Cost-Effectiveness of Sleep Apnea Diagnosis and Treatment in Hospitalized Persons With Moderate to Severe Traumatic Brain Injury.

OBJECTIVE: To assess the cost-effectiveness of alternative approaches to diagnose and treat obstructive sleep apnea (OSA) in patients with traumatic brain injury (TBI) during inpatient rehabilitation. SETTING: Data collected during the Comparison of Sleep Apnea Assessment Strategies to Maximize TBI Rehabilitation Participation and Outcome (C-SAS) clinical trial (NCT03033901) on an inpatient rehabilitation TBI cohort were used in this study. STUDY DESIGN: Decision tree analysis was used to determine the cost-effectiveness of approaches to diagnosing and treating sleep apnea. Costs were determined using 2021 Centers for Medicare and Medicaid Services reimbursement codes. Effectiveness was defined in terms of the appropriateness of treatment. Costs averted were extracted from the literature. A sensitivity analysis was performed to account for uncertainty. Analyses were performed for all severity levels of OSA and a subgroup of those with moderate to severe OSA. Six inpatient approaches using various phases of screening, testing, and treatment that conform to usual care or guideline-endorsed interventions were evaluated: (1) usual care; (2) portable diagnostic testing followed by laboratory-quality testing; (3) screening with the snoring, tiredness, observed apnea, high BP, BMI, age, neck circumference, and male gender (STOP-Bang) questionnaire; (4) Multivariable Apnea Prediction Index (MAPI) followed by portable diagnostic testing and laboratory-quality testing; (5) laboratory-quality testing for all; and (6) treatment for all patients. MAIN MEASURES: Cost, Effectiveness, and Incremental Cost-Effectiveness Ratio (ICER). RESULTS: Phased approaches utilizing screening and diagnostic tools were more effective in diagnosing and allocating treatment for OSA than all alternatives in patients with mild to severe and moderate to severe OSA. Usual care was more costly and less effective than all other approaches for mild to severe and moderate to severe OSA. CONCLUSIONS: Diagnosing and treating OSA in patients with TBI is a cost-effective strategy when compared with usual care.

A multifactorial intervention to increase adherence to oral appliance therapy with a titratable mandibular advancement device for obstructive sleep apnea: a randomized controlled trial.

PURPOSE: Obstructive sleep apnea (OSA) is a common chronic condition, associated with several conditions that account for leading causes of mortality. Adherence to treatment of a chronic condition is, along with treatment efficacy, a major determinant of treatment outcome. The aim of this study was to test whether or not a multifactorial intervention in addition to standard care increases adherence rates in patients using a titratable oral appliance for OSA. METHODS: All subjects were 18 years old or older, had a diagnosis of OSA, and were treated with an oral appliance with an embedded sensor to measure appliance wear time objectively. The control group received routine care, while the experimental subjects received an additional multifactorial intervention. Comparison of adherence was at 30 days (Phase I) and 90 days (Phase II) after appliance delivery. RESULTS: Data are reported for 82 subjects in Phase I (control 43; experimental 39) and 66 subjects in Phase II (control 36; experimental 30). There were no significant differences for age, sex, body mass index, and apnea-hypopnea index (p > 0.05) between groups. In both Phase I and Phase II, the mean number of nights the appliance was worn 4 or more hours and the mean time the appliance was worn nightly were significantly greater in the experimental than in the control group (p < 0.05). CONCLUSIONS: Interventions were well received by subjects and can be carried out by auxiliary personnel. The experimental interventions resulted in clinically important and statistically significant improvements in patient adherence to treatment.

Macrophage HIF-1α mediates obesity-related adipose tissue dysfunction via interleukin-1 receptor-associated kinase M.

