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Naima Laharnar,1,* Sebastian Herberger,1,* Lisa-Kristin Prochnow,1 Ning-Hung Chen,2 Peter A Cistulli,3,4 Allan I Pack,5 Richard Schwab,5 Brendan T Keenan,5 Diego R Mazzotti,5,6 Ingo Fietze,1,7 Thomas Penzel1,8 1Department of Internal Medicine and Dermatology, Interdisciplinary Center of Sleep Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany; 2Department of Pulmonary and Critical Care Medicine, Sleep Center, Chang Gung Memorial Hospital, Taipei, Taiwan; 3Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia; 4Department of Respiratory Medicine, Royal North Shore Hospital, Sydney, NSW, Australia; 5Department of Medicine/Division of Sleep Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 6Department of Internal Medicine, Division of Medical Informatics, University of Kansas Medical Center, Kansas City, KS, USA; 7The Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov, First Moscow State Medical University of the Ministry of Health of the Russian Federation, Moscow, Russia; 8Department of Biology, Saratov State University, Saratov, Russia*These authors contributed equally to this workCorrespondence: Naima LaharnarDepartment of Internal Medicine and Dermatology, Interdisciplinary Center of Sleep Medicine, Charité – Universitätsmedizin Berlin, Campus Charité Mitte, Chariteplatz 1, Berlin, 10117, GermanyTel +49-30 450 513 120Email naima.laharnar@charite.dePurpose: An early prescreening in suspected obstructive sleep apnea (OSA) patients is desirable to expedite diagnosis and treatment. However, the accuracy and applicability of current prescreening tools is insufficient. We developed and tested an unbiased scoring system based solely on objective variables, which focuses on the diagnosis of severe OSA and exclusion of OSA.Patients and Methods: The OSA prediction score was developed (n = 150) and validated (n = 50) within German sleep center patients that were recruited as part of the Sleep Apnea Global Interdisciplinary Consortium (SAGIC). Six objective variables that were easy to assess and highly correlated with the apnea–hypopnea index were chosen for the score, including some known OSA risk factors: body-mass index, neck circumference, waist circumference, tongue position, male gender, and age (for women only). To test the predictive ability of the score and identify score thresholds, the receiver-operating characteristics (ROC) and curve were calculated.Results: A score ≥ 8 for predicting severe OSA resulted in an area under the ROC curve (ROC-AUC) of 90% (95% confidence interval: 84%, 95%), test accuracy of 82% (75%, 88%), sensitivity of 82% (65%, 93%), specificity of 82% (74%, 88%), and positive likelihood ratio of 4.55 (3.00, 6.90). A score ≤ 5 for predicting the absence of OSA resulted in a ROC-AUC of 89% (83%, 94%), test accuracy of 80% (73%, 86%), sensitivity of 72% (55%, 85%), specificity of 83% (75%, 89%), and positive likelihood ratio of 4.20 (2.66, 6.61). Performance characteristics were comparable in the small validation sample.Conclusion: We introduced a novel prescreening tool combining easily obtainable objective measures with predictive power and high general applicability. The proposed tool successfully predicted severe OSA (important due to its high risk of cardiovascular disease) and the exclusion of OSA (rarely a feature of previous screening instruments, but important for better differential diagnosis and treatment).Keywords: obstructive sleep apnea, diagnostic, sensitivity, specificity, screening

Here, we leverage a unique collection of 708 prospectively collected autopsied brains to assess the methylation state of the brain's DNA in relation to Alzheimer's disease (AD). We find that the level of methylation at 71 of the 415,848 interrogated CpGs is significantly associated with the burden of AD pathology, including CpGs in the ABCA7 and BIN1 regions, which harbor known AD susceptibility variants. We validate 11 of the differentially methylated regions in an independent set of 117 subjects. Further, we functionally validate these CpG associations and identify the nearby genes whose RNA expression is altered in AD: ANK1, CDH23, DIP2A, RHBDF2, RPL13, RNF34, SERPINF1 and SERPINF2. Our analyses suggest that these DNA methylation changes may have a role in the onset of AD since (1) they are seen in presymptomatic subjects and (2) six of the validated genes connect to a known AD susceptibility gene network.

Study Objectives: There is limited knowledge regarding the progression or consistency of symptoms in obstructive sleep apnea (OSA) over time. Our objective was to examine the changes in symptom subtypes and identify predictors over a span of 5 years., Methods: Data of 2,643 participants of the Sleep Heart Health Study with complete baseline and 5-year follow-up visits were analyzed. Latent class analysis on 14 symptoms at baseline and follow-up determined symptom subtypes. Individuals without OSA (apnea-hypopnea index < 5) were incorporated as a known class at each time point. Multinomial logistic regression assessed the effect of age, sex, body mass index, and apnea-hypopnea index on specific class transitions., Results: The sample consisted of 1,408 females (53.8%) and mean (standard deviation) age 62.4 (10.5) years. We identified 4 OSA symptom subtypes at both baseline and follow-up visits: minimally symptomatic , disturbed sleep , moderately sleepy , and excessively sleepy . Nearly half (44.2%) of the sample transitioned to a different subtype; transitions to moderately sleepy were the most common (77% of all transitions). A 5-year older age was associated with a 50% increase in odds to transit from excessively sleepy to moderately sleepy (odds ratio [95% confidence interval]: 1.52 [1.17, 1.97]). Females had 1.97 times higher odds (95% confidence interval: 1.21, 3.18) to transition from moderately sleepy to minimal symptoms . A 5-unit increase in body mass index was associated with 2.39 greater odds (95% confidence interval: 1.30, 4.40) to transition from minimal symptoms to excessively sleepy . Changes in apnea-hypopnea index did not significantly predict any transitions., Conclusions: The symptoms of OSA may fluctuate or remain stable over time. Knowledge of symptom progression in OSA may support clinicians with treatment decisions., Citation: Morris JL, Scott PW, Magalang U, et al. Symptom subtype progression in obstructive sleep apnea over 5 years. J Clin Sleep Med . 2024;20(11):1773-1783., (© 2024 American Academy of Sleep Medicine.)

The preoptic area of the hypothalamus (POA) is essential for sleep regulation. However, the cellular makeup of the POA is heterogeneous, and the molecular identities of the sleep-promoting cells remain elusive. To address this question, this study compares mice during recovery sleep following sleep deprivation to mice allowed extended sleep. Single-nucleus RNA sequencing (single-nucleus RNA-seq) identifies one galanin inhibitory neuronal subtype that shows upregulation of rapid and delayed activity-regulated genes during recovery sleep. This cell type expresses higher levels of growth hormone receptor and lower levels of estrogen receptor compared to other galanin subtypes. single-nucleus RNA-seq also reveals cell-type-specific upregulation of purinergic receptor (P2ry14) and serotonin receptor (Htr2a) during recovery sleep in this neuronal subtype, suggesting possible mechanisms for sleep regulation. Studies with RNAscope validate the single-nucleus RNA-seq findings. Thus, the combined use of single-nucleus RNA-seq and activity-regulated genes identifies a neuronal subtype functionally involved in sleep regulation., Competing Interests: Declaration of interests B.C.R. receives funding from Novo Nordisk and Boehringer Ingelheim that was not utilized for this project., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Study Objectives: The objectives of this study were to understand the relative comorbidity burden of obstructive sleep apnea (OSA), determine whether these relationships were modified by sex or age, and identify patient subtypes defined by common comorbidities., Methods: Cases with OSA and noncases (controls) were defined using a validated electronic health record (EHR)-based phenotype and matched for age, sex, and time period of follow-up in the EHR. We compared prevalence of the 20 most common comorbidities between matched cases and controls using conditional logistic regression with and without controlling for body mass index. Latent class analysis was used to identify subtypes of OSA cases defined by combinations of these comorbidities., Results: In total, 60,586 OSA cases were matched to 60,586 controls (from 1,226,755 total controls). Patients with OSA were more likely to have each of the 20 most common comorbidities compared with controls, with odds ratios ranging from 3.1 to 30.8 in the full matched set and 1.3 to 10.2 after body mass index adjustment. Associations between OSA and these comorbidities were generally stronger in females and patients with younger age at diagnosis. We identified 5 distinct subgroups based on EHR-defined comorbidities: High Comorbidity Burden, Low Comorbidity Burden, Cardiovascular Comorbidities, Inflammatory Conditions and Less Obesity, and Inflammatory Conditions and Obesity., Conclusions: Our study demonstrates the power of leveraging the EHR to understand the relative health burden of OSA, as well as heterogeneity in these relationships based on age and sex. In addition to enrichment for comorbidities, we identified 5 novel OSA subtypes defined by combinations of comorbidities in the EHR, which may be informative for understanding disease outcomes and improving prevention and clinical care. Overall, this study adds more evidence that OSA is heterogeneous and requires personalized management., Citation: Te TT, Keenan BT, Veatch OJ, Boland MR, Hubbard RA, Pack AI. Identifying clusters of patient comorbidities associated with obstructive sleep apnea using electronic health records. J Clin Sleep Med . 2024;20(4):521-533., (© 2024 American Academy of Sleep Medicine.)

