), constitutes a major health problem due to the large number of patients. Intermittent hypoxia caused by SDB induces alterations in metabolic function. Nevertheless, metabolites characteristic for SDB are largely unknown. In this study, we performed gas chromatography-mass spectrometry-based targeted metabolome analysis using data from The Nagahama Study (n = 6373). SDB-related metabolites were defined based on their variable importance score in orthogonal partial least squares discriminant analysis and fold changes in normalized peak-intensity levels between moderate-severe SDB patients and participants without SDB. We identified 20 metabolites as SDB-related, and interestingly, these metabolites were frequently included in pathways related to fructose. Multivariate analysis revealed that moderate-severe SDB was a significant factor for increased plasma fructose levels (β = 0.210, P = 0.006, generalized linear model) even after the adjustment of confounding factors. We further investigated changes in plasma fructose levels after continuous positive airway pressure (CPAP) treatment using samples from patients with OSA (n = 60) diagnosed by polysomnography at Kyoto University Hospital, and found that patients with marked hypoxemia exhibited prominent hyperfructosemia and their plasma fructose levels lowered after CPAP treatment. These data suggest that hyperfructosemia is the abnormality characteristic to SDB, which can be reduced by CPAP treatment., (© 2023. Springer Nature Limited.)

Background: Delirium is common in critically ill patients. Haloperidol has long been used for the treatment of delirium. Dexmedetomidine has recently been used to treat delirium among intubated critically ill patients. However, the efficacy of dexmedetomidine for delirium in non-intubated critically ill patients remains unknown. We hypothesize that dexmedetomidine is superior to haloperidol for sedation of patients with hyperactive delirium, and would reduce the prevalence of delirium among non-intubated patients after administration. We will conduct a randomized controlled trial to compare dexmedetomidine and haloperidol for the treatment of nocturnal hyperactive delirium in non-intubated patients in high dependency units (HDUs)., Methods: This is an open-label, parallel-group, randomized controlled trial to compare the efficacy and safety of dexmedetomidine and haloperidol for nocturnal hyperactive delirium in non-intubated patients at two HDUs of a tertiary hospital. We will recruit consecutive non-intubated patients who are admitted to the HDU from the emergency room, and allocate them in a 1:1 ratio to the dexmedetomidine or haloperidol group in advance. The allocated investigational drug will be administered only when participants develop hyperactive delirium (Richmond Agitation-Sedation Scale [RASS] score ≥1 and a positive score on the Confusion Assessment Method for the ICU between 19:00 and 6:00 the next day) during the night at an HDU. Dexmedetomidine is administered continuously, while haloperidol is administered intermittently. The primary outcome is the proportion of participants who achieve the targeted sedation level (RASS score of between -3 and 0) 2h after the administration of the investigational drug. Secondary outcomes include the sedation level and prevalence of delirium on the day following the administration of the investigational drugs, and safety. We plan to enroll 100 participants who develop nocturnal hyperactive delirium and receive one of the two investigational drugs., Discussion: This is the first randomized controlled trial to compare the efficacy and safety of dexmedetomidine and haloperidol for sedation of non-intubated critically ill patients with hyperactive delirium in HDUs. The results of this study may confirm whether dexmedetomidine could be another option to sedate patients with hyperactive delirium., Trial Registration: Japan Registry of Clinical Trials, jRCT1051220015, registered on 21 April 2022., (© 2023. The Author(s).)

Recently an association between blood glucose dysregulation and sleep disruption was suggested. The association between sleep disordered breathing, most of which is due to obstructive sleep apnea (OSA) in the general population, and diabetic severity, as well as the impact of antidiabetic treatment, remains unclear. This study aimed to investigate these associations as well as age and sex differences. This cross-sectional study evaluated 7,680 community participants as the main cohort (population-based cohort). OSA was assessed by the 3% oxygen desaturation index from pulse oximetry, which was corrected for sleep duration obtained by wrist actigraphy. For arguing the limitations for using pulse oximetry, 597 hospitalised patients, who were assessed by the apnea-hypopnea index from attended polysomnography, were also evaluated as the validation cohort (hospital-based cohort). Moderate-to-severe OSA was more prevalent as haemoglobin A1c (HbA1c) levels increased (<5.6%/5.6%-<6.5%/6.5%-<7.5%/≥7.5%, respectively) in both cohorts (p < 0.001), but only in those without antidiabetic treatment. The HbA1c level was an independent factor for moderate-to-severe OSA (population-based cohort, odds ratio [OR] 1.26, 95% confidence interval [CI] 1.10-1.45; hospital-based cohort, OR 1.69, 95% CI 1.22-2.33, per 1% increase). These associations were more prominent in the middle-aged (aged <60 years) than in the elderly (aged ≥60 years) and in women than in men in both cohorts. The prevalence of moderate-to-severe OSA in patients with antidiabetic treatment in the hospital-based cohort was ≥75% regardless of HbA1c levels. In conclusion, an association between the prevalence of OSA and HbA1c level even within or over the normal range was found only in patients without antidiabetic treatment and was more prominent in the middle-aged and in women., (© 2022 European Sleep Research Society.)