Hypoxia leading to stabilization of hypoxia-inducible factor 1α (HIF-1α) serves as an early upstream initiator for adipose tissue (AT) dysfunction. Monocyte-derived macrophage infiltration in AT contributes to inflammation, fibrosis and obesity-related metabolic dysfunction. It was previously reported that myeloid cell-specific deletion of Hif-1α protected against high-fat diet (HFD)-induced AT dysfunction. Prolyl hydroxylases (PHDs) are key regulators of HIF-1α. We examined the effects of myeloid cell-specific upregulation and stabilization of Hif-1α via deletion of prolyl-hydroxylase 2 (Phd2) and whether interleukin-1 receptor associated kinase-M (Irak-M), a known downstream target of Hif-1α, contributes to Hif-1α-induced AT dysfunction. Our data show that with HFD, Hif-1α and Irak-M expressions were increased in the AT macrophages of Phd2flox/flox/LysMcre mice compared with LysMcre mice. With HFD, Phd2flox/flox/LysMcre mice exhibited increased AT inflammation, fibrosis, and systemic insulin resistance compared with control mice. Furthermore, Phd2flox/flox/LysMcre mice bone marrow-derived macrophages exposed to hypoxia in vitro also had increased expressions of both Hif-1α and Irak-M. In wild-type mice, HFD induced upregulation of both HIF-1a and Irak-M in adipose tissue. Despite equivalent expression of Hif-1α compared with wild-type mice, globally-deficient Irak-M mice fed a HFD exhibited less macrophage infiltration, decreased inflammation and fibrosis and improved glucose tolerance. Global Irak-M deficiency was associated with an alternatively-activated macrophage phenotype in the AT after HFD. Together, these data show for the first time that an Irak-M-dependent mechanism likely mediates obesity-related AT dysfunction in conjunction with Hif-1α upregulation.

Global burden of sleep-disordered breathing and its implications.

One-seventh of the world's adult population, or approximately one billion people, are estimated to have OSA. Over the past four decades, obesity, the main risk factor for OSA, has risen in striking proportion worldwide. In the past 5 years, the WHO estimates global obesity to affect almost two billion adults. A second major risk factor for OSA is advanced age. As the prevalence of the ageing population and obesity increases, the vulnerability towards having OSA increases. In addition to these traditional OSA risk factors, studies of the global population reveal select contributing features and phenotypes, including extreme phenotypes and symptom clusters that deserve further examination. Untreated OSA is associated with significant comorbidities and mortality. These represent a tremendous threat to the individual and global health. Beyond the personal toll, the economic costs of OSA are far-reaching, affecting the individual, family and society directly and indirectly, in terms of productivity and public safety. A better understanding of the pathophysiology, individual and ethnic similarities and differences is needed to better facilitate management of this chronic disease. In some countries, measures of the OSA disease burden are sparse. As the global burden of OSA and its associated comorbidities are projected to further increase, the infrastructure to diagnose and manage OSA will need to adapt. The use of novel approaches (electronic health records and artificial intelligence) to stratify risk, diagnose and affect treatment are necessary. Together, a unified multi-disciplinary, multi-organizational, global approach will be needed to manage this disease.

Cost-Benefit Analysis From the Payor's Perspective for Screening and Diagnosing Obstructive Sleep Apnea During Inpatient Rehabilitation for Moderate to Severe TBI.

OBJECTIVE: To describe the cost benefit of 4 different approaches to screening for sleep apnea in a cohort of participants with moderate to severe traumatic brain injury (TBI) receiving inpatient rehabilitation from the payor's perspective. DESIGN: A cost-benefit analysis of phased approaches to sleep apnea diagnosis. SETTING: Six TBI Model System Inpatient Rehabilitation Centers. PARTICIPANTS: Trial data from participants (N=214) were used in analyses (mean age 44±18y, 82% male, 75% white, with primarily motor vehicle-related injury [44%] and falls [33%] with a sample mean emergency department Glasgow Coma Scale of 8±5). INTERVENTION: Not applicable. MAIN OUTCOME: Cost benefit. RESULTS: At apnea-hypopnea index (AHI) ≥15 (34%), phased modeling approaches using screening measures (Snoring, Tired, Observed, Blood Pressure, Body Mass Index, Age, Neck Circumference, and Gender [STOPBANG] [-$5291], Multivariable Apnea Prediction Index MAPI [-$5262]) resulted in greater cost savings and benefit relative to the portable diagnostic approach (-$5210) and initial use of laboratory-quality polysomnography (-$5,011). Analyses at AHI≥5 (70%) revealed the initial use of portable testing (-$6323) relative to the screening models (MAPI [-$6250], STOPBANG [-$6237) and initial assessment with polysomnography (-$5977) resulted in greater savings and cost-effectiveness. CONCLUSIONS: The high rates of sleep apnea after TBI highlight the importance of accurate diagnosis and treatment of this comorbid disorder. However, financial and practical barriers exist to obtaining an earlier diagnosis during inpatient rehabilitation hospitalization. Diagnostic cost savings are demonstrated across all phased approaches and OSA severity levels with the most cost-beneficial approach varying by incidence of OSA.