Aim: To assess respiratory symptoms and nocturnal gastro-oesophageal reflux (nGER) among untreated obstructive sleep apnoea (OSA) patients, compared with the general population. Also, if nGER associates differently with respiratory symptoms among OSA patients., Methods: 2 study cohorts were included: 822 newly diagnosed subjects with moderate-severe OSA and 738 Icelandic general population study participants. All participants answered the same questionnaires. Those reporting nGER symptoms at least once per week were defined as 'with nGER'; those without nGER symptoms and without nGER medication were defined as 'no nGER'; and other participants were defined as having 'possible nGER'. Propensity score-based weights were used to minimise confounding and selection bias and facilitate causal interpretations., Results: The prevalence of nGER among OSA patients was 14.1%, compared with 5.8% in the general population. This increased prevalence in OSA was not explained by differences in age, gender, body mass index, smoking, hypertension and diabetes (adjusted OR (95% CI)=3.79 (2.24 to 6.43)). OSA patients 'with nGER' and with 'possible nGER' reported more wheezing (44% and 44% vs 25%, respectively) and productive cough (47% and 42% vs 29%, respectively), compared with OSA patients with 'no nGER'. The same pattern was seen in the general population, although with a generally lower prevalence. The effect of nGER on respiratory symptoms was similar between the two cohorts., Conclusion: nGER was more often reported among untreated moderate-severe OSA patients than in the general population. Participants with nGER had more wheezing and productive cough, both among untreated OSA patients and in the general population., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels generate electrical rhythmicity in various tissues although primarily heart, retina and brain. The HCN channel blocker compound, Ivabradine (Corlanor), is approved by the US Food and Drug Administration (FDA) as a medication to lower heart rate by blocking hyperpolarization activated inward current in the sinoatrial node. In addition, a growing body of evidence suggests a role for HCN channels in regulation of sleep/wake behavior. Zebrafish larvae are ideal model organisms for high throughput drug screening, drug repurposing and behavioral phenotyping studies. We leveraged this model system to investigate effects of three HCN channel blockers (Ivabradine, Zatebradine Hydrochloride and ZD7288) at multiple doses on sleep/wake behavior in wild type zebrafish. Results of interest included shorter latency to daytime sleep at 0.1 μM dose of Ivabradine (ANOVA, p: 0.02), moderate reduction in average activity at 30 μM dose of Zatebradine Hydrochloride (ANOVA, p: 0.024) in daytime, and increased nighttime sleep at 4.5 μM dose of ZD7288 (ANOVA, p: 0.036). Taken together, shorter latency to daytime sleep, decrease in daytime activity and increased nighttime sleep indicate that different HCN channel antagonists affected different parameters of sleep and activity., Competing Interests: SPS, CMP, GB, and MHP are employees of Vanda Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Vanda Pharmaceuticals Inc. The funder had the following involvement in the study: development of the hypothesis, interpretation of data, the review and editing of this article, and the decision to submit it for publication. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Doldur-Balli, Smieszek, Keenan, Zimmerman, Veatch, Polymeropoulos, Birznieks and Polymeropoulos.)

Aim: To study the effect of positive airway pressure (PAP) treatment on nocturnal gastro-oesophageal reflux (nGOR) and respiratory symptoms among clinical obstructive sleep apnoea (OSA) patients., Methods: 822 patients newly diagnosed with OSA referred for PAP treatment were recruited. 732 patients had a 2-year follow-up visit with continuous PAP compliance data (366 full PAP users, 366 partial/non-PAP users). They answered questionnaires, including reporting of nGOR, sleep and respiratory symptoms and general health. Patients with nGOR symptoms once a week or more were defined as "with nGOR". Those without nGOR symptoms and nGOR medication were defined as "no nGOR". Others were defined as "possible nGOR"., Results: At 2-year follow-up, PAP treatment among full users resulted in decreased nGOR (adjusted OR 0.58, 95% CI 0.40-0.86) and wheezing (adjusted OR 0.56, 95% CI 0.35-0.88) compared with partial/non-PAP users. Decreased nGOR, among both full and partial/non-users of PAP treatment, was associated with a decrease in productive morning cough (adjusted OR 4.70, 95% CI 2.22-9.99) and a decrease in chronic bronchitis (adjusted OR 3.86, 95% CI 1.74-8.58), but not decreased wheezing (adjusted OR 0.90, 95% CI 0.39-2.08). A mediation analysis found that PAP treatment directly led to a decrease in wheezing, not mediated through nGOR. Conversely, PAP treatment decreased productive cough mediated through a decrease in nGOR., Conclusion: In an unselected group of OSA patients, PAP treatment for 2 years was associated with a decrease in nGOR and respiratory symptoms. The PAP treatment itself was associated with less wheezing. A decrease in nGOR through PAP treatment was associated with a decrease in productive cough., Competing Interests: Conflict of interest: All authors have nothing to disclose., (Copyright ©The authors 2023.)

Fatigue is a common symptom associated with cancer treatments. Brain mechanisms underlying cancer-related fatigue (CRF) and its progression following therapy are poorly understood. Previous studies have suggested a role of the default mode network (DMN) in fatigue. In this study we used arterial spin labeling (ASL) perfusion functional magnetic resonance imaging (fMRI) and compared resting cerebral blood flow (CBF) differences in the posterior cingulate cortex (PCC), a core hub of the DMN, between 16 patients treated with radiation therapy (RAT) for prostate (9 males) or breast (7 females) cancer and 18 healthy controls (HC). Resting CBF in patients was also measured immediately after the performance of a fatiguing 20-min psychomotor vigilance task (PVT). Twelve of 16 cancer patients were further followed between 3 and 7 months after completion of the RAT (post-RAT). Patients reported elevated fatigue on RAT in comparison to post-RAT, but no change in sleepiness, suggesting that the underlying neural mechanisms of CRF progression are distinct from those regulating sleep drive progression. Compared to HC, patients showed significantly increased resting CBF in the PCC and the elevated PCC CBF persisted during the follow up visit. Post-PVT, but not pre-PVT, resting CBF changes in the PCC correlated with fatigue changes after therapy in patients with CRF, suggesting that PCC CBF following a fatiguing cognitive task may be a biomarker for CRF recovery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Raizen, Bhavsar, Keenan, Liu, Kegelman, Chao, Vapiwala and Rao.)

Study Objectives: Chronic noncancer pain (CP) commonly co-occurs with obstructive sleep apnea (OSA) and may contribute to greater symptom burden. The study aims were to (1) characterize CP among veterans with OSA and (2) examine differences in sleepiness (Epworth Sleepiness Scale), insomnia symptoms (Insomnia Severity Index), and quality of life (Short Form Health Survey-20) in veterans with OSA with or without pre-existing CP., Methods: An observational, cross-sectional, study of 111 veterans with newly diagnosed, untreated OSA was conducted. Descriptive statistics characterized the sample and comorbid CP outcomes. Regression analyses were performed to investigate associations between self-reported CP and sleep-related symptoms or quality of life while controlling for potential confounders., Results: CP was reported by 69.5% (95% confidence interval: 61.8%, 76.2%) of participants. Having CP was associated with increased Epworth Sleepiness Scale (12.7 ± 5.5 vs 10.2 ± 5.2; P = .021) and Insomnia Severity Index scores (18.1 ± 6.2 vs 13.7 ± 7.4; P = .002), and worse quality of life across all Short Form Health Survey-20 domains., Conclusions: There is a high prevalence of CP among veterans with OSA and symptom burden is higher in patients with OSA and CP. Future investigations should address symptom response and burden to OSA treatment in comorbid OSA and CP to guide outcome expectancies and residual OSA symptom treatment plans., Citation: Saconi B, Kuna ST, Polomano RC, Compton PA, Keenan BT, Sawyer AM. Chronic pain is common and worsens daytime sleepiness, insomnia, and quality of life in veterans with obstructive sleep apnea. J Clin Sleep Med . 2023;19(6):1121-1132., (© 2023 American Academy of Sleep Medicine.)

Sleep fulfills critical functions in neurodevelopment, such as promoting synaptic plasticity, neuronal wiring, and brain connectivity which are critical phenomena in Autism Spectrum Disorder (ASD) pathophysiology. Sleep disturbance, specifically insomnia, accompanies ASD and is associated with more severe core symptoms (e.g., social impairment). It is possible that focusing on identifying effective ways to treat sleep problems can help alleviate other ASD-related symptoms. A body of evidence indicates shared mechanisms and neurobiological substrates between sleep and ASD and investigation of these may inform therapeutic effects of improving sleep at both behavioral and molecular levels. In this study, we tested if sleep and social behavior were different in a zebrafish model with the arid1b gene mutated compared to controls. This gene was selected for study as expert curations conducted for the Simons Foundation for Autism Research Institute (SFARI) Gene database define it is as a 'high confidence' ASD gene (i.e., clearly implicated) encoding a chromatin remodeling protein. Homozygous arid1b mutants displayed increased arousability and light sleep compared to their heterozygous and wild type counterparts, based on testing a mechano-acoustic stimulus presenting different vibration frequencies of increasing intensity to detect sleep depth. In addition, decreased social preference was observed in arid1b heterozygous and homozygous mutant zebrafish. The behavioral phenotypes reported in our study are in line with findings from mouse models and human studies and demonstrate the utility of zebrafish as a vertebrate model system with high throughput phenotyping in the investigation of changes in sleep in models relevant to ASD. Furthermore, we demonstrate the importance of including assessments of arousal threshold when studying sleep using in vivo models., Competing Interests: Declarations of interest: None., (© 2023 The Authors.)