Background: Telemonitoring the use of CPAP devices and remote feedback on device data effectively optimizes CPAP adherence in patients with OSA., Research Question: Can expanding the scope of telemonitoring and remote feedback to body weight (BW), BP, and physical activity enhance efforts for BW reduction in Patients with OSA receiving CPAP?, Study Design and Methods: Participants were recruited from patients at 16 sleep centers in Japan with OSA and obesity who were receiving CPAP therapy. Obesity was defined as a BMI of ≥ 25 kg/m 2 , based on Japanese obesity guidelines. Implementation of CPAP telemonitoring was enhanced with electronic scales, BP monitors, and pedometers that could transmit data from devices wirelessly. Participants were randomized to the multimodal telemonitoring group or the usual CPAP telemonitoring group and were followed up for 6 months. Attending physicians provided monthly telephone feedback calls to the usual CPAP telemonitoring group on CPAP data obtained remotely. In the multimodal telemonitoring group, physicians additionally encouraged participants to reduce their BW, after sharing the remotely obtained data on BW, BP, and step count. The primary outcome was set as ≥ 3% BW reduction from baseline., Results: One hundred sixty-eight participants (BMI, 31.7 ± 4.9 kg/m 2 ) completed the study, and ≥ 3% BW reduction occurred in 33 of 84 participants (39.3%) and 21 of 84 participants (25.0%) in the multimodal telemonitoring and usual CPAP telemonitoring groups, respectively (P = .047). Whereas no significant differences were found between the two groups in the change in office and home BP, daily step counts during the study period were significantly higher in the multimodal telemonitoring group than in the usual CPAP telemonitoring group (4,767 steps/d [interquartile range (IQR), 2,864-6,617 steps/d] vs 3,592 steps/d [IQR, 2,117-5,383 steps/d]; P = .02) INTERPRETATION: Multimodal telemonitoring may enhance BW reduction efforts in patients with OSA and obesity., Trial Registry: UMIN Clinical Trials Registry; No.: UMIN000033607; URL: www.umin.ac.jp/ctr/index.htm., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

A 55-year-old woman with extreme obesity presenting with limb weakness since 1 year was diagnosed with amyotrophic lateral sclerosis (ALS) based on clinical findings and needle electromyography. She had a habit of overeating, and her body mass index (BMI) was 38.2. MRI showed an enlargement of the right central cerebral sulcus, and N-isopropyl-p-[‍ 123 I]-iodoamphetamine single-photon emission computed tomography demonstrated reduced blood flow predominantly in the right frontal lobes, suggesting overlapping frontotemporal dementia (FTD). She maintained adequate dietary intake, and her BMI was stable at 38.2 until 3 months after diagnosis. However, over the next 2 months, her dietary intake decreased owing to pronounced bulbar palsy and BMI decreased to 34.5. At this point, forced vital capacity decreased from 69.3% to 39.0%, while forced expiratory volume in 1 second decreased from 75.3% to 47.7%. Consequently, noninvasive ventilation at night was initiated, followed by tracheostomy invasive ventilation at the emergency department after 2 months. We assume that the frontotemporal lobar degeneration pathology progressed to the frontal lobe and hypothalamus over time, which increased the patient's excessive appetite and body weight. Her obesity reduced the compliance of the thorax and increased the workload of the respiratory muscles, resulting in rapid respiratory deterioration. Additionally, the extensive neurodegeneration, extending to the area other than the primary motor cortex, might have played a pivotal role in rapid ALS progression. High-calorie nutritional management is generally recommended in patients with ALS. Although the prognosis of patients with ALS having BMI under 27 can be improved via high calorie intake and BMI maintenance, the nutritional management strategy for patients with ALS and high obesity (BMI ≥ 35) remains unclear. Through this case we emphasize that in patients with ALS and FTD excessive appetite and obesity can lead to rapid respiratory deterioration, and therefore, prudent calorie management is recommended.

Rationale: Although sleep-disordered breathing (SDB) may increase urinary albumin excretion (UAE) by raising nocturnal blood pressure (BP) in addition to diurnal BP, the correlation has not been investigated in a general population. Objectives: To evaluate the relationships among UAE, SDB, and BP during sleep in a large population cohort. Methods: Among 9,850 community residents, UAE was assessed by the urinary albumin-to-creatinine ratio (UACR) in spot urine. Sleep duration and SDB were evaluated by a wearable actigraph and pulse oximeter, respectively. We calculated the actigraphy-modified 3% oxygen desaturation index (Acti-3%ODI) by correcting the time measured by pulse oximetry according to sleep duration obtained by actigraphy. Furthermore, participants were instructed to measure morning and sleep BP at home by a timer-equipped oscillometric device. Results: Measurements of sleep parameters, UAE, and office BP were obtained in 6,568 participants. The multivariate analysis that included confounders showed a significant association of Acti-3%ODI with UACR (β = 0.06, P  < 0.001). Furthermore, a positive interaction between office systolic BP (SBP) and Acti-3%ODI for UACR was found (β = 0.06, P  < 0.001). Among the 6,568 persons enrolled in the analysis, 5,313 completed measurements of BP at home. In this cohort, the association of Acti-3%ODI with UACR remained significant (β = 0.06, P  < 0.001) even after morning and sleep SBP were included in the analysis. Furthermore, a mediation analysis revealed that 28.3% (95% confidence interval, 14.9-41.7%; P  < 0.001) of the association of Acti-3%ODI with UACR was explained by the mediation of morning and sleep SBP metrics. Conclusions: SDB and office SBP were independently and synergistically associated with UAE, which is considered a risk factor for chronic kidney disease and cardiovascular events. SDB may raise UAE not only by increasing BP but also by involving other pathologic pathways.