Comparative Effectiveness of Sleep Apnea Screening Instruments During Inpatient Rehabilitation Following Moderate to Severe TBI.

OBJECTIVE: To determine the diagnostic sensitivity and specificity and comparative effectiveness of traditional sleep apnea screening tools in traumatic brain injury (TBI) neurorehabilitation admissions. DESIGN: Prospective diagnostic comparative effectiveness trial of sleep apnea screening tools relative to the criterion standard, attended level 1 polysomnography including encephalography. SETTING: Six TBI Model System Inpatient Rehabilitation Centers. PARTICIPANTS: Between May 2017 and February 2019, 449 of 896 screened were eligible for the trial with 345 consented (77% consented). Additional screening left 263 eligible for and completing polysomnography with final analyses completed on 248. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Area under the curve (AUC) of screening tools relative to total apnea hypopnea index≥15 (AHI, moderate to severe apnea) measured at a median of 47 days post-TBI (interquartile range, 29-47). RESULTS: The Berlin high-risk score (receiving operating curve [ROC] AUC=0.634) was inferior to the Multivariable Apnea Prediction Index (MAPI) (ROC AUC=0.780) (P=.0211; CI, 0.018-0.223) and Snoring, Tired, Observed, Blood Pressure, Body Mass Index, Age, Neck Circumference, and Gender (STOPBANG) score (ROC AUC=0.785) (P=.001; CI, 0.063-0.230), both of which had comparable AUC (P=.7245; CI, -0.047 to 0.068). Findings were similar for AHI≥30 (severe apnea); however, no differences across scales was observed at AHI≥5. The pattern was similar across TBI severity subgroups except for posttraumatic amnesia (PTA) status wherein the MAPI outperformed the Berlin. Youden's index to determine risk yielded lower sensitivities but higher specificities relative to non-TBI samples. CONCLUSION: This study is the first to provide clinicians with data to support a choice for which sleep apnea screening tools are more effective during inpatient rehabilitation for TBI (STOPBANG, MAPI vs Berlin) to help reduce comorbidity and possibly improve neurologic outcome.

Home sleep apnea testing: comparison of manual and automated scoring across international sleep centers.

PURPOSE: To determine the agreement between the manual scoring of home sleep apnea tests (HSATs) by international sleep technologists and automated scoring systems. METHODS: Fifteen HSATs, previously recorded using a type 3 monitor, were saved in European Data Format. The studies were scored by nine experienced technologists from the sleep centers of the Sleep Apnea Global Interdisciplinary Consortium (SAGIC) using the locally available software. Each study was scored separately by human scorers using the nasal pressure (NP), flow derived from the NP signal (transformed NP), or respiratory inductive plethysmography (RIP) flow. The same procedure was followed using two automated scoring systems: Remlogic (RLG) and Noxturnal (NOX). RESULTS: The intra-class correlation coefficients (ICCs) of the apnea-hypopnea index (AHI) scoring using the NP, transformed NP, and RIP flow were 0.96 [95% CI 0.93-0.99], 0.98 [0.96-0.99], and 0.97 [0.95-0.99], respectively. Using the NP signal, the mean differences in AHI between the average of the manual scoring and the automated systems were - 0.9 ± 3.1/h (AHIRLG vs AHIMANUAL) and - 1.3 ± 2.6/h (AHINOX vs AHIMANUAL). Using the transformed NP, the mean differences in AHI were - 1.9 ± 3.3/h (AHIRLG vs AHIMANUAL) and 1.6 ± 3.0/h (AHINOX vs AHIMANUAL). Using the RIP flow, the mean differences in AHI were - 2.7 ± 4.5/h (AHIRLG vs AHIMANUAL) and 2.3 ± 3.4/h (AHINOX vs AHIMANUAL). CONCLUSIONS: There is very strong agreement in the scoring of the AHI for HSATs between the automated systems and experienced international technologists. Automated scoring of HSATs using commercially available software may be useful to standardize scoring in future endeavors involving international sleep centers.