Objectives: To evaluate the cost-effectiveness of a 3-year tele-messaging intervention for positive airway pressure (PAP) use in obstructive sleep apnea (OSA)., Study Design: A post hoc cost-effectiveness analysis (from US payers' perspective) of data from a 3-month tele-OSA trial, augmented with 33 months of epidemiologic follow-up., Methods: Cost-effectiveness was compared among 3 groups of participants with an apnea-hypopnea index of at least 15 events/hour: (1) no messaging (n = 172), (2) messaging for 3 months (n = 124), and (3) messaging for 3 years (n = 46). We report the incremental cost (2020 US$) per incremental hour of PAP use and the fraction probability of acceptability based on a willingness-to-pay threshold of $1825 per year ($5/day)., Results: The use of 3 years of messaging had similar mean annual costs ($5825) compared with no messaging ($5889; P = .89) but lower mean cost compared with 3 months of messaging ($7376; P = .02). Those who received messaging for 3 years had the highest mean PAP use (4.11 hours/night), followed by no messaging (3.03 hours/night) and 3 months of messaging (2.84 hours/night) (all P < .05). The incremental cost-effectiveness ratios indicated that 3 years of messaging showed lower costs and greater hours of PAP use compared with both no messaging and 3 months of messaging. Based on a willingness-to-pay threshold of $1825, there is a greater than 97.5% chance (ie, 95% confidence) that 3 years of messaging is acceptable compared with the other 2 interventions., Conclusions: Long-term tele-messaging is highly likely to be cost-effective compared with both no and short-term messaging, with an acceptable willingness-to-pay threshold. Future long-term cost-effectiveness studies in a randomized controlled trial setting are warranted.

This study found no evidence that obesity significantly modifies the effect of 4 months of CPAP treatment on HOMA-IR. Longer duration of CPAP treatment may be needed in order to reduce insulin resistance and determine whether obesity modifies the effect. https://bit.ly/3CtX7jZ., Competing Interests: Conflict of Interest: All authors have nothing to disclose., (Copyright ©The authors 2023.)

Rationale and Objectives: Accurate segmentation of the upper airway lumen and surrounding soft tissue anatomy, especially tongue fat, using magnetic resonance images is crucial for evaluating the role of anatomic risk factors in the pathogenesis of obstructive sleep apnea (OSA). We present a convolutional neural network to automatically segment and quantify upper airway structures that are known OSA risk factors from unprocessed magnetic resonance images., Materials and Methods: Four datasets (n = [31, 35, 64, 76]) with T1-weighted scans and manually delineated labels of 10 regions of interest were used for model training and validations. We investigated a modified U-Net architecture that uses multiple convolution filter sizes to achieve multi-scale feature extraction. Validations included four-fold cross-validation and leave-study-out validations to measure generalization ability of the trained models. Automatic segmentations were also used to calculate the tongue fat ratio, a biomarker of OSA. Dice coefficient, Pearson's correlation, agreement analyses, and expert-derived clinical parameters were used to evaluate segmentations and tongue fat ratio values., Results: Cross-validated mean Dice coefficient across all regions of interests and scans was 0.70 ± 0.10 with highest mean Dice coefficient in the tongue (0.89) and mandible (0.81). The accuracy was consistent across all four folds. Also, leave-study-out validations obtained comparable accuracy across uniquely acquired datasets. Segmented volumes and the derived tongue fat ratio values showed high correlation with manual measurements, with differences that were not statistically significant (p < 0.05)., Conclusion: High accuracy of automated segmentations indicate translational potential of the proposed method to replace time consuming manual segmentation tasks in clinical settings and large-scale research studies., (Copyright © 2022 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Study Objectives: Patients with obstructive sleep apnea (OSA) are at increased risk of cardiovascular and cerebrovascular disease, but predicting those at greatest risk is challenging. Using latent class analysis, patients with OSA can be placed into discrete symptom subtypes. The aim of this study was to determine whether symptom subtypes are associated with future cerebrovascular disease in patients with OSA in a clinic-based cohort., Methods: Patients with suspected OSA referred for a polysomnogram at an academic sleep center completed a comprehensive symptom survey. Patients with OSA (apnea-hypopnea index ≥ 5 events/h) were then placed into symptom subtypes based on responses to survey questions using latent class analysis. Cardiovascular events (stroke, myocardial infarction, unstable angina, bypass grafting, percutaneous coronary intervention, cardiac resynchronization therapy, defibrillation) occurring within 8 years of polysomnogram were identified by linkage to provincial health databases., Results: 1,607 patients were studied, of whom 1,292 had OSA. One hundred forty first events occurred within 8 years of polysomnogram. Patients in the excessively sleepy with disturbed sleep subtype had a significantly increased rate of events compared to the minimally symptomatic subtype (hazard ratio = 2.25, 95% confidence interval: 1.02-4.94; P = .04). Two symptoms (restless legs and dozing off or sleeping while talking to someone) were significantly associated with future risk of cerebrovascular disease (hazard ratio = 1.68, 1.12-2.49 and 4.23, 1.61-11.16, respectively)., Conclusions: Patients with OSA in the clinic who are in the excessively sleepy with disturbed sleep subtype are significantly more likely to have a future cardiovascular event. This underscores the importance of understanding clinical heterogeneity and incorporating symptom subtype definitions into routine clinical care., Citation: Allen AJH, Jen R, Mazzotti DR, et al. Symptom subtypes and risk of incident cardiovascular and cerebrovascular disease in a clinic-based obstructive sleep apnea cohort. J Clin Sleep Med . 2022;18(9):2093-2102., (© 2022 American Academy of Sleep Medicine.)

Many aspects of sleep are heritable, but only a few sleep-regulating genes have been reported. Here, we leverage mouse models to identify and confirm a previously unreported gene affecting sleep duration-dihydropyrimidine dehydrogenase (Dpyd). Using activity patterns to quantify sleep in 325 Diversity Outbred (DO) mice-a population with high genetic and phenotypic heterogeneity-a linkage peak for total sleep in the active lights off period was identified on chromosome 3 (LOD score = 7.14). Mice with the PWK/PhJ ancestral haplotype at this location demonstrated markedly reduced sleep. Among the genes within the linkage region, available RNA sequencing data in an independent sample of DO mice supported a highly significant expression quantitative trait locus for Dpyd, wherein reduced expression was associated with the PWK/PhJ allele. Validation studies were performed using activity monitoring and EEG/EMG recording in Collaborative Cross mouse strains with and without the PWK/PhJ haplotype at this location, as well as EEG and EMG recording of sleep and wake in Dpyd knockout mice and wild-type littermate controls. Mice lacking Dpyd had 78.4 min less sleep during the lights-off period than wild-type mice (p = 0.007; Cohen's d = -0.94). There was no difference in other measured behaviors in knockout mice, including assays evaluating cognitive-, social-, and affective-disorder-related behaviors. Dpyd encodes the rate-limiting enzyme in the metabolic pathway that catabolizes uracil and thymidine to β-alanine, an inhibitory neurotransmitter. Thus, data support β-alanine as a neurotransmitter that promotes sleep in mice., Competing Interests: Declaration of interests A.I.P. is The John L. Miclot Professor of Medicine at the University of Pennsylvania; funds for this endowment were provided by the Philips Respironics Foundation. G.A.C., E.J.C., and K.L.S. disclose that The Jackson Laboratory produces and sells a wide variety of mice for research, including Collaborative Cross and Diversity Outbred mice. The other authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

It is unclear if the response to positive airway pressure (PAP) treatment is different between African American (AA) and European Americans (EA). We examined whether race modifies the effects of PAP on sleep and daytime function. We assessed Epworth Sleepiness Scale (ESS), Functional Outcomes of Sleep Questionnaire, Psychomotor Vigilance Task and actigraphy in 185 participants with moderate-to-severe obstructive sleep apnea before and 3-4 months after PAP treatment. The participants were middle-aged (mean, 55.1 years), 83.8% men and 60.5% AA. Linear regression models were used to examine the effect of race on outcomes. The AA had smaller reductions in ESS (mean change (95% confidence interval, CI) AA, -2.30 [-3.35, -1.25] vs. EA, -4.16 [-5.48, -2.84] and frequency of awakenings (AA, -0.73 [-4.92, 3.47] vs. EA, -9.35 [-15.20, -3.51]). A race × PAP usage interaction term was added to the model to examine if the change in outcomes per 1 h increase in PAP usage differed by race. AA exhibited greater improvement in wake after sleep onset (β (95% CI) AA, -8.89 [-16.40, -1.37] vs. EA, 2.49 [-4.15, 9.12]) and frequency of awakening (β (95% CI) AA, -2.59 [-4.44, -0.75] vs. EA, 1.71 [-1.08, 4.50]). The results indicate the importance of race in evaluating outcomes following PAP treatment.

The interneurons ALA and RIS both regulate stress induced sleep in C. elegans but their roles in awake animal movement has been reported to differ. We describe the development of a motivated mobility-based assay that distinguishes between animals mutant for ALA function and those mutant for RIS function., (Copyright: © 2021 by the authors.)

Study Objectives: To evaluate home sleep apnea testing (HSAT) using a type 3 portable monitor to help diagnose sleep-disordered breathing (SDB) and identify respiratory events including obstructive sleep apnea, central sleep apnea, and Cheyne-Stokes respiration in adults with stable chronic heart failure., Methods: Eighty-four adults with chronic heart failure (86.9% males, age [mean ± standard deviation] 58.7 ± 16.3 years, body mass index 29.4 ± 13.0 kg/m², left ventricular ejection fraction 40.3% ± 11.5%) performed unattended HSAT followed by an in-laboratory polysomnography (PSG) with simultaneous portable monitor recording., Results: The apnea-hypopnea index was 22.0 ± 17.0 events/h according to HSAT, 26.8 ± 20.5 events/h on an in-laboratory portable monitor, and 23.8 ± 21.3 events/h using PSG (P = .373). A Bland-Altman analysis of the apnea-hypopnea index using HSAT vs PSG showed a mean difference (95% confidence interval) of -2.4 (-4.9 to 0.1) events/h and limits of agreement (±2 standard deviations) of -24.1 to 19.2 events/h. HSAT underestimated the apnea-hypopnea index to a greater extent at a higher apnea-hypopnea index (rho = -.358; P < .001). Similar levels of agreement from HSAT vs PSG were observed when comparing the obstructive apnea index, central apnea index, and percentage of time in a Cheyne-Stokes respiration pattern. When we used an apnea-hypopnea index ≥ 5 events/h to diagnose SDB, HSAT had 86.7% sensitivity, 76.5% specificity, 92.9% positive predictive value, and 61.9% negative predictive value compared to PSG. Detection of Cheyne-Stokes respiration using HSAT showed 94.6% sensitivity, 91.1% specificity, 88.6% positive predictive value, and 97.6% negative predictive value compared to PSG., Conclusions: HSAT with a type 3 portable monitor can help diagnose SDB and identify obstructive sleep apnea, central sleep apnea, and Cheyne-Stokes respiration events in adults with chronic heart failure., (© 2021 American Academy of Sleep Medicine.)

