Lateral epiglottic collapse in obstructive sleep apnea is associated with laterally directed pharyngeal collapse.

Study Objectives: Epiglottic collapse can obstruct the airway in obstructive sleep apnea (OSA) patients in an anteroposterior (E-ap) or lateral direction (E-lat). The present study investigates the concept that lateral or concentric pharyngeal collapse patterns may remodel the epiglottis and predispose it to lateral collapse. To do so, we hypothesized that the presence of-any form of laterally directed pharyngeal collapse, e.

Arrayed CRISPR libraries for the genome-wide activation, deletion and silencing of human protein-coding genes.

Arrayed CRISPR libraries extend the scope of gene-perturbation screens to non-selectable cell phenotypes. However, library generation requires assembling thousands of vectors expressing single-guide RNAs (sgRNAs). Here, by leveraging massively parallel plasmid-cloning methodology, we show that arrayed libraries can be constructed for the genome-wide ablation (19,936 plasmids) of human protein-coding genes and for their activation and epigenetic silencing (22,442 plasmids), with each plasmid encoding an array of four non-overlapping sgRNAs designed to tolerate most human DNA polymorphisms.

Mouth Closure and Airflow in Patients With Obstructive Sleep Apnea: A Nonrandomized Clinical Trial.

Importance: Mouth breathing is associated with increased airway resistance, pharyngeal collapsibility, and obstructive sleep apnea (OSA) severity. The common belief is that closing the mouth can mitigate the negative effects of mouth breathing during sleep. However, mouth breathing may serve as an essential route to bypassing obstruction along the nasal route (eg, the velopharynx).

Combination Tonsillectomy and Hypoglossal Nerve Stimulation for Sleep Apnea Patients With Oropharyngeal Lateral Wall Collapse.

Objective: The efficacy of hypoglossal nerve stimulation (HGNS) therapy is limited by obstruction of the oropharyngeal lateral walls (OLWs). Our objective was to investigate the effect of palatine tonsillectomy on HGNS efficacy in obstructive sleep apnea (OSA) patients with OLW collapse.

Study Design: Case-control study of patients with moderate-to-severe OSA, complete-or-partial OLW collapse, and small tonsils (1 - 2+).

Sleep apnea patients with epiglottic collapse elevate their larynx more with swallowing; videofluoroscopic swallowing study of 80 patients.

Objective: The epiglottis plays an integral role in the swallowing mechanism and is also implicated as an obstruction site in obstructive sleep apnea (OSA). The underlying causes of epiglottic collapse during sleep remain unclear. This study aimed to investigate the cognitive functions using the Loewenstein Occupational Therapy Cognitive Assessment (LOTCA) and the neurophysiological and anatomical factors using videofluoroscopic swallowing studies (VFSS).

Adverse pregnancy outcomes and pharyngeal flow limitation during sleep: Nulliparous Pregnancy Outcomes Study Monitoring Mothers-to-be (nuMoM2b).

Background: Pharyngeal flow limitation during pregnancy may be a risk factor for adverse pregnancy outcomes but was previously challenging to quantify. Our objective was to determine whether a novel objective measure of flow limitation identifies an increased risk of pre-eclampsia (primary outcome) and other adverse outcomes in a prospective cohort: Nulliparous Pregnancy Outcomes Study Monitoring Mothers-to-be (nuMoM2b).

Methods: Flow limitation severity scores (0%=fully obstructed, 100%=open airway), quantified from breath-by-breath airflow shape, were obtained from home sleep tests during early (6-15 weeks) and mid (22-31 weeks) pregnancy.

Treatment of Sleep Apnea and Reduction in Blood Pressure: The Role of Heart Rate Response and Hypoxic Burden.

Background: Obstructive sleep apnea is associated with increased blood pressure (BP). Obstructive sleep apnea treatment reduces BP with substantial variability, not explained by the apnea-hypopnea index, partly due to inadequate characterization of obstructive sleep apnea's physiological consequences, such as oxygen desaturation, cardiac autonomic response, and suboptimal treatment efficacy. We sought to examine whether a high baseline heart rate response (ΔHR), a marker of high cardiovascular risk in obstructive sleep apnea, predicts a larger reduction in post-treatment systolic BP (SBP).