Influence of gonadal hormones on the behavioral effects of intermittent hypoxia in mice.

Obstructive sleep apnea (OSA) is characterized by repetitive upper airway obstruction resulting in cyclic intermittent hypoxia (IH) during sleep in affected individuals. OSA occurs more frequently in postmenopausal than premenopausal women and the severity of OSA increases after menopause. Gonadal hormones can influence brain and behavior; testosterone and estrogens in particular can enhance spatial learning and memory. We hypothesized that estrogens may protect mice from IH-induced hippocampal morphological and behavioral changes. To test this hypothesis we exposed intact or gonadectomized male and female mice to room air or IH [15 cycles/h, 8 h/day, fraction of inspired oxygen (FiO 2) nadir of 5%] for a total of 30 days. During the final 4 days of IH, mice were tested for anxiety- and depressive-like behaviors. After cessation of IH exposure mice were tested on the Barnes maze and passive avoidance tests to assess learning and memory. Ovariectomy paired with IH treatment, impaired spatial learning and memory compared to all other female groups. Intact male mice receiving IH treatment also had impaired learning and memory compared with intact or castrated male mice exposed to room air. Learning and memory changes were mirrored by changes in basilar dendritic length of the CA1 region of the hippocampus. These data suggest that estrogens provide protection against IH-induced deficits, whereas androgens partially exacerbate IH-induced deficits on learning and memory.

Symptom subtype progression in obstructive sleep apnea over 5 years.

STUDY OBJECTIVES: There is limited knowledge regarding the progression or consistency of symptoms in 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 (AHI<5) were incorporated as a known class at each time point. Multinomial logistic regression assessed the effect of age, sex, body mass index (BMI) and AHI on specific class transitions. RESULTS: The sample consisted of 1,408 women (53.8%) and mean (SD) age 62.4 (10.5) years. We identified four 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 five-year older age was associated with a 50% increase in odds to transit from excessively sleepy to moderately sleepy [OR (95% CI: 1.52 (1.17, 1.97)]. Women had 1.97 times higher odds (95% CI: 1.21, 3.18) to transition from moderately sleepy to minimal symptoms. A 5-unit increase in BMI was associated with 2.39 greater odds (95% CI: 1.30, 4.40) to transition from minimal symptoms to excessively sleepy. Changes in AHI 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.

Polysomnographic characteristics of excessive daytime sleepiness phenotypes in obstructive sleep apnea: results from the international sleep apnea global interdisciplinary consortium.

STUDY OBJECTIVES: Excessive daytime sleepiness (EDS) is a major symptom of obstructive sleep apnea (OSA). Traditional polysomnographic (PSG) measures only partially explain EDS in OSA. This study analyzed traditional and novel PSG characteristics of two different measures of EDS among patients with OSA. METHODS: Sleepiness was assessed using the Epworth Sleepiness Scale (>10 points defined as "risk of dozing") and a measure of general sleepiness (feeling sleepy ≥ 3 times/week defined as "feeling sleepy"). Four sleepiness phenotypes were identified: "non-sleepy," "risk of dozing only," "feeling sleepy only," and "both at risk of dozing and feeling sleepy." RESULTS: Altogether, 2083 patients with OSA (69% male) with an apnea-hypopnea index (AHI) ≥ 5 events/hour were studied; 46% were "non-sleepy," 26% at "risk of dozing only," 7% were "feeling sleepy only," and 21% reported both. The two phenotypes at "risk of dozing" had higher AHI, more severe hypoxemia (as measured by oxygen desaturation index, minimum and average oxygen saturation [SpO2], time spent < 90% SpO2, and hypoxic impacts) and they spent less time awake, had shorter sleep latency, and higher heart rate response to arousals than "non-sleepy" and "feeling sleepy only" phenotypes. While statistically significant, effect sizes were small. Sleep stages, frequency of arousals, wake after sleep onset and limb movement did not differ between sleepiness phenotypes after adjusting for confounders. CONCLUSIONS: In a large international group of patients with OSA, PSG characteristics were weakly associated with EDS. The physiological measures differed among individuals characterized as "risk of dozing" or "non-sleepy," while "feeling sleepy only" did not differ from "non-sleepy" individuals.

Dim light at night interacts with intermittent hypoxia to alter cognitive and affective responses.