Study Objectives: Since subjective sleep duration (SSD) is considered to be longer than objective sleep duration (OSD), results of SSD minus OSD (SSD-OSD) might always be thought to be positive. Some recent reports showed different results, but exact results have not been obtained. The difference between SSD and OSD may change according to OSD. We investigated this difference and its association with sleep-disordered breathing (SDB) or nonrestorative sleep., Methods: This cross-sectional study evaluated 6,908 community residents in Nagahama, Japan. SSD was determined by self-administered questionnaire. OSD was measured by wrist actigraphy and sleep diary. SDB was assessed according to the 3% oxygen desaturation index adjusted for OSD., Results: Worthy of notice was that SSD was shorter than OSD for those with SSD longer than 6.98 hours in all participants, 7.36 hours in males, and 6.80 hours in females. However, SSD was longer than OSD (mean ± SD: 6.49 ± 1.07 vs 6.01 ± 0.96; P < .001) overall, as SSD is considered to be longer than OSD. In patients with SDB, the difference between SSD-OSD was greater when OSD was s horter. The difference also depended on SDB severity. The degree of positivity between OSD and SSD was a significant factor in nonrestorative sleep (odds ratio: 2.691; P < .001)., Conclusions: When OSD was slightly less than 7 (6.98) hours, participants reported or perceived SSD > OSD. When OSD was > 6.98 hours, participants reported or perceived SSD < OSD. Patients with SDB reported longer SSD than OSD according to severity of SDB. Evaluating SSD, OSD, and their differences may be useful for managing sleep disturbances, including nonrestorative sleep., Citation: Takahashi N, Matsumoto T, Nakatsuka Y, et al. Differences between subjective and objective sleep duration according to actual sleep duration and sleep-disordered breathing: the Nagahama Study. J Clin Sleep Med . 2022;18(3):851-859., (© 2022 American Academy of Sleep Medicine.)

Study Objectives: Whether the association between sleep-disordered breathing (SDB) and cardiovascular disease is independent of comorbid risk factors for cardiovascular disease is controversial. The objective of this study was to elucidate whether the association between SDB severity and the surrogate markers of cardiovascular disease events differs in relation to the number of comorbidities., Methods: This cross-sectional study included 7,731 participants. Severity of SDB was determined by the oxygen desaturation index adjusted by actigraph-measured objective sleep time. Participants were stratified according to SDB severity and the number of comorbidities (hypertension, diabetes, dyslipidemia, and obesity), and the associations between the maximum value of intima-media thickness of the common carotid artery (CCA-IMT-max), brachial-ankle pulse wave velocity, and cardio-ankle vascular index were evaluated., Results: Among participants with no risk factors, CCA-IMT-max increased according to SDB severity (n = 1022, P < .0001). Even after matching the background, the median CCA-IMT-max value was 14% higher in moderate-severe SDB patients than those without SDB (n = 45 in each group, P = .020). The difference was not significant for brachial-ankle pulse wave velocity and cardio-ankle vascular index. On the other hand, a significant difference in CCA-IMT-max was not found in those with multiple comorbidities. Consistently, multiple regression analysis revealed an independent association between CCA-IMT-max and moderate-severe SDB for all study participants (β: 0.0222, 95% confidence interval: 0.0039-0.0405, P = .017), but the association was not significant for stratified participants with multiple comorbidities., Conclusions: SDB severity is associated with the CCA-IMT-max level, but the independent association becomes weaker for those with multiple comorbidities., Citation: Nakatsuka Y, Murase K, Matsumoto T, et al. Markers of cardiovascular disease risk in sleep-disordered breathing with or without comorbidities: the Nagahama Study. J Clin Sleep Med . 2021;17(12):2467-2475., (© 2021 American Academy of Sleep Medicine.)

Purpose: Our previous cross-sectional study showed that periodic limb movements during sleep (PLMS) were frequently found in patients with obstructive sleep apnea (OSA) and that both OSA and PLMS were associated with higher plasma fibrinogen levels. We explored the longitudinal relationships among these factors., Methods: Plasma fibrinogen levels were measured in 333 consecutive patients who underwent polysomnography to diagnose OSA. Patients who initiated continuous positive airway pressure (CPAP) underwent follow-up polysomnography after 3 months of CPAP use. They were categorized into groups with good or poor adherence (% days with ≥ 4 h/night of CPAP use ≥ 70% or < 70%, respectively). Changes in sleep parameters and plasma fibrinogen levels during the treatment period were compared between these groups., Results: The cross-sectional analysis of all reviewed 333 patients indicated that fibrinogen levels were associated with the severities of OSA and PLMS. The 60 patients (27 good and 33 poor adherence) who underwent follow-up polysomnography were included in the longitudinal analysis. The median (interquartile range) periodic limb movement index did not change significantly from CPAP titration to the 3-month follow-up (good adherence: 10.5 (0-23.8) to 10.8 (0-70.2) events/h, p = 0.21; poor adherence: 1.2 (0-14.3) to 0.8 (0-15.7) events/h, p = 0.67). However, the plasma fibrinogen level significantly decreased only in the good adherence group (good adherence: baseline 275 ± 46 to follow-up 255 ± 47 mg/dl, p < 0.01; poor adherence: 277 ± 52 to 284 ± 70 mg/dl, p = 0.48)., Conclusions: These results did not support a longitudinal association between PLMS and OSA. However, good adherence to CPAP could reduce plasma fibrinogen levels, thus ameliorating elevations in plasma fibrinogen as a risk factor for future cardiovascular events.