Combination pharmacological therapy targeting multiple mechanisms of sleep apnoea: a randomised controlled cross-over trial.

Rationale: Acetazolamide and atomoxetine-plus-oxybutynin ('AtoOxy') can improve obstructive sleep apnoea (OSA) by stabilising ventilatory control and improving dilator muscle responsiveness respectively. Given the different pathophysiological mechanisms targeted by each intervention, we tested whether AtoOxy-plus-acetazolamide would be more efficacious than AtoOxy alone.

Methods: In a multicentre randomised crossover trial, 19 patients with moderate-to-severe OSA received AtoOxy (80/5 mg), acetazolamide (500 mg), combined AtoOxy-plus-acetazolamide or placebo at bedtime for three nights (half doses on first night) with a 4-day washout between conditions.

Physiological Determinants of Snore Loudness.

The physiological factors modulating the severity of snoring have not been adequately described. Airway collapse or obstruction is generally the leading determinant of snore sound generation; however, we suspect that ventilatory drive is of equal importance. To determine the relationship between airway obstruction and ventilatory drive on snore loudness.

Hypoxic Burden Based on Automatically Identified Desaturations Is Associated with Adverse Health Outcomes.

Recent studies have shown that sleep apnea-specific intermittent hypoxemia quantified by the hypoxic burden (HB) predicted cardiovascular disease (CVD)-related mortality in community-based and clinical cohorts. Calculation of HB is based on manual scoring of hypopneas and apneas, which is time-consuming and prone to interscorer variability. To validate a novel method to quantify the HB that is based on automatically scored desaturations.

Sleep Apnea Physiological Burdens and Cardiovascular Morbidity and Mortality.

Obstructive sleep apnea is characterized by frequent reductions in ventilation, leading to oxygen desaturations and/or arousals. In this study, association of hypoxic burden with incident cardiovascular disease (CVD) was examined and compared with that of "ventilatory burden" and "arousal burden." Finally, we assessed the extent to which the ventilatory burden, visceral obesity, and lung function explain variations in hypoxic burden.

Drive versus Pressure Contributions to Genioglossus Activity in Obstructive Sleep Apnea.

Loss of pharyngeal dilator muscle activity is a key determinant of respiratory events in obstructive sleep apnea (OSA). After the withdrawal of wakefulness stimuli to the genioglossus at sleep onset, mechanoreceptor negative pressure and chemoreceptor ventilatory drive feedback govern genioglossus activation during sleep, but the relative contributions of drive and pressure stimuli to genioglossus activity across progressive obstructive events remain unclear. We recently showed that drive typically falls during events, whereas negative pressures increase, providing a means to assess their individual contributions to the time course of genioglossus activity.

Pathophysiology Underlying Demographic and Obesity Determinants of Sleep Apnea Severity.

Sleep apnea is the manifestation of key endotypic traits, including greater pharyngeal collapsibility, reduced dilator muscle compensation, and elevated chemoreflex loop gain. We investigated how endotypic traits vary with obesity, age, sex, and race/ethnicity to influence sleep apnea disease severity (apnea-hypopnea index [AHI]). Endotypic traits were estimated from polysomnography in a diverse community-based cohort study (Multi-Ethnic Study of Atherosclerosis,  = 1,971; age range, 54-93 yr).

Patients with Epiglottic Collapse Are Less Adherent to Autotitrating Positive Airway Pressure Therapy for Obstructive Sleep Apnea.

The anatomic orientation of the epiglottis is such that it points in the opposite direction to inspiratory flow, thereby potentially making positive airway pressure (PAP) treatment challenging in patients with epiglottic collapse. However, no previous studies have analyzed PAP adherence in these patients. This study aimed to analyze adherence to autotitrating PAP (APAP) treatment in patients with epiglottic collapse.

Effect of Pimavanserin on the Respiratory Arousal Threshold from Sleep: A Randomized Trial.

A low respiratory arousal threshold is a key endotype responsible for obstructive sleep apnea (OSA) pathogenesis. Pimavanserin is an antiserotoninergic capable of suppressing CO-mediated arousals without affecting the respiratory motor response in animal models, and thus it holds potential for increasing the arousal threshold in OSA and subsequently reducing OSA severity. We measured the effect of pimavanserin on arousal threshold (primary outcome), OSA severity, arousal index, and other OSA endotypes (secondary outcomes).