Specific fat distributions are risk factors for complex diseases, including coronary heart disease and obstructive sleep apnea. To demonstrate the utility of high-diversity mouse models for elucidating genetic associations, we describe the phenotyping and heritability of fat distributions within the five classical inbred and three wild-derived founder mouse strains of the Collaborative Cross and Diversity Outbred mice. Measurements of subcutaneous and internal fat volumes in the abdomen, thorax and neck, and fat volumes in the tongue and pericardium were obtained using magnetic resonance imaging in male mice from the A/J (n = 12), C57BL/6J (n = 17), 129S1/SvlmJ (n = 12), NOD/LtJ (n = 14), NZO/HILtJ (n = 12), CAST/EiJ (n = 14), PWK/PhJ (n = 12), and WSB/EiJ (n = 15) strains. Phenotypes were compared across strains using analysis of variance and heritability estimated as the proportion of phenotypic variability attributable to strain. Heritability ranged from 44 to 91% across traits, including >70% heritability of tongue fat. A majority of heritability estimates remained significant controlling for body weight, suggesting genetic influences independent of general obesity. Principal components analysis supports genetic influences on overall obesity and specific to increased pericardial and intra-neck fat. Thus, among the founder strains of the Collaborative Cross and Diversity Outbred mice, we observed significant heritability of subcutaneous and internal fat volumes in the neck, thorax and abdomen, pericardial fat volume and tongue fat volume, consistent with genetic architecture playing an important role in explaining trait variability. Findings pave the way for studies utilizing high-diversity mouse models to identify genes affecting fat distributions and, in turn, influencing risk for associated complex disorders., (© The Author(s) 2021. Published by Oxford University Press on behalf of Genetics Society of America.)

It is unknown whether obesity modifies the effect of obstructive sleep apnea (OSA) and positive airway pressure (PAP) therapy on cardiac remodeling and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels. We compared NT-proBNP and cardiac magnetic resonance imaging in adults without OSA (n=56) and nonobese (n=73; body mass index <30 kg/m 2 ) and obese (n=136; body mass index ≥30 kg/m 2 ) adults with OSA. We also investigated these traits in nonobese (n=45) and obese (n=78) participants with OSA adherent to 4 months of PAP treatment. At baseline, left ventricular mass to end-diastolic volume ratio, a measure of left ventricular concentricity, was greater in both nonobese and obese participants with OSA compared with those without OSA. Participants with OSA and obesity exhibited reduced phasic right atrial function. No significant differences in baseline NT-proBNP were observed across groups. The effect of PAP treatment on NT-proBNP and left atrial volume index was significantly modified by obesity. In nonobese participants, PAP therapy was associated with a decrease in NT-proBNP ( P <0.0001) without a change in left atrial volume index, whereas in obese participants, PAP was associated with an increase in left atrial volume index ( P =0.006) without a change in NT-proBNP. OSA was associated with left ventricular concentric remodeling independent of obesity and right atrial dysfunction in participants who were obese. PAP treatment was associated with reduced NT-proBNP in nonobese participants with OSA, but left atrial enlargement in obese participants with OSA, suggesting that PAP-induced reduction in BNP release (which is known to occur during obstructive apnea episodes) may lead to volume retention in obese participants with OSA. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01578031.

Background: Previous studies show that galanin neurons in ventrolateral preoptic nucleus (VLPO-Gal) are essential for sleep regulation. Here, we explored the transcriptional regulation of the VLPO-Gal neurons in sleep by comparing their transcriptional responses between sleeping mice and those kept awake, sacrificed at the same diurnal time., Results: RNA-sequencing (RNA-seq) analysis was performed on eGFP(+) galanin neurons isolated using laser captured microdissection (LCM) from VLPO. Expression of Gal was assessed in our LCM eGFP(+) neurons via real time qPCR and showed marked enrichment when compared to LCM eGFP(-) cells and to bulk VLPO samples. Gene set enrichment analysis utilizing data from a recent single-cell RNA-seq study of the preoptic area demonstrated that our VLPO-Gal samples were highly enriched with galanin-expressing inhibitory neurons, but not galanin-expressing excitatory neurons. A total of 263 genes were differentially expressed between sleep and wake in VLPO-Gal neurons. When comparing differentially expressed genes in VLPO-Gal neurons to differentially expressed genes in a wake-active neuronal region (the medial prefrontal cortex), evidence indicates that both systemic and cell-specific mechanisms contribute to the transcriptional regulation in VLPO-Gal neurons. In both wake-active and sleep-active neurons, ER stress pathways are activated by wake and cold-inducible RNA-binding proteins are activated by sleep. In contrast, expression of DNA repair genes is increased in VLPO-Gal during wakefulness, but increased in wake-active cells during sleep., Conclusion: Our study identified transcriptomic responses of the galanin neurons in the ventrolateral preoptic nucleus during sleep and sleep deprivation. Data indicate that VLPO contains mainly sleep-active inhibitory galaninergic neurons. The VLPO galanin neurons show responses to sleep and wake similar to wake-active regions, indicating these responses, such as ER stress and cold-inducible RNA-binding proteins, are systemic affecting all neuronal populations. Region-specific differences in sleep/wake responses were also identified, in particular DNA repair. Our study expands knowledge about the transcriptional response of a distinct group of neurons essential for sleep.

Background: Obstructive sleep apnea (OSA) is defined by frequent episodes of reduced or complete cessation of airflow during sleep and is linked to negative health outcomes. Understanding the genetic factors influencing expression of OSA may lead to new treatment strategies. Electronic health records (EHRs) can be leveraged to both validate previously reported OSA-associated genomic variation and detect novel relationships between these variants and comorbidities., Methods: We identified candidate single nucleotide polymorphisms (SNPs) via systematic literature review of existing research. Using datasets available at Geisinger (n = 39,407) and Vanderbilt University Medical Center (n = 24,084), we evaluated associations between 40 previously implicated SNPs and OSA diagnosis, defined using clinical codes. We also evaluated associations between these SNPs and OSA severity measures obtained from sleep reports at Geisinger (n = 6571). Finally, we used a phenome-wide association study approach to help reveal pleiotropic genetic effects between OSA candidate SNPs and other clinical codes and laboratory values available in the EHR., Results: Most previously reported OSA candidate SNPs showed minimal to no evidence for associations with OSA diagnosis or severity in the EHR-derived datasets. Three SNPs in LEPR, MMP-9, and GABBR1 validated for an association with OSA diagnosis in European Americans; the SNP in GABBR1 was associated following meta-analysis of results from both clinical populations. The GABBR1 and LEPR SNPs, and one additional SNP, were associated with OSA severity measures in European Americans from Geisinger. Three additional candidate OSA SNPs were not associated with OSA-related traits but instead with hyperlipidemia and autoimmune diseases of the thyroid., Conclusions: To our knowledge, this is one of the largest candidate gene studies and one of the first phenome-wide association studies of OSA genomic variation. Results validate genetic associates with OSA in the LEPR, MMP-9 and GABBR1 genes, but suggest that the majority of previously identified genetic associations with OSA may be false positives. Phenome-wide analyses provide evidence of mediated pleiotropy. Future well-powered genome-wide association analyses of OSA risk and severity across populations with diverse ancestral backgrounds are needed. The comprehensive nature of the analyses represents a platform for informing future work focused on understanding how genetic data can be useful to informing treatment of OSA and related comorbidities.

Homer proteins are a component of the post-synaptic density of neurons that are necessary for the maintenance and consolidation of behavioral state. The dominant negative protein homer1a is rapidly increased by neuronal activity and sleep loss. Homer1a knockout mice with globally absent homer1a have reduced ability to sustain wakefulness during the active period. It is not known whether homer1a is required globally or in very specific brain regions or neurons for its role in maintaining wake. In this study, we examined the expression of homer1a , an immediate early gene involved in intracellular signaling cascades, in mice subjected to extended wakefulness. We found that mice displayed increased expression of homer1a in the claustrum, a brain region thought to be involved in consciousness, as well as the cingulate and piriform cortices compared to non-sleep deprived mice. In situ hybridization (ISH) studies also indicate that homer1a is not induced in the known wake promoting regions with sleep deprivation, but is instead upregulated primarily in the claustrum and piriform cortex. Examination of homer1a expression levels with recovery sleep after sleep deprivation indicate that baseline homer1a expression levels were restored. Further, we have identified that homer1a is upregulated in excitatory neurons of the claustrum suggesting that homer1a promotes wakefulness through activating excitatory neurons. This work identifies regions previously unknown to be involved in sleep regulation that respond to acute sleep deprivation or enhanced waking., (Copyright © 2020 Zhu, Hafycz, Keenan, Guo, Pack and Naidoo.)