Obstructive sleep apnea (OSA) and dim light at night (dLAN) have both been independently associated with alterations in mood and cognition. We aimed to determine whether dLAN would interact with intermittent hypoxia (IH), a condition characteristic of OSA, to alter the behavioral, cognitive, and affective responses. Adult male mice were housed in either standard lighting conditions (14:10-h light-dark cycle; 150 lux:0 lux) or dLAN (150 lux:5 lux). Mice were then exposed to IH (15 cycles/h, 8 h/day, FiO2 nadir of 5%) for 3 wk, then tested in assays of affective and cognitive responses; brains were collected for dendritic morphology and PCR analysis. Exposure to dLAN and IH increased anxiety-like behaviors, as assessed in the open field, elevated plus maze, and the light/dark box. dLAN and IH increased depressive-like behaviors in the forced swim test. IH impaired learning and memory performance in the passive avoidance task; however, no differences were observed in spatial working memory, as assessed by y-maze or object recognition. IH combined with dLAN decreased cell body area in the CA1 and CA3 regions of the hippocampus. Overall, IH decreased apical spine density in the CA3, whereas dLAN decreased spine density in the CA1 of the hippocampus. TNF-α gene expression was not altered by IH or lighting condition, whereas VEGF expression was increased by dLAN. The combination of IH and dLAN provokes negative effects on hippocampal dendritic morphology, affect, and cognition, suggesting that limiting nighttime exposure to light in combination with other established treatments may be of benefit to patients with OSA.

Sleep deprivation attenuates endotoxin-induced cytokine gene expression independent of day length and circulating cortisol in male Siberian hamsters (Phodopus sungorus).

Sleep is restorative, whereas reduced sleep leads to negative health outcomes, such as increased susceptibility to disease. Sleep deprivation tends to attenuate inflammatory responses triggered by infection or exposure to endotoxin, such as bacterial lipopolysaccharide (LPS). Previous studies have demonstrated that Siberian hamsters (Phodopus sungorus), photoperiodic rodents, attenuate LPS-induced fever, sickness behavior and upstream pro-inflammatory gene expression when adapted to short day lengths. Here, we tested whether manipulation of photoperiod alters the suppressive effects of sleep deprivation upon cytokine gene expression after LPS challenge. Male Siberian hamsters were adapted to long (16 h:8 h light:dark) or short (8 h:16 h light:dark) photoperiods for >10 weeks, and were deprived of sleep for 24 h using the multiple platform method or remained in their home cage. Hamsters received an intraperitoneal injection of LPS or saline (control) 18 h after starting the protocol, and were killed 6 h later. LPS increased liver and hypothalamic interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF) gene expression compared with vehicle. Among LPS-challenged hamsters, sleep deprivation reduced IL-1 mRNA levels in liver and hypothalamus, but not TNF. IL-1 attenuation was independent of circulating baseline cortisol, which did not increase after sleep deprivation. Conversely, photoperiod altered baseline cortisol, but not pro-inflammatory gene expression in sleep-deprived hamsters. These results suggest that neither photoperiod nor glucocorticoids influence the suppressive effect of sleep deprivation upon LPS-induced inflammation.

Airborne agricultural particulate matter induces inflammatory cytokine secretion by respiratory epithelial cells: mechanisms of regulation by eicosanoid lipid signal mediators.

The purpose of this study was to elucidate the mechanism of the airborne poultry dust (particulate matter, PM)-induced respiratory tract inflammation, a common symptom in agricultural respiratory diseases. The study was based on the hypothesis that poultry PM would induce the release of inflammatory cytokine interleukin-8 (IL-8) by respiratory epithelial cells under the upstream regulation by cytosolic phospholipase A2 (cPLA2) activation and subsequent formation of cyclooxygenase (COX)- and lipoxygenase (LOX)-catalyzed arachidonic acid (AA) metabolites (eicosanoids). Human lung epithelial cells (A549) in culture were treated with the poultry PM (0.1-1.0 mg) for different lengths of time, following which PLA2 activity, release of eicosanoids and secretion of IL-8 in cells were determined. Poultry PM (1.0 mg/ml) caused a significant activation of PLA2 in a time-dependent manner (15-60 min), which was significantly attenuated by the calcium-chelating agents, cPLA2-specific inhibitor (AACOCF3) and antioxidant (vitamin C) in A549 cells. Poultry PM also significantly induced the release of COX- and LOX-catalyzed eicosanoids (prostaglandins, thromboxane A2 and leukotrienes B4 and C4) and upstream activation of AA LOX in the cells. Poultry PM also significantly induced release of IL-8 by the cells in a dose- and time-dependent manner, which was significantly attenuated by the calcium chelating agents, antioxidants and COX- and LOX-specific inhibitors. The current study for the first time revealed that the poultry PM-induced IL-8 release from the respiratory epithelial cells was regulated upstream by reactive oxygen species, cPLA2-, COX- and LOX-derived eicosanoid lipid signal mediators.