Atomoxetine and fesoterodine combination improves obstructive sleep apnoea severity in patients with milder upper airway collapsibility.

Background And Objective: The combination of the noradrenergic atomoxetine plus the anti-muscarinic oxybutynin acutely increased genioglossus activity and reduced obstructive sleep apnoea (OSA) severity. However, oxybutynin has shorter half-life than atomoxetine and side effects that might discourage long-term usage. Accordingly, we aimed to test the combination of atomoxetine and fesoterodine (Ato-Feso), a newer anti-muscarinic with extended release formulation, on OSA severity and endotypes.

Treatment of Anal High-Grade Squamous Intraepithelial Lesions to Prevent Anal Cancer.

Background: The incidence of anal cancer is substantially higher among persons living with the human immunodeficiency virus (HIV) than in the general population. Similar to cervical cancer, anal cancer is preceded by high-grade squamous intraepithelial lesions (HSILs). Treatment for cervical HSIL reduces progression to cervical cancer; however, data from prospective studies of treatment for anal HSIL to prevent anal cancer are lacking.

Within-night repeatability and long-term consistency of sleep apnea endotypes: the Multi-Ethnic Study of Atherosclerosis and Osteoporotic Fractures in Men Study.

Study Objectives: Obstructive sleep apnea (OSA) is characterized by multiple "endotypic traits," including pharyngeal collapsibility, muscle compensation, loop gain, and arousal threshold. Here, we examined (1) within-night repeatability, (2) long-term consistency, and (3) influences of body position and sleep state, of endotypic traits estimated from in-home polysomnography in mild-to-severe OSA (apnea-hypopnea index, AHI > 5 events/h).

Methods: Within-night repeatability was assessed using Multi-Ethnic Study of Atherosclerosis (MESA): Traits derived separately from "odd" and "even" 30-min periods were correlated and regression (error vs.

Cardiovascular Benefit of Continuous Positive Airway Pressure in Adults with Coronary Artery Disease and Obstructive Sleep Apnea without Excessive Sleepiness.

Randomized controlled trials of continuous positive airway pressure (CPAP) in patients with obstructive sleep apnea (OSA) have not demonstrated protection against adverse cardiovascular outcomes. Recently, observational studies revealed that OSA-related cardiovascular risk is concentrated in patients with an elevated pulse rate response to respiratory events (ΔHR). Here, in this analysis of a prospective clinical trial, we test the hypothesis that a greater pretreatment ΔHR is associated with greater CPAP-related protection against adverse cardiovascular outcomes.

Mouth Closing to Improve the Efficacy of Mandibular Advancement Devices in Sleep Apnea.

Mouth breathing increases upper airway collapsibility, leading to decreased efficacy of obstructive sleep apnea (OSA) treatments. We hypothesized that the use of mandibular advancement devices (MAD) increases mouth breathing, and thus, using an adhesive mouthpiece (AMT) to prevent mouth breathing in combination with MAD can improve the treatment efficacy. To evaluate the efficacy of MAD + AMT in comparison with MAD alone.

Clinical polysomnographic methods for estimating pharyngeal collapsibility in obstructive sleep apnea.

Study Objectives: Obstructive sleep apnea has major health consequences but is challenging to treat. For many therapies, efficacy is determined by the severity of underlying pharyngeal collapsibility, yet there is no accepted clinical means to measure it. Here, we provide insight into which polysomnographic surrogate measures of collapsibility are valid, applicable across the population, and predictive of therapeutic outcomes.

Comparison of Drug-Induced Sleep Endoscopy and Natural Sleep Endoscopy in the Assessment of Upper Airway Pathophysiology During Sleep: Protocol and Study Design.

Obstructive sleep apnea (OSA) is increasingly recognized as a complex and heterogenous disorder. As a result, a "one-size-fits-all" management approach should be avoided. Therefore, evaluation of pathophysiological endotyping in OSA patients is emphasized, with upper airway collapse during sleep as one of the main features.