Study Objectives: We examined the performance of a simple algorithm to accurately distinguish cases of diagnosed obstructive sleep apnea (OSA) and noncases using the electronic health record (EHR) across six health systems in the United States., Methods: Retrospective analysis of EHR data was performed. The algorithm defined cases as individuals with ≥ 2 instances of specific International Classification of Diseases (ICD)-9 and/or ICD-10 diagnostic codes (327.20, 327.23, 327.29, 780.51, 780.53, 780.57, G4730, G4733 and G4739) related to sleep apnea on separate dates in their EHR. Noncases were defined by the absence of these codes. Using chart reviews on 120 cases and 100 noncases at each site (n = 1,320 total), positive predictive value (PPV) and negative predictive value (NPV) were calculated., Results: The algorithm showed excellent performance across sites, with a PPV (95% confidence interval) of 97.1 (95.6, 98.2) and NPV of 95.5 (93.5, 97.0). Similar performance was seen at each site, with all NPV and PPV estimates ≥ 90% apart from a somewhat lower PPV of 87.5 (80.2, 92.8) at one site. A modified algorithm of ≥ 3 instances improved PPV to 94.9 (88.5, 98.3) at this site, but excluded an additional 18.3% of cases. Thus, performance may be further improved by requiring additional codes, but this reduces the number of determinate cases., Conclusions: A simple EHR-based case-identification algorithm for diagnosed OSA showed excellent predictive characteristics in a multisite sample from the United States. Future analyses should be performed to understand the effect of undiagnosed disease in EHR-defined noncases. This algorithm has wide-ranging applications for EHR-based OSA research., (© 2020 American Academy of Sleep Medicine.)

Sleep abnormalities are common with aging. Studies show that sleep plays important roles in brain functions, and loss of sleep is associated with increased risks for neurological diseases. Here, we used RNA sequencing to explore effects of age on transcriptome changes between sleep and sleep deprivation (SD) in medial prefrontal cortex and found that transcriptional changes with sleep are attenuated in old. In particular, old mice showed a 30% reduction in the number of genes significantly altered between sleep/wake and, in general, had smaller magnitudes of changes in differentially expressed genes compared to young mice. Gene ontology analysis revealed differential age effects on certain pathways. Compared to young mice, many of the wake-active functions were similarly induced by SD in old mice, whereas many of the sleep-active pathways were attenuated in old mice. We found similar magnitude of changes in synaptic homeostasis genes (Fos, Arc, and Bdnf) induced by SD, suggesting intact synaptic upscaling on the transcript level during extended wakefulness with aging. However, sleep-activated processes, such as DNA repair, synaptogenesis, and axon guidance, were sensitive to the effect of aging. Old mice expressed elevated levels of immune response genes when compared to young mice, and enrichment analysis using cell-type-specific markers indicated upregulation of microglia and oligodendrocyte genes in old mice. Moreover, gene sets of the two cell types showed age-specific sleep/wake regulation. Ultimately, this study enhances understanding of the transcriptional changes with sleep and aging, providing potential molecular targets for future studies of age-related sleep abnormalities and neurological disorders., (© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Many patients with obstructive sleep apnea (OSA), but not all, have a reduction in blood pressure (BP) with positive airway pressure (PAP) treatment. Our objective was to determine whether the BP response following PAP treatment is related to obesity. A total of 188 adults with OSA underwent 24-hour BP monitoring and 24-hour urinary norepinephrine collection at baseline. Obesity was assessed by waist circumference, body mass index, and abdominal visceral fat volume. Participants adherent to PAP treatment were reassessed after 4 months. Primary outcomes were 24-hour mean arterial pressure (MAP) and 24-hour urinary norepinephrine level. Obstructive sleep apnea participants had a significant reduction in 24-hour MAP following PAP treatment (-1.22 [95% CI: -2.38, -0.06] mm Hg; P = .039). No significant correlations were present with any of the 3 obesity measures for BP or urinary norepinephrine measures at baseline in all OSA participants or for changes in BP measures in participants adherent to PAP treatment. Changes in BP measures following treatment were not correlated with baseline or change in urinary norepinephrine. Similar results were obtained when BP or urinary norepinephrine measures were compared between participants dichotomized using the sex-specific median of each obesity measure. Greater reductions in urinary norepinephrine were correlated with higher waist circumference (rho = -0.21, P = .037), with a greater decrease from baseline in obese compared to non-obese participants (-6.26 [-8.82, -3.69] vs -2.14 [-4.63, 0.35] ng/mg creatinine; P = .027). The results indicate that the BP response to PAP treatment in adults with OSA is not related to obesity or urinary norepinephrine levels., (©2019 Wiley Periodicals, Inc.)

Study Objectives: Obstructive sleep apnea (OSA) is a global health issue and is associated with obesity and oropharyngeal crowding. Global data are limited on the effect of ethnicity and sex on these relationships. We compare associations between the apnea-hypopnea index (AHI) and these risk factors across ethnicities and sexes within sleep clinics., Methods: This is a cross-sectional, multicenter study of patients with OSA from eight sleep centers representing the Sleep Apnea Global Interdisciplinary Consortium (SAGIC). Four distinct ethnic groups were analyzed, using a structured questionnaire: Caucasians (Australia, Iceland, Germany, United States), African Americans (United States), Asians (Taiwan), and South Americans (Brazil). Regression analyses and interaction tests were used to assess ethnic and sex differences in relationships between AHI and anthropometric measures (body mass index [BMI], neck circumference, waist circumference) or Mallampati score., Results: Analyses included 1,585 individuals from four ethnic groups: Caucasian (60.6%), African American (17.5%), Asian (13.1%), and South American (8.9%). BMI was most strongly associated with AHI in South Americans (7.8% increase in AHI per 1 kg/m 2 increase in BMI; P < .0001) and most weakly in African Americans (1.9% increase in AHI per 1 kg/m 2 increase in BMI; P = .002). In Caucasians and South Americans, associations were stronger in males than females. Mallampati score differed between ethnicities but did not influence AHI differently across groups., Conclusions: We demonstrate ethnic and sex variations in associations between obesity and OSA. For similar BMI increases, South American patients show greatest AHI increases compared to African Americans. Findings highlight the importance of considering ethnicity and sex in clinical assessments of OSA risk., (© 2019 American Academy of Sleep Medicine.)

Study Objectives: Clinical practice guidelines recommend polysomnography (PSG) for diagnosis of obstructive sleep apnea (OSA) in patients with major comorbidities. We evaluated home sleep apnea testing (HSAT) using a type 3 portable monitor (PM, Nox-T3, Nox Medical, Reykjavik, Iceland) to diagnose OSA in adults with chronic obstructive pulmonary disease (COPD)., Methods: Ninety adults with COPD (89.0% males, mean ± standard deviation age 66.5 ± 7.8 years, body mass index 27.5 ± 5.8 kg/m 2 , forced expiratory volume in the first second/forced vital capacity [FEV 1 / FVC] 53.5 ± 12.4%, FEV 1 54.0 ± 18.4% predicted) underwent unattended HSAT followed by an in-laboratory PSG with simultaneous PM recording., Results: Scoring hypopneas with a ≥ 4% oxygen desaturation, the apnea-hypopnea index (AHI) was 16.7 ± 20.6 events/h on HSAT, 20.0 ± 23.3 events/h on in-laboratory PM, and 21.2 ± 26.2 events/h on PSG ( P < .0001). Bland-Altman analysis of AHI on HSAT versus PSG showed a mean difference (95% confidence interval) of -5.08 (-7.73, -2.42) events/h ( P = .0003) and limits of agreement (± 2 standard deviations) of -30.00 to 19.85 events/h; HSAT underestimated AHI to a greater extent for more severe values (rho = -.529, P < .0001). Using an AHI ≥ 5 events/h to diagnose OSA, HSAT had 95% sensitivity, 78% specificity, 88% positive predictive value, and 89% negative predictive value compared to PSG. Mean oxygen saturation was 93.2 ± 3.7% on PSG, 91.0 ± 3.3% on in-laboratory PM, and 90.8 ± 4.0% on HSAT ( P < .0001). Percentage time oxygen saturation ≤ 88% was 17.9 ± 26.4% on HSAT, 17.4 ± 25.5% on in-laboratory PM, and 10.0 ± 21.1% on PSG ( P < .0001)., Conclusions: The Nox-T3 PM can be used to diagnose OSA in patients with COPD but, most likely due to differences among pulse oximeters, a greater number of patients with COPD and without OSA qualified for nocturnal oxygen treatment using this PM than PSG., (© 2019 American Academy of Sleep Medicine.)