Study Objectives: It is well known that a family history of diabetes (FHD) is a definitive risk factor for type 2 diabetes. It has not been known whether sleep-disordered breathing (SDB) increases the prevalence of diabetes in those with an FHD., Methods: We assessed SDB severity in 7,477 study participants by oximetry corrected by objective sleep duration determined by wrist actigraphy. Glycated hemoglobin ≥6.5% and/or current medication for diabetes indicated the presence of diabetes. In addition to the overall prevalence, the prevalence of recent-onset diabetes during the nearly 5 years before the SDB measurements were made was investigated., Results: Of the 7,477 participants (mean age: 57.9; range: 34.2-80.7; SD: 12.1 years; 67.7% females), 1,569 had an FHD. The prevalence of diabetes in FHD participants with moderate-to-severe SDB (MS-SDB) was higher than in those without SDB (MS-SDB vs without SDB: all, 29.3% vs 3.3% [P < .001]; females, 32.6% vs 1.9% [P < .001]; males, 26.2% vs 11.7% [P = .037]). However, multivariate analysis showed that MS-SDB was significantly associated with a higher prevalence of diabetes only in FHD-positive females (odds ratio [95% confidence interval]: females, 7.43 [3.16-17.45]; males, 0.92 [0.37-2.31]). Among the FHD-positive participants, the prevalence of recent-onset diabetes was higher in those with MS-SDB than those without SDB, but only in females (MS-SDB vs without SDB: 21.4% vs 1.1%; P < 0.001)., Conclusions: MS-SDB was associated with diabetes risk in females with an FHD, and future studies are needed on whether treatment of SDB in females with an FHD would prevent the onset of diabetes., (© 2021 American Academy of Sleep Medicine.)

It is well known that the prevalence of sleep disordered breathing (SDB) is increased in patients with obesity or metabolic comorbidities. However, the way in which the prevalence of SDB increases in relation to comorbidities according to the severity of obesity remains unclear.This cross-sectional study evaluated 7713 community participants using nocturnal oximetry ≥2 nights. SDB was assessed by the 3% oxygen desaturation index corrected for sleep duration obtained by wrist actigraphy (acti-ODI3%). SDB severity was defined by acti-ODI3%. Obesity was defined as body mass index ≥25 kg·m -2 The prevalence of SDB was 41.0% (95% CI 39.9-42.1%), 46.9% (45.8-48.0%), 10.1% (9.5-10.8%) and 2.0% (1.7-2.3%) in normal, mild, moderate and severe SDB, respectively, with notable sex differences evident (males>post-menopausal females>premenopausal females). Comorbidities such as hypertension, diabetes and metabolic syndrome were independently associated with the prevalence of moderate-to-severe SDB, and coincidence of any one of these with obesity was associated with a higher probability of moderate-to-severe SDB (hypertension OR 8.2, 95% CI 6.6-10.2; diabetes OR 7.8, 95% CI 5.6-10.9; metabolic syndrome OR 6.7, 95% CI 5.2-8.6). Dyslipidaemia in addition to obesity was not additively associated with the prevalence of moderate-to-severe SDB. The number of antihypertensive drugs was associated with SDB (p for trend <0.001). Proportion of a high cumulative percentage of sleep time with oxygen saturation measured by pulse oximetry <90% increased, even among moderate-to-severe SDB with increases in obesity.Metabolic comorbidities contribute to SDB regardless of the degree of obesity. We should recognise the extremely high prevalence of moderate-to-severe SDB in patients with obesity and metabolic comorbidities., Competing Interests: Conflict of interest: T. Matsumoto has nothing to disclose. K. Murase reports grants from Philips-Respironics, Teijin Pharma, Fukuda Denshi, Fukuda Lifetec Keiji, ResMed and Japan Society for the Promotion of Science, outside the submitted work. Conflict of interest: Y. Tabara reports grants from Japan Agency for Medical Research and Development (AMED) and The Ministry of Education, Culture, Sports, Science and Technology in Japan, during the conduct of the study. Conflict of interest: T. Minami reports personal fees from Teijin Zaitakuiryou, outside the submitted work. Conflict of interest: O. Kanai has nothing to disclose. Conflict of interest: H. Takeyama reports grants from Philips-Respironics, ResMed, Fukuda Denshi, Fukuda Lifetec Keiji and Teijin Pharma, outside the submitted work. Conflict of interest: N. Takahashi reports grants from Philips-Respironics, ResMed, Fukuda Denshi and Fukuda Lifetec Keiji, outside the submitted work. Conflict of interest: S. Hamada reports grants from Teijin Pharma, outside the submitted work. Conflict of interest: K. Tanizawa has nothing to disclose. Conflict of interest: T. Wakamura has nothing to disclose. Conflict of interest: N. Komenami has nothing to disclose. Conflict of interest: K. Setoh has nothing to disclose. Conflict of interest: T. Kawaguchi has nothing to disclose. Conflict of interest: T. Tsutsumi has nothing to disclose. Conflict of interest: S. Morita has nothing to disclose. Conflict of interest: Y. Takahashi has nothing to disclose. Conflict of interest: T. Nakayama has nothing to disclose. Conflict of interest: T. Hirai has nothing to disclose. Conflict of interest: F. Matsuda reports grants from Kyoto University, the Ministry of Education, Culture, Sports, Science and Technology in Japan, Japan Agency for Medical Research and Development (AMED) and The Takeda Medical Research Foundation, during the conduct of the study. Conflict of interest: K. Chin reports grants from the Japanese Ministry of Education, Culture, Sports, Science and Technology, grants from the Intractable Respiratory Diseases and Pulmonary Hypertension Research Group, the Ministry of Health, Labour and Welfare, Japan, grants from the Research Foundation for Healthy Aging, grants from Health, Labour and Welfare Sciences Research Grants, Research on Region Medical, grants from the Center of Innovation Program, and the Global University Project from Japan Science and Technology Agency, Japan Agency for Medical Research and Development, during the conduct of the study; grants and personal fees from Philips-Respironics, Teijin Pharma, Fukuda Denshi, Fukuda Lifetec Keiji, GlaxoSmithKline and Resmed, grants from KYORIN Pharmaceutical Co., Ltd and Nippon Boehringer Ingelheim Co., Ltd, personal fees from MSD, Astellas Pharma and Eisai Co., Ltd, outside the submitted work., (Copyright ©ERS 2020.)