Scoring sleep with artificial intelligence enables quantification of sleep stage ambiguity: hypnodensity based on multiple expert scorers and auto-scoring.

STUDY OBJECTIVES: To quantify the amount of sleep stage ambiguity across expert scorers and to validate a new auto-scoring platform against sleep staging performed by multiple scorers. METHODS: We applied a new auto-scoring system to three datasets containing 95 PSGs scored by 6-12 scorers, to compare sleep stage probabilities (hypnodensity; i.e. the probability of each sleep stage being assigned to a given epoch) as the primary output, as well as a single sleep stage per epoch assigned by hierarchical majority rule. RESULTS: The percentage of epochs with 100% agreement across scorers was 46 ± 9%, 38 ± 10% and 32 ± 9% for the datasets with 6, 9, and 12 scorers, respectively. The mean intra-class correlation coefficient between sleep stage probabilities from auto- and manual-scoring was 0.91, representing excellent reliability. Within each dataset, agreement between auto-scoring and consensus manual-scoring was significantly higher than agreement between manual-scoring and consensus manual-scoring (0.78 vs. 0.69; 0.74 vs. 0.67; and 0.75 vs. 0.67; all p < 0.01). CONCLUSIONS: Analysis of scoring performed by multiple scorers reveals that sleep stage ambiguity is the rule rather than the exception. Probabilities of the sleep stages determined by artificial intelligence auto-scoring provide an excellent estimate of this ambiguity. Compared to consensus manual-scoring, sleep staging derived from auto-scoring is for each individual PSG noninferior to manual-scoring meaning that auto-scoring output is ready for interpretation without the need for manual adjustment.

Five-year Transitions of Symptom Subtypes in Untreated Obstructive Sleep Apnea.

Objectives: It is unknown if symptom subtypes of obstructive sleep apnea (OSA) transition over time and what clinical factors may predict transitions. Methods: Data from 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 (AHI<5) were incorporated as a known class at each time point. Multinomial logistic regression assessed the effect of age, sex, body mass index (BMI) and AHI on specific class transitions. Results: The sample consisted of 1,408 women (53.8%) and mean (SD) age 62.4 (10.5) years. We identified four 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 from baseline to follow-up visits; transitions to moderately sleepy were the most common (77% of all transitions). A five-year older age was associated with a 6% increase in odds to transit from excessively sleepy to moderately sleepy [OR (95% CI) = 1.06 (1.02, 1.12)]. Women had 2.35 times higher odds (95% CI: 1.27, 3.27) to transition from moderately sleepy to minimal symptoms . A 5-unit increase in BMI was associated with 2.29 greater odds (95% CI: 1.19, 4.38) to transition from minimal symptoms to excessively sleepy . Interpretation: While over half of the sample did not transition their subtype over 5 years, among those who did, the likelihood of transitioning between subtypes was significantly associated with a higher baseline age, higher baseline BMI and with women, but was not predicted by AHI. Clinical Trials: Sleep Heart Health Study (SHHS) Data Coordinating Center, (SHHS) https://clinicaltrials.gov/ct2/show/NCT00005275 , NCT00005275. Statement of significance: There is very little research assessing symptom progression and its contributions to clinical heterogeneity in OSA. In a large sample with untreated OSA, we grouped common OSA symptoms into subtypes and assessed if age, sex, or BMI predicted transitions between the subtypes over 5 years. Approximately half the sample transitioned to a different symptom subtype and improvements in symptom subtype presentation were common. Women and older individuals were more likely to transition to less severe subtypes, while increased BMI predicted transition to more severe subtype. Determining whether common symptoms like disturbed sleep or excessive daytime sleepiness occur early in the course of the disease or as a result of untreated OSA over an extended period can improve clinical decisions concerning diagnosis and treatment.