Background: Epidemiological data suggests that obstructive sleep apnea (OSA) is associated with increased cancer incidence and mortality. We investigate the effects of cyclical intermittent hypoxia (CIH), akin to the underlying pathophysiology of OSA, on lung cancer progression and metastatic profile in a mouse model., Methods: Intrathoracic injection of Ad5CMVCre virus into a genetically engineered mouse (GEM) KrasG12D+/-; p53fl/fl; myristolated-p110αfl/fl-ROSA-gfp was utilized to induce a solitary lung cancer. Male mice were then exposed to either CIH or Sham for 40-41 days until harvest. To monitor malignant progression, serial micro CT scans with respiratory gating (no contrast) was performed. To detect spontaneous metastases in distant organs, H&E and immunohistochemistry were performed., Results: Eighty-eight percent of injected Ad5CMVCre virus was recovered from left lung tissue, indicating reliable and accurate injections. Serial micro CT demonstrated that CIH increases primary lung tumor volume progression compared to Sham on days 33 (p = 0.004) and 40 (p<0.001) post-injection. In addition, CIH increases variability in tumor volume on day 19 (p<0.0001), day 26 (p<0.0001), day 33 (p = 0.025) and day 40 (p = 0.004). Finally, metastases are frequently detected in heart, mediastinal lymph nodes, and right lung using H&E and immunohistochemistry., Conclusions: Using a GEM mouse model of metastatic lung cancer, we report that male mice with solitary lung cancer have accelerated malignant progression and increased variability in tumor growth when exposed to cyclical intermittent hypoxia. Our results indicate that cyclical intermittent hypoxia is a pathogenic factor in non-small cell lung cancer that promotes the more rapid growth of developing tumors., Competing Interests: This is not an industry-supported study. JCG: External Advisory Boards: KSQ Therapeutics, ITUS, Compass Therapeutics; Sponsored research: Compass Therapeutics, ITUS. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Study Objectives: Obstructive sleep apnea (OSA) is common in commercial motor vehicle operators (CMVOs); however, polysomnography (PSG), the gold-standard diagnostic test, is expensive and inconvenient for screening. OSA is associated with changes in heart rate and voltage on electrocardiography (EKG). We evaluated the utility of EKG parameters in identifying CMVOs at greater risk for sleepiness-related crashes (apnea-hypopnea index [AHI] ≥ 30 events/h)., Methods: In this prospective study of CMVOs, we performed EKGs with concurrent PSG, and calculated the respiratory power index (RPI) on EKG, a surrogate for AHI calculated from PSG. We evaluated the utility of two-stage predictive models using simple clinical measures (age, body mass index [BMI], neck circumference, Epworth Sleepiness Scale score, and the Multi-Variable Apnea Prediction [MVAP] score) in the first stage, followed by RPI in a subset as the second-stage. We assessed area under the receiver operating characteristic curve (AUC), sensitivity, and negative posttest probability (NPTP) for this two-stage approach and for RPI alone., Results: The best-performing model used the MVAP, which combines BMI, age, and sex with three OSA symptoms, in the first stage, followed by RPI in the second. The model yielded an estimated (95% confidence interval) AUC of 0.883 (0.767-0.924), sensitivity of 0.917 (0.706-0.962), and NPTP of 0.034 (0.015-0.133). Predictive characteristics were similar using a model with only BMI as the first-stage screen., Conclusions: A two-stage model that combines BMI or the MVAP score in the first stage, with EKG in the second, had robust discriminatory power to identify severe OSA in CMVOs., (© 2019 American Academy of Sleep Medicine.)

Rationale: Obesity is a major risk factor for obstructive sleep apnea. Although greater dimensional changes in the upper airway during wake respiration have been noted in patients with apnea compared with control subjects, whether these differences remain in the presence of obesity is unknown., Objectives: To evaluate upper airway anatomic characteristics and airway compliance (distensibility) in obese subjects with obstructive sleep apnea compared with obese control subjects., Methods: Dynamic magnetic resonance imaging was performed in 157 obese subjects with apnea and 46 obese control subjects during wakefulness in the midsagittal and three axial upper airway regions (retropalatal, retroglossal, epiglottal). Differences in measurements between subjects with apnea and control subjects, and correlations with apnea-hypopnea index among subjects with apnea, were examined., Measurements and Main Results: Measurements included airway areas and linear dimensions. Subject-specific coefficients of variation were calculated to examine variability in airway size. Controlling for covariates, the retropalatal area during respiration was significantly smaller in subjects with apnea than control subjects, based on the average (P = 0.003), maximum (P = 0.004), and minimum (P = 0.001) airway area. Airway narrowing was observed in anteroposterior and lateral dimensions (adjusted P < 0.05). Results were similar in an age, sex, and body mass index-matched subsample. There were significant correlations between apnea-hypopnea index and dynamic measures of airway caliber in the retropalatal and retroglossal regions among subjects with apnea., Conclusions: Upper airway caliber during respiration was significantly narrower in obese subjects with apnea than obese control subjects in the retropalatal region. These findings provide further evidence that retropalatal airway narrowing plays an important role in the pathogenesis of obstructive sleep apnea in obese subjects.

Study Objectives: To examine the level of physical activity (PA) before and following positive airway pressure (PAP) treatment in adults who have obstructive sleep apnea (OSA) with obesity versus without obesity., Methods: Simultaneous waist accelerometer and wrist actigraphy recordings were obtained in 129 adults with obesity and 69 adults without obesity and who had OSA prior to and following 4 months of PAP therapy and in 52 patients in a control group. Primary PA measurements were average steps per day on waist accelerometry and average counts per minute (CPM) per day on wrist actigraphy., Results: At baseline, participants with obesity and OSA exhibited fewer steps per day on waist accelerometer and fewer CPM per day on wrist actigraphy compared to participants without obesity and with OSA (despite similar apnea-hypopnea index between groups). Following PAP treatment, participants with OSA had modestly increased CPM per day on wrist actigraphy (17.69 [95% confidence interval (CI), 5.67-29.71], P = .005) and increased light PA time (0.26 [95% CI, 0.07-0.44] hours, P = .008) on waist accelerometer. Participants without obesity and with OSA had greater improvements in PA measures on average compared to participants with obesity and OSA, although the differences were not statistically significant. Weight increased following PAP treatment in the participants with obesity and OSA (1.71 [95% CI, 0.41-3.02] kg, P = .010) but was unchanged in the group without obesity (0.93 [95% CI, -0.89 to 2.76] kg, P = .311)., Conclusions: Compared to study participants without obesity and with OSA, participants with obesity and OSA had reduced PA at baseline. PA increased significantly in participants without obesity, with OSA, and who were adherent to PAP treatment. Results indicate that treatment of OSA is unlikely to be associated with a change in PA in adults with obesity and OSA and help explain the absence of weight loss following PAP treatment in adults with OSA., Clinical Trial Registration: Registry: ClinicalTrials.gov, title: The Effects of Treating Obese and Lean Patients With Sleep Apnea (PISA), identifier: NCT01578031, URL: https://clinicaltrials.gov/ct2/show/NCT01578031., (© 2018 American Academy of Sleep Medicine.)

Study Objectives: Few studies have objectively evaluated sleep characteristics during pregnancy or investigated the relationship between altered spectral electroencephalogram (EEG) bands and sleep-disordered breathing (SDB). The study aimed to describe changes in sleep as measured by polysomnography (PSG) and spectral EEG bands during pregnancy and to examine the relationship between delta power in non-rapid eye movement (NREM) sleep and SDB., Methods: This is a secondary analysis of a prospective study. One hundred twenty-three women underwent full PSG in early pregnancy, and 97 repeated PSG in late pregnancy. Spectral analysis of the EEG in NREM sleep was performed. We used linear and logistic mixed-model regression to analyze the sleep measures and linear regression to explore the association between delta power and apnea-hypopnea index (AHI) changes during pregnancy., Results: In late pregnancy, women had shorter sleep duration, poorer sleep efficiency, more awakenings, more stage N2 sleep, less slow wave sleep, less REM sleep, higher AHI, and higher periodic limb movement index compared to early pregnancy. The percentage of stage N1 sleep, sleep latency, REM sleep latency, and arousal index frequency did not change. Regarding EEG-spectra, delta and theta powers decreased, but beta-2 power increased during pregnancy. In multivariable analyses, greater reduction of delta power was associated with larger increases in AHI (β [95% confidence interval] = -0.038 [-0.073, -0.002], P = .040). Estimates suggest that each one-unit increase in AHI reduces delta power by 4% in late pregnancy., Conclusions: PSG-measured sleep characteristics change during pregnancy. Delta power decreases when the severity of SDB increases during pregnancy., Commentary: A commentary on this article appears in this issue on page 1095., (© 2018 American Academy of Sleep Medicine.)

Background and Aims: Associated with numerous metabolic and behavioral abnormalities, obesity is classified by metrics reliant on body weight (such as body mass index). However, overnutrition is the common cause of obesity, and may independently contribute to these obesity-related abnormalities. Here, we use dietary challenges to parse apart the relative influence of diet and/or energy balance from body weight on various metabolic and behavioral outcomes., Materials and Methods: Seventy male mice (mus musculus) were subjected to the diet switch feeding paradigm, generating groups with various body weights and energetic imbalances. Spontaneous activity patterns, blood metabolite levels, and unbiased gene expression of the nutrient-sensing ventral hypothalamus (using RNA-sequencing) were measured, and these metrics were compared using standardized multivariate linear regression models., Results: Spontaneous activity patterns were negatively related to body weight (p<0.0001) but not diet/energy balance (p = 0.63). Both body weight and diet/energy balance predicted circulating glucose and insulin levels, while body weight alone predicted plasma leptin levels. Regarding gene expression within the ventral hypothalamus, only two genes responded to diet/energy balance (neuropeptide y [npy] and agouti-related peptide [agrp]), while others were related only to body weight., Conclusions: Collectively, these results demonstrate that individual components of obesity-specifically obesogenic diets/energy imbalance and elevated body mass-can have independent effects on metabolic and behavioral outcomes. This work highlights the shortcomings of using body mass-based indices to assess metabolic health, and identifies novel associations between blood biomarkers, neural gene expression, and animal behavior following dietary challenges.

Study Objectives: Recently, the Icelandic Sleep Apnea Cohort (ISAC) identified three subgroups in patients with obstructive sleep apnea (OSA) recruited from the sleep clinic based on clinical symptoms and comorbidities: excessively sleepy, minimally symptomatic, and disturbed sleep. This study sought to determine whether the three OSA subgroups are applicable to a population-based cohort in Korea., Methods: Study subjects are participants of an ongoing cohort study in Korea. Of the 2,918 participants, 422 new moderate to severe OSA cases (apneahypopnea index [AHI] ≥ 15 events/h) were diagnosed by home sleep studies. All participants completed a detailed questionnaire on sleep-related symptoms, comorbidities, medication, and other information. A latent class analysis was performed., Results: When examining solutions for up to 10 clusters, the a priori three-cluster solution was the optimal clustering solution. The three-cluster solution demonstrated a subgroup presentation similar to the clusters identified in the ISAC. The minimally symptomatic subgroup was most prevalent (55.7%) in the Korean cohort. Among the three subgroups, there were no differences in mean AHI and body mass index; however, the disturbed sleep subgroup was older and had more females., Conclusions: Combined with the ISAC data, we suggest that the three-symptom cluster solution for patients with OSA may be more widely applicable, irrespective of ethnicity and study population., (© 2018 American Academy of Sleep Medicine.)