Background: Pulmonary arterial hypertension (PAH) is frequently complicated by sleep disordered breathing (SDB), and previous studies have largely focused on hypoxemic SDB. Even though nocturnal hypercapnia was shown to exacerbate pulmonary hypertension, the clinical significance of nocturnal hypercapnia among PAH patients has been scarcely investigated., Method: Seventeen patients with PAH were identified from 246 consecutive patients referred to Kyoto University Hospital for the evaluation of lung transplant registration from January 2010 to December 2017. Included in this study were 13 patients whose nocturnal transcutaneous carbon dioxide partial pressure (PtcCO2) monitoring data were available. Nocturnal hypercapnia was diagnosed according to the guidelines of the American Academy of Sleep Medicine. Associations of nocturnal PtcCO2 measurements with clinical features, the findings of right heart catheterization and pulmonary function parameters were evaluated., Results: Nocturnal hypercapnia was diagnosed in six patients (46.2%), while no patient had daytime hypercapnia. Of note, nocturnal hypercapnia was found for 5 out of 6 patients with idiopathic PAH (83.3%). Mean nocturnal PtcCO2 levels correlated negatively with the percentage of predicted total lung capacity (TLC), and positively with cardiac output and cardiac index., Conclusion: Nocturnal hypercapnia was prevalent among advanced PAH patients who were waiting for lung transplantation, and associated with %TLC. Nocturnal hypercapnia was associated with the increase in cardiac output, which might potentially worsen pulmonary hypertension especially during sleep. Further studies are needed to investigate hemodynamics during sleep and to clarify whether nocturnal hypercapnia can be a therapeutic target for PAH patients., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: Yoshinari Nakatsuka and Naomi Takahashi reports grants from Philips-Respironics, grants from ResMed Japan, grants from Fukuda Denshi, grants from Fukuda Lifetec Keiji. Kimihiko Murase and Hirofumi Takeyama reports grants from Philips-Respironics, grants from Teijin Pharma, grants from Fukuda Denshi, grants from Fukuda Lifetec Keiji. Kazuo Chin reports grants and personal fees from Philips-Respironics, grants and personal fees from Teijin Pharma, grants and personal fees from Fukuda Denshi, grants and personal fees from Fukuda Lifetec Keiji, grants from KYORIN Pharmaceutical Co., Ltd, grants from Nippon Boehringer Ingelheim Co., Ltd, grants and personal fees from GlaxoSmithKline, personal fees from MSD, personal fees from ResMed, personal fees from Astellas Pharma, personal fees from Eisai Co., Ltd. Hideyuki Kinoshita reports personal fees from Actelion Pharmaceuticals Japan Ltd., Nippon Shinyaku Co., Ltd, Bayer Yakuhin, Ltd., and research grant from Bayer Yakuhin, Ltd. Toyofumi Chen-Yoshikawa, Akihiro Aoyama, Hiroyasu Kubo, Satoshi Hamada, Takuma Minami, Kiminobu Tanizawa, Tomohiro Handa, Toyohiro Hirai and Hiroshi Date declare no potential conflict of interests. The Department of Respiratory Care and Sleep Control Medicine is funded by endowments from Philips-Respironics, ResMed, Fukuda Denshi and Fukuda Lifetec-Keiji to Kyoto University. These competing interests do not alter our adherence to PLOS ONE policies on sharing data and materials.