Facial and Intraoral Photographic Traits Related to Sleep Apnea in a Clinical Sample with Genetic Ancestry Analysis.

Rationale: Craniofacial and pharyngeal morphology influences risk for obstructive sleep apnea (OSA). Quantitative photography provides phenotypic information about these anatomical factors and is feasible in large samples. However, whether associations between morphology and OSA severity differ among populations is unknown. Objectives: The aim of this study was to examine this question in a large sample encompassing people from different ancestral backgrounds. Methods: Participants in SAGIC (Sleep Apnea Global Interdisciplinary Consortium) with genotyping data were included (N = 2,393). Associations between photography-based measures and OSA severity were assessed using linear regression, controlling for age, sex, body mass index, and genetic ancestry. Subgroups (on the basis of 1000 Genomes reference populations) were identified: European (EUR), East Asian, American, South Asian, and African (AFR). Interaction tests were used to assess if genetically determined ancestry group modified these relationships. Results: Cluster analysis of genetic ancestry proportions identified four ancestrally defined groups: East Asia (48.3%), EUR (33.6%), admixed (11.7%; 46% EUR, 27% Americas, and 22% AFR), and AFR (6.4%). Multiple anatomical traits were associated with more severe OSA independent of ancestry, including larger cervicomental angle (standardized ß [95% confidence interval (CI)] = 0.11 [0.06-0.16]; P < 0.001), mandibular width (standardized ß [95% CI] = 0.15 [0.10-0.20]; P < 0.001), and tongue thickness (standardized ß [95% CI] = 0.06 [0.02-0.10]; P = 0.001) and smaller airway width (standardized ß [95% CI] = -0.08 [-0.15 to -0.002]; P = 0.043). Other traits, including maxillary and mandibular depth angles and lower face height, demonstrated different associations with OSA severity on the basis of ancestrally defined subgroups. Conclusions: We confirm that multiple facial and intraoral photographic measurements are associated with OSA severity independent of ancestral background, whereas others differ in their associations among the ancestrally defined subgroups.

Thiol-redox antioxidants protect against lung vascular endothelial cytoskeletal alterations caused by pulmonary fibrosis inducer, bleomycin: comparison between classical thiol-protectant, N-acetyl-L-cysteine, and novel thiol antioxidant, N,N'-bis-2-mercaptoethyl isophthalamide.

Lung vascular alterations and pulmonary hypertension associated with oxidative stress have been reported to be involved in idiopathic lung fibrosis (ILF). Therefore, here, we hypothesize that the widely used lung fibrosis inducer, bleomycin, would cause cytoskeletal rearrangement through thiol-redox alterations in the cultured lung vascular endothelial cell (EC) monolayers. We exposed the monolayers of primary bovine pulmonary artery ECs to bleomycin (10 µg) and studied the cytotoxicity, cytoskeletal rearrangements, and the macromolecule (fluorescein isothiocyanate-dextran, 70,000 mol. wt.) paracellular transport in the absence and presence of two thiol-redox protectants, the classic water-soluble N-acetyl-L-cysteine (NAC) and the novel hydrophobic N,N'-bis-2-mercaptoethyl isophthalamide (NBMI). Our results revealed that bleomycin induced cytotoxicity (lactate dehydrogenase leak), morphological alterations (rounding of cells and filipodia formation), and cytoskeletal rearrangement (actin stress fiber formation and alterations of tight junction proteins, ZO-1 and occludin) in a dose-dependent fashion. Furthermore, our study demonstrated the formation of reactive oxygen species, loss of thiols (glutathione, GSH), EC barrier dysfunction (decrease of transendothelial electrical resistance), and enhanced paracellular transport (leak) of macromolecules. The observed bleomycin-induced EC alterations were attenuated by both NAC and NBMI, revealing that the novel hydrophobic thiol-protectant, NBMI, was more effective at µM concentrations as compared to the water-soluble NAC that was effective at mM concentrations in offering protection against the bleomycin-induced EC alterations. Overall, the results of the current study suggested the central role of thiol-redox in vascular EC dysfunction associated with ILF.