Study Objectives: Positive airway pressure (PAP) adherence data are a routine aspect of clinical care for obstructive sleep apnea (OSA), but not uniformly available. We hypothesized that mask refills are a measure of PAP adherence., Methods: We measured PAP use over the first 90 days of treatment in 123 patients with OSA. The number and timing of mask refills was assessed over 18 months. Demographic and medical information was obtained from the electronic medical record., Results: Average PAP use in the first week of more than 4 h/d was a predictor of adherence over the first 90 days ( P < .0001). PAP use over 90 days was greater in datacard-derived data dependent on patients presenting a datacard to the clinic compared to modem-derived data ( P = .0006). A mask refill within the first 30 days of treatment was associated with a 1.3 h/d lower PAP usage in the first 90 days ( P = .0044). Conversely, the number of mask refills between 30 days and 18 months was associated with higher PAP adherence during the first 90 days, with an additional 0.61 h/d of use for each additional refill ( P = .0015)., Conclusions: In a retrospective cohort of veterans with OSA, first week PAP use was a strong predictor of 90-day use. Use of autonomously transmitted modem data avoided potential selection bias in adherence estimates. Mask refills in the first month were associated with less 90-day PAP use, whereas more mask refills after 30 days were associated with greater PAP use., (© 2017 American Academy of Sleep Medicine)

Study Objectives: To evaluate the performance of a portable monitor (Nox-T3, Nox Medical Inc. Reykjavik, Iceland) used to diagnose obstructive sleep apnea in Chinese adults., Methods: Eighty Chinese adults (mean ± standard deviation age 47.6 ± 14.0 years, 77.5% males, body mass index 27.5 ± 5.4 kg/m 2 ) underwent overnight, unattended home sleep apnea testing (HSAT) with the Nox-T3 portable monitor followed by an overnight in-laboratory polysomnogram (PSG) with simultaneous portable monitor recording. The portable monitor recordings were scored using automated analysis and then manually edited using different criteria for scoring hypopneas. Polysomnography was scored based on recommended guidelines., Results: When scoring of hypopneas required a ≥ 4% oxygen desaturation event, the mean ± standard deviation apnea-hypopnea index (AHI) was 24.4 ± 20.8 events/h on HSAT, 28.0 ± 22.9 events/h on in-laboratory portable monitor recording, and 28.6 ± 23.9 events/h on PSG ( P < .0001). Bland-Altman analysis of AHI on PSG versus HSAT showed a mean difference (95% confidence interval) of -4.64 (-7.15, -2.13); limits of agreement (equal to ± 2 standard deviations) was -26.62 to 17.35 events/h. Based on a threshold of AHI ≥ 5 events/h, HSAT had 95% sensitivity, 69% specificity, 94% positive predictive value, and 75% negative predictive value compared to PSG. Using an AHI ≥ 15 events/h, HSAT had 93% sensitivity, 85% specificity, 89% positive predictive value, and 91% negative predictive value. Closer agreements were present when comparing the simultaneous recordings. Similar results were obtained using different scoring criteria for hypopneas., Conclusions: Despite known differences between HSAT and PSG, the results show close agreement between the two diagnostic tests in Chinese adults, especially when controlling for night-to-night variability and changes in sleeping environment., (© 2017 American Academy of Sleep Medicine)

Objectives: We explored how restaurant inspection frequency and restaurant neighborhood sociodemographic characteristics are related to food safety inspection outcomes in chain and nonchain restaurants to better understand external factors that may influence inspection outcomes., Methods: We categorized the results of restaurant inspections in Philadelphia, Pennsylvania, in 2013 and 2014 by restaurant type (chain or nonchain), inspection frequency (1, 2, or ≥3 per 2-year study period), and violation type (total number of violations, foodborne-illness risk factor violation, or good retail practice violation). We collected 2013 US Census block group sociodemographic data for each restaurant neighborhood. We used nested mixed-effects regression analyses to determine the association between restaurant inspection frequency and inspection violations, as well as between inspection violations and restaurant neighborhood sociodemographic variables, stratified by restaurant type., Results: Compared with nonchain restaurants, chain restaurants had significantly fewer total violations per inspection (mean [SD]: 6.5 [4.6] vs 9.6 [6.8] violations, P < .001). For nonchain restaurants, an increase from 1 to 2 inspections resulted in 0.8 ( P < .001) fewer mean violations per inspection, and an increase from 1 to ≥3 inspections resulted in 1.6 ( P < .001) fewer mean violations; this association was not seen in chain restaurants. For nonchain restaurants, a higher proportion of black residents in a restaurant neighborhood was associated with 0.6 ( P < .001) fewer mean foodborne-illness risk factor violations but 1.0 ( P < .001) more mean good retail practice violations per inspection., Conclusions: A risk-based stratified approach to restaurant food safety inspection frequency, based on whether or not restaurants are part of chains, could reduce the frequency of violations, particularly in restaurants with the most violations.

Recent studies have shown an association between obstructive sleep apnea (OSA) and cognitive impairment. This study was done to investigate whether varied levels of cyclical intermittent hypoxia (CIH) differentially affect the microvasculature in the hippocampus, operating as a mechanistic link between OSA and cognitive impairment. We exposed C57BL/6 mice to sham [continuous air, arterial O2 saturation (SaO2 ) 97%], severe CIH to inspired O2 fraction (FiO2 ) = 0.10 (CIH10; SaO2 nadir of 61%), or very severe CIH to FiO2 = 0.05 (CIH5; SaO2 nadir of 37%) for 12 h/day for 2 wk. We quantified capillary length using neurostereology techniques in the dorsal hippocampus and utilized quantitative PCR methods to measure changes in sets of genes related to angiogenesis and to metabolism. Next, we employed immunohistochemistry semiquantification algorithms to quantitate GLUT1 protein on endothelial cells within hippocampal capillaries. Capillary length differed among CIH severity groups (P = 0.013) and demonstrated a linear relationship with CIH severity (P = 0.002). There was a strong association between CIH severity and changes in mRNA for VEGFA (P < 0.0001). Less strong, but nominally significant associations with CIH severity were also observed for ANGPT2 (PANOVA = 0.065, PTREND = 0.040), VEGFR2 (PANOVA = 0.032, PTREND = 0.429), and TIE-2 (PANOVA = 0.006, PTREND = 0.010). We found that the CIH5 group had increased GLUT1 protein relative to sham (P = 0.006) and CIH10 (P = 0.001). There was variation in GLUT1 protein along the microvasculature in different hippocampal subregions. An effect of CIH5 on GLUT1 mRNA was seen (PANOVA = 0.042, PTREND = 0.012). Thus CIH affects the microvasculature in the hippocampus, but consequences depend on CIH severity., (Copyright © 2016 the American Physiological Society.)

Objective: Obstructive sleep apnea (OSA) is common among candidates for bariatric surgery. OSA and its associated intermittent hypoxia have been implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis. A large cohort of bariatric surgery patients was studied in an effort to explore the relationship between OSA severity, hypoxia, metabolic syndrome, and the severity of NAFLD., Methods: Bariatric surgery candidates who underwent both polysomnography and liver biopsy were studied. The severity of OSA as determined by the apnea-hypopnea index (AHI) and parameters of hypoxia was studied in relation to extent of abnormalities of liver histology as measured by the presence of hepatic steatosis, inflammation, and fibrosis., Results: The study cohort included 362 patients with a mean age of 46.2 years and BMI of 49.9 kg/m(2) . On the basis of AHI, 26% of the cohort had no OSA, 32% mild OSA, 22% moderate OSA, and 20% severe OSA. For the study subjects without metabolic syndrome, positive correlations were found between OSA severity, as measured by AHI, and parameters of hypoxia, with the severity of NAFLD., Conclusions: OSA severity and its accompanying hypoxia are associated with the severity of NAFLD., (© 2016 The Obesity Society.)

Obstructive sleep apnea (OSA) is associated with extensive neurologic comorbidities. It is hypothesized that the repeated nocturnal apneas experienced in patients with OSA may inhibit the normal apneic response, resulting in hypoxic brain injury and subsequent neurologic dysfunction. In this study, we applied the recently developedOxFlowMRI method for rapid quantification of cerebral metabolic rate of oxygen (CMRO2) during a volitional apnea paradigm. MRI data were analyzed in 11 OSA subjects and 10 controls (mean ± SD apnea-hypopnea index (AHI): 43.9 ± 18.1 vs. 2.9 ± 1.6 events/hour,P < 0.0001; age: 53.8 ± 8.2 vs. 45.3 ± 8.5 years,P = 0.027; BMI: 36.6 ± 4.4 vs. 31.9 ± 2.2 kg/m(2),P = 0.0064). Although total cerebral blood flow and arteriovenous oxygen difference were not significantly different between apneics and controls (P > 0.05), apneics displayed reduced baseline CMRO2(117.4 ± 37.5 vs. 151.6 ± 29.4 µmol/100 g/min,P = 0.013). In response to apnea, CMRO2decreased more in apneics than controls (-10.9 ± 8.8 % vs. -4.0 ± 6.7 %,P = 0.036). In contrast, group differences in flow-based cerebrovascular reactivity were not significant. Results should be interpreted with caution given the small sample size, and future studies with larger independent samples should examine the observed associations, including potential independent effects of age or BMI. Overall, these data suggest that dysregulation of the apneic response may be a mechanism for OSA-associated neuropathology., (© The Author(s) 2015.)