Rationale: The effects of telemedicine on adherence in patients with obstructive sleep apnea with long-term continuous positive airway pressure (CPAP) use have never been investigated. Objectives: To examine effects of a telemedicine intervention on adherence in long-term CPAP users. Methods: In a prospective, randomized, multicenter noninferiority trial conducted in 17 sleep centers across Japan, patients who had used CPAP for >3 months and were receiving face-to-face follow-up by physicians every 1 or 2 months were randomized by a coordinating center in a blind manner to the following three groups: 1 ) follow-up every 3 months accompanied by a monthly telemedicine intervention (telemedicine group: TM-group), 2 ) follow-up every 3 months (3-month group: 3M-group), or 3 ) monthly follow-up (1-month group: 1M-group). Each group was followed up for 6 months. The change in percentage of days with ≥4 h/night of CPAP use from baseline to the end of the study period was evaluated. A decline of ≥5% from baseline was considered deterioration of adherence. Noninferiority of TM- and 3M-groups compared with the 1M-group according to the number of patients with deterioration of adherence was evaluated with the Farrington and Manning test (noninferiority margin 15%). Results: A total of 483 patients were analyzed (median duration of CPAP use, 29 [interquartile range, 12-71] mo), and deterioration of adherence was found in 41 of 161 (25.5%), 55 of 166 (33.1%), and 35 of 156 (22.4%) patients in the TM-, 3M-, and 1M-groups, respectively. The noninferiority of the TM-group compared with the 1M-group was verified (difference in percentage of patients with adherence deterioration, 3.0%; 95% confidence interval [CI], -4.8% to 10.9%; P  < 0.01). Conversely, the 3M-group did not show noninferiority to the 1M-group (percentage difference, 10.7%; 95% CI, 2.6% to 18.8%; P  = 0.19). In the stratified analysis, adherence in TM- and 1M-group patients with poor adherence at baseline improved (TM: 45.8% ± 18.2% to 57.3% ± 24.4%; P  < 0.01; 1M: 43.1% ± 18.5% to 53.6% ± 24.3%; P  < 0.01), whereas that of the 3M-group did not (39.3% ± 20.8% to 39.8% ± 24.8%; P  = 0.84). Conclusions: Intensive telemedicine support could help to optimize CPAP adherence even after long-term CPAP use.Clinical trial registered with www.umin.ac.jp/ctr/index.htm (trial number: UMIN000023118).

Objectives: The association of obstructive sleep apnea (OSA) with hypothalamic pituitary adrenal (HPA) axis activation has not been fully understood from results of previous studies using hormonal assessments. We aimed to investigate the relationship between adrenal size, a potential marker reflecting HPA axis activity, and sleep parameters related to OSA., Methods: We retrospectively reviewed data on 284 consecutive adult patients aged 20 to 80 y who had undergone polysomnography and abdominal computed tomography (CT). OSA was defined as none/mild (apnea-hypopnea index [AHI] <15, n = 75), moderate (AHI 15 to 30, n = 80), and severe OSA (AHI ≥30, n = 129). Widths of adrenal body and limbs were measured by abdominal CT., Results: Adrenal size was greater in participants with severe OSA than in those with none/mild or moderate OSA (adrenal body width: 6.03 mm, none/mild OSA; 6.09 mm, moderate OSA; 6.78 mm, severe OSA; p <0.001; adrenal limb width: 3.75 mm, none/mild OSA; 3.95 mm, moderate OSA; 4.26 mm, severe OSA, p <0.001). Multivariate regression analysis showed that not the 3% oxygen desaturation index and time of SpO2 <90% but a higher arousal index was the only determinant factor for increased adrenal limb width (β = 0.27, p <0.001) after adjusting for other variables that could affect adrenal size. Neither the arousal index nor hypoxic parameters were associated with adrenal body width., Conclusions: Results indicated that adrenal glands may enlarge in response to longstanding sleep fragmentation, suggesting the involvement of OSA in HPA axis augmentation., Competing Interests: The Department of Respiratory Care and Sleep Control Medicine is funded by endowments from Philips-Respironics, ResMed, Fukuda Denshi and Fukuda Lifetec-Keiji to Kyoto University. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

Study Objectives: The individual prevalence of sleep-disordered breathing (SDB), short sleep duration, and obesity is high and increasing. The study aimed to investigate potential associations between SDB, objective sleep duration, obesity, diabetes and hypertension across genders, and the effect of pre- or post-menopausal status., Methods: A cross-sectional study evaluated 7051 community participants with wrist actigraphy for a week, and nocturnal oximetry ≥ 2 nights. SDB was assessed by 3 per cent oxygen desaturation index (ODI) corrected for sleep duration obtained from wrist actigraphy. Moderate-to-severe SDB was defined as ODI3% levels ≥ 15 per hour., Results: Both logODI3% and body mass index showed independent negative associations with sleep duration (β = -0.16, p < 0.001 and β = -0.07, p < 0.001, respectively). Moderate-to-severe SDB (men/premenopausal women/postmenopausal women; 23.7/1.5/9.5%, respectively) was associated with a higher risk of diabetes in premenopausal women (OR 28.1; 95%CI 6.35-124.6; p < 0.001) and postmenopausal women (OR 3.25; 95%CI 1.94-5.46; p < 0.001), but not in men (OR 1.47; 95%CI 0.90-2.40; p = 0.119). Moderate-to-severe SDB was associated with a higher risk of hypertension in men (OR 3.11; 95%CI 2.23-4.33; p < 0.001), premenopausal women (OR 3.88; 95%CI 1.42-10.6; p = 0.008), and postmenopausal women (OR 1.96; 95%CI 1.46-2.63; p < 0.001). Short sleep duration was not associated with diabetes or hypertension. The associations of obesity with diabetes or hypertension were indirectly mediated by SDB (24.0% and 21.5%, respectively), with possible sex differences emerging (men/women; 15.3/27.8% and 27.0/16.9%, respectively)., Conclusions: Notwithstanding the cross-sectional design, SDB and obesity, but not short sleep duration, were independently associated with diabetes and hypertension, with gender and menopausal status-related differences in risk emerging.