In this paper, we present an objective method for localization of proteins in blood brain barrier (BBB) vasculature using standard immunohistochemistry (IHC) techniques and bright-field microscopy. Images from the hippocampal region at the BBB are acquired using bright-field microscopy and subjected to our segmentation pipeline which is designed to automatically identify and segment microvessels containing the protein glucose transporter 1 (GLUT1). Gabor filtering and k-means clustering are employed to isolate potential vascular structures within cryosectioned slabs of the hippocampus, which are subsequently subjected to feature extraction followed by classification via decision forest. The false positive rate (FPR) of microvessel classification is characterized using synthetic and non-synthetic IHC image data for image entropies ranging between 3 and 8 bits. The average FPR for synthetic and non-synthetic IHC image data was found to be 5.48% and 5.04%, respectively.

Obstructive sleep apnea (OSA) is highly prevalent in patients undergoing total joint arthroplasty (TJA) and is a major risk factor for postoperative cardiovascular complications and death. Recognizing this, the American Society of Anesthesiologists urges clinicians to implement special considerations in the perioperative care of OSA patients. However, as the volume of patients presenting for TJA increases, resources to implement these recommendations are limited. This necessitates mechanisms to efficiently risk stratify patients having OSA who may be susceptible to post-TJA cardiovascular complications. We explore the role of perioperative measurement of cardiac troponins (cTns) and brain natriuretic peptides (BNPs) in helping determine which OSA patients are at increased risk for post-TJA cardiovascular-related morbidity.

Study Objectives: The aims of this study were: (1) to use a standardized psychiatric interview, conducted by a trained psychologist to assess the prevalence of depression among patients with untreated OSA, and (2) to identify if OSA severity or other comorbid disorders (insomnia, hypertension, and diabetes) are related to depression among patients with untreated OSA., Methods: Participants were newly diagnosed patients with OSA (n = 284) waiting to start positive airway pressure (PAP) treatment. The Mini International Neuropsychiatric Interview (MINI) was used to assess depression., Results: Overall, 15.5% of the sample met the diagnosis for dysthymia. Women had a significantly higher prevalence (29.5% versus 11.7% among men, p < 0.001). The prevalence of major depression was 6% in the overall sample and there was no difference in the prevalence among sexes (5.8% among men versus 6.6 % among women). Obesity, daytime sleepiness, low physical activity, initial and late insomnia, low quality of life, and sleep medication and antidepressant use were all related to depression, whereas OSA severity, as measured by apnea-hypopnea index or oxygen desaturation index, was not. Daytime sleepiness, initial insomnia, and sleep medication use were the strongest predictors of depression in multivariable analyses., Conclusions: Sleep medication use, daytime sleepiness, and symptoms of initial insomnia were independently related to depression but OSA severity was not. Increased awareness of the relationship between depression and OSA and the appropriate use of assessment tools might substantially improve diagnostic accuracy as well as treatment outcome for both disorders., (© 2016 American Academy of Sleep Medicine.)

Rationale: Structural risk factors for obstructive sleep apnea syndrome (OSAS) in adolescents have not been well characterized. Because many adolescents with OSAS are obese, we hypothesized that the anatomic OSAS risk factors would be more similar to those in adults than those in children., Objectives: To investigate the anatomic risk factors in adolescents with OSAS compared with obese and lean control subjects using magnetic resonance imaging (MRI)., Methods: Three groups of adolescents (age range: 12-16 yr) underwent MRI: obese individuals with OSAS (n = 49), obese control subjects (n = 38), and lean control subjects (n = 50)., Measurements and Main Results: We studied 137 subjects and found that (1) obese adolescents with OSAS had increased adenotonsillar tissue compared with obese and lean control subjects; (2) obese OSAS adolescents had a smaller nasopharyngeal airway than control subjects; (3) the size of other upper airway soft tissue structures (volume of the tongue, parapharyngeal fat pads, lateral walls, and soft palate) was similar between subjects with OSAS and obese control subjects; (4) although there were no major craniofacial abnormalities in most of the adolescents with OSAS, the ratio of soft tissue to craniofacial space surrounding the airway was increased; and (5) there were sex differences in the pattern of lymphoid proliferation., Conclusions: Increased size of the pharyngeal lymphoid tissue, rather than enlargement of the upper airway soft tissue structures, is the primary anatomic risk factor for OSAS in obese adolescents. These results are important for clinical decision making and suggest that adenotonsillectomy should be considered as the initial treatment for OSAS in obese adolescents, a group that has poor continuous positive airway pressure adherence and difficulty in achieving weight loss.

Background: Elevated levels of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) may contribute to cardiovascular disease and are associated with obstructive sleep apnea (OSA) and obesity. The relationship between OSA and obesity in determining ICAM-1 and VCAM-1 levels, and the effect of treatment, is unclear., Objective: Our aim was to study whether positive airway pressure (PAP) usage resulted in changes in ICAM-1 and VCAM-1 after 2 years within 309 OSA patients from the Icelandic Sleep Apnea Cohort, and determine how obesity affected such changes., Subjects/methods: The mean body mass index (BMI) was 32.4±5.1 kg m(-2); subjects had moderate-to-severe OSA (apnea-hypopnea index=45.0±20.2) and 79% were male. There were 177 full PAP users (⩾4 h per night and ⩾20 of last 28 nights), 44 partial (<4 h per night or <20 nights) and 88 nonusers., Results: ICAM-1 (P<0.001) and VCAM-1 (P=0.012) change was significantly different among the PAP groups. The largest ICAM-1 differences were among the most obese subjects (P<0.001). At follow-up, nonusers had increased ICAM-1 compared with decreased levels in full users. All groups had increased VCAM-1, but nonusers had a significantly larger increase than full users., Conclusions: Within moderate-to-severe OSA patients, PAP usage prevents increases in adhesion molecules observed in nonusers after 2 years. For ICAM-1, the largest effect is in the most obese subjects. As OSA and obesity commonly coexist, the usage of PAP to limit increases in adhesion molecules may decrease the rate of progression of OSA-related cardiovascular disease.

Mouse models of cyclical intermittent hypoxia (CIH) are used to study the consequences of both hypoxia and oxidative stress in obstructive sleep apnea (OSA). Whether or not a mouse model of CIH that simulates OSA patients' oxygenation characteristics would translate into improved patient care remains unanswered. First we identified oxygenation characteristics using the desaturation and resaturation time in 47 OSA subjects from the Molecular Signatures of Obstructive Sleep Apnea Cohort (MSOSA). We observe that a cycle of intermittent hypoxia is not sinusoidal; specifically, desaturation time increases in an almost linear relationship to the degree of hypoxia (nadir), whereas resaturation time is somewhat constant (∼15 s), irrespective of the nadir. Second, we modified the Hycon mouse model of CIH to accommodate a 15-s resaturation time. Using this modified CIH model, we explored whether a short resaturation schedule (15 s), which includes the characteristics of OSA patients, had a different effect on levels of oxidative stress (i.e., urinary 8,12-iso-iPF2α-VI levels) compared with sham and a long resaturation schedule (90 s), a schedule that is not uncommon in rodent models of CIH. Results suggest that shorter resaturation time may result in a higher level of 8,12-iso-iPF2α-VI compared with long resaturation or sham conditions. Therefore, simulating the rodent model of CIH to reflect this and other OSA patients' oxygenation characteristics may be worthy of consideration to better understand the effects of hypoxia, oxidative stress, and their interactions., (Copyright © 2015 the American Physiological Society.)

Background: Sleep disordered breathing (SDB) is associated with significant cardiovascular sequelae and positive airway pressure (PAP) has been shown to improve heart failure and prevent the recurrence of atrial fibrillation in cardiac patients with sleep apnea. Patients who are hospitalized with cardiac conditions frequently have witnessed symptoms of SDB but often do not have a diagnosis of sleep apnea. We implemented a clinical paradigm to perform unattended sleep studies and initiate treatment with PAP in hospitalized cardiac patients with symptoms consistent with SDB. We hypothesized that PAP adherence in cardiac patients with SDB would reduce readmission rates 30 days after discharge., Methods: 106 consecutive cardiac patients hospitalized for heart failure, arrhythmias, and myocardial infarction and who reported symptoms of SDB were evaluated. Patients underwent a type III portable sleep study and those patients diagnosed with sleep apnea were started on PAP. Demographic data, SDB type, PAP adherence, and data regarding 30-day hospital readmission/ED visits were collected., Results: Of 106 patients, 104 had conclusive diagnostic studies using portable monitoring systems. Seventy-eight percent of patients (81/104) had SDB (AHI ≥ 5 events/h). Eighty percent (65/81) had predominantly obstructive sleep apnea, and 20% (16/81) had predominantly central sleep apnea. None of 19 patients (0%) with adequate PAP adherence, 6 of 20 (30%) with partial PAP use, and 5 of 17 (29%) of patients who did not use PAP were readmitted to the hospital or visited the emergency department (ED) for a cardiac issue within 30 days from discharge (p = 0.025)., Conclusions: Performing diagnostic unattended sleep studies and initiating PAP treatment in hospitalized cardiac patients was feasible and provided important clinical information. Our data indicate that hospital readmission and ED visits 30 days after discharge were significantly lower in patients with cardiac disease and SDB who adhered to PAP treatment than those who were not adherent., Commentary: A commentary on this article appears in this issue on page 1067.