Sarcopenia has been associated with several conditions relevant to obstructive sleep apnea (OSA), such as aging and obesity, but a direct relationship between OSA and skeletal muscle alterations has not been identified. This study investigated associations between computed tomography (CT)-measured skeletal muscle indices and OSA severity. Analyzed were 334 patients who underwent polysomnography to diagnose OSA. Lumbar skeletal muscles were assessed with CT for the skeletal muscle mass index (SMI, cross-sectional area, normalized for height squared) and skeletal muscle density (SMD, fat infiltration). The apnea-hypopnea index (AHI) correlated positively with the SMI and negatively with SMD in both men and women. The AHI was weakly associated with SMI only in men (β = 0.11, P = 0.017) after adjustment for the body mass index (BMI) (BMI: β = 0.61, P < 0.001 in men, β = 0.65, P < 0.001 in women). The association of AHI and SMD was not significant after adjustment for BMI (BMI: β = -0.42, P < 0.001 in men, β = -0.64, P < 0.001 in women). Severity of OSA correlated with increases in skeletal muscle mass rather than muscle depletion and skeletal muscle adiposity. These associations were limited compared with the stronger associations between obesity and skeletal muscles.

Rationale: Obstructive sleep apnea (OSA) can affect not only sleep quality but also sleep duration. Determining the therapeutic effects of continuous positive airway pressure (CPAP) on habitual sleep profiles may shed light on the impact of OSA on sleep duration., Objectives: To determine whether and how CPAP affects habitual sleep duration in patients with OSA., Methods: Assessments of sleep duration and sleep quality were performed on 57 newly diagnosed study subjects with OSA (46 men; median age, 63 yr; apnea-hypopnea index, >20 h -1 ) at baseline and 3 months after initiation of CPAP therapy. Measurements included in-laboratory sleep tests (polysomnography), assessments of habitual sleep (actigraphy with sleep diary for 7 d), and questionnaires on subjective symptoms (Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, and Hospital Anxiety and Depression Scale)., Results: Actigraphic night sleep time did not change after CPAP (from 354.0 ± 64.5 min to 353.0 ± 57.0 min; P = 0.87) in the entire group, despite improvements in sleep efficiency and sleep fragmentation. Changes in habitual night sleep duration varied among the participants; habitual night sleep duration increased by 33 minutes (interquartile range, 14-45 min) in 28 participants (sleep time restorers) and decreased by 23 minutes (interquartile range, -48 to -11 min) in 29 participants (sleep time nonrestorers). Subgroup analyses revealed that sleep time restorers were characterized at baseline as having shorter and more fragmented sleep with frequent daytime napping. Nonrestorers were characterized by frequent use of hypnotic drugs and comorbid insomnia, despite longer habitual sleep duration. Actigraphic sleep fragmentation, sleep efficiency, daytime sleepiness, and the frequency of daytime napping were improved after CPAP only in the sleep time restorers, whereas subjective sleep quality was improved in the nonrestorers. Multivariate linear regression showed that shorter baseline night sleep time, baseline daytime napping, and percentage of sleep time under CPAP were positive predictors of the restoration of actigraphic night sleep time, whereas hypnotic use was a negative predictor., Conclusions: Short-term CPAP did not affect habitual night sleep duration in the group as a whole but induced intraindividual changes in relation to phenotypic features of OSA. Clinical trial registered with www.umin.ac.jp (UMIN000012639).

Endogenous carbon monoxide (CO) levels are recognized as a surrogate marker for activity of heme oxygenase-1, which is induced by various factors, including hypoxia and oxidative stress. Few reports have evaluated endogenous CO in patients with obstructive sleep apnea (OSA). Whether OSA more greatly affects exhaled or blood CO is not known. Sixty-nine patients with suspected OSA were prospectively included in this study. Exhaled and blood CO were evaluated at night and morning. Blood and exhaled CO levels were well correlated both at night and morning (r = 0.52, P < 0.0001 and r = 0.61, P < 0.0001, respectively). Although exhaled CO levels both at night and morning significantly correlated with total sleep time with arterial oxygen saturation < 90% (ρ = 0.41, P = 0.0005 and ρ = 0.27, P = 0.024, respectively), blood CO levels did not correlate with any sleep parameter. Seventeen patients with an apnea and hypopnea index (AHI) < 15 (control group) were compared with 52 patients with AHI ≥ 15 (OSA group). Exhaled CO levels at night in the OSA group were significantly higher than in the control group (3.64 ± 1.2 vs. 2.99 ± 0.70 ppm, P < 0.05). Exhaled CO levels at night decreased after 3 mo of continuous positive airway pressure (CPAP) therapy in OSA patients (n = 36; P = 0.016) to become nearly the same level as in the control group (P = 0.21). Blood CO levels did not significantly change after CPAP therapy. Exhaled CO was positively related to hypoxia during sleep in OSA patients, but blood CO was not. Exhaled CO might better correlate with oxidative stress associated with OSA than blood CO., New & Noteworthy: Endogenous carbon monoxide (CO) levels are recognized to be a surrogate marker of oxidative stress. No study has evaluated both exhaled and blood CO at the same time in obstructive sleep apnea (OSA) patients. Here we provide evidence that exhaled CO levels positively correlated with hypoxia during sleep in OSA patients, but blood CO levels did not, and that continuous positive airway pressure therapy significantly decreased exhaled CO levels in the OSA group, but did not significantly affect blood CO., (Copyright © 2017 the American Physiological Society.)

Rationale: Disrupted energy homeostasis in obstructive sleep apnea (OSA) may lead to weight gain. Paradoxically, treating OSA with continuous positive airway pressure (CPAP) may also promote weight gain, although the underlying mechanism remains unclear., Objectives: To explore the underlying mechanism by which patients with OSA gain weight after CPAP., Methods: A comprehensive assessment of energy metabolism was performed in 63 newly diagnosed OSA study participants (51 men; 60.8 ± 10.1 yr; apnea-hypopnea index >20 h(-1)) at baseline, CPAP initiation, and at a 3-month follow-up. Measurements included polysomnography, body weight, body composition, basal metabolic rate (BMR), hormones (norepinephrine, cortisol, leptin, ghrelin, insulin-like growth factor-1), dietary intake, eating behavior, and physical activity., Measurements and Main Results: BMR significantly decreased after CPAP (1,584 kcal/d at baseline, 1,561 kcal/d at CPAP initiation, and 1,508 kcal/d at follow-up; P < 0.001), whereas physical activity and total caloric intake did not significantly change. In multivariate regression, baseline apnea-hypopnea index, Δurine norepinephrine, and CPAP adherence were significant predictors of ΔBMR. The weight gainers had higher leptin levels, lower ghrelin levels, and higher eating behavior scores than the non-weight gainers, indicating a positive energy balance and disordered eating behavior among the weight gainers. Among the parameters related to energy metabolism, increased caloric intake was a particularly significant predictor of weight gain., Conclusions: Although a reduction in BMR after CPAP predisposes to a positive energy balance, dietary intake and eating behavior had greater impacts on weight change. These findings highlight the importance of lifestyle modifications combined with CPAP. Clinical trial registered with http://www.umin.ac.jp/english/ (UMIN000012639).

Rationale: Incretin hormones, namely glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide/glucose-dependent insulinotropic polypeptide (GIP), and dipeptidyl peptidase-4 (DPP-4) activity are important factors in glucose metabolism and have not been investigated in patients with obstructive sleep apnea (OSA)., Objectives: The objective of this study was to investigate the association between OSA and incretin and DPP-4 activity., Methods: This study included 96 consecutive patients without diabetes who were suspected of having OSA. We investigated the fasting and post-prandial incremental area under the curve (IAUC) of GLP-1, GIP serum levels, and serum DPP-4 activity levels, as well as their association with OSA. Changes in clinical variables were evaluated in the 43 patients who continued continuous positive airway pressure therapy for 3 months., Measurements and Main Results: Apnea-hypopnea index was an independent determining factor for fasting GLP-1 (β = 0.31; P = 0.0019) and IAUC GIP (β = -0.21; P = 0.037) after adjusting for known confounding factors. In those with very severe OSA (apnea-hypopnea index ≥50), the IAUCs for GLP-1 and GIP were significantly decreased, while fasting GLP-1 and fasting GIP were significantly increased. DPP-4 activity had no relation to OSA parameters or severity, while body mass index was significantly higher in those with severe OSA. Although significant changes in incretin secretion were not seen for 3 months after onset of continuous positive airway pressure therapy, the fasting GLP-1 level in the treated patients with severe OSA decreased to the same level as in untreated patients with normal to moderately severe OSA., Conclusions: OSA is associated with elevated serum levels of the incretin hormones GLP-1 (fasting) and GIP (post-prandial) in patients without diabetes. A significant association between body mass index and DPP-4, which is said to exist in healthy persons, was not found in the patients with OSA. Fasting GLP-1 in patients without diabetes with OSA may influence fasting glucose levels.

Rationale: Microalbuminuria is said to reflect systemic vascular damage and endothelial dysfunction and is an established indicator of cardiovascular morbidity and mortality. Patients with obstructive sleep apnea (OSA)-chronic obstructive pulmonary disease (COPD) overlap syndrome have worse survival than those with OSA or COPD alone., Objectives: This study evaluated the association between overlap syndrome and microalbuminuria., Methods: Data on patients in whom OSA was suspected and who underwent polysomnography between January 2010 and December 2012 were reviewed. Microalbuminuria was defined as an albumin-creatinine ratio between 20 and 299 mg/g in men and between 30 and 299 mg/g in women., Measurements and Main Results: Of 740 consecutive patients, 344 were analyzed. Sixty-four were control participants, 248 had OSA only, 4 had COPD only, and 28 had OSA-COPD overlap syndrome. Prevalence of microalbuminuria significantly increased in the order of control, OSA, and overlap syndrome groups (3.1, 12.9, and 32.1%, respectively; P = 0.0006). After adjusting for age and sex, multivariate logistic regression analysis demonstrated a significant association of overlap syndrome with microalbuminuria compared with OSA (odds ratio, 2.61; 95% confidence interval, 1.02-6.38; P = 0.047), but after adjusting for other confounding factors, the difference in the association did not reach significance (odds ratio, 2.54; 95% confidence interval, 0.93-6.72; P = 0.070). Of 63 patients reevaluated after 3 months of continuous positive airway pressure therapy, the logarithm of the albumin-creatinine ratio in 36 patients with good compliance significantly decreased, but there was no difference in patients with poor compliance., Conclusions: OSA-COPD overlap syndrome was more prevalent than OSA alone in patients with microalbuminuria, but the difference might be mediated by conventional risk factors rather than the addition of COPD itself.