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Maria Rosa Costanzo,1 Shahrokh Javaheri,2,3 Piotr Ponikowski,4 Olaf Oldenburg,5 Ralph Augostini,3 Lee R Goldberg,6 Christoph Stellbrink,7 Henrik Fox,8 Alan R Schwartz,6 Sanjaya Gupta,9 Scott McKane,10 Timothy E Meyer,10 William T Abraham3 for the remedē®System Pivotal Trial Study Group1Advocate Heart Institute, Naperville, IL, USA; 2Bethesda North Hospital, Cincinnati, OH, USA; 3The Ohio State University, Columbus, OH, USA; 4Department of Heart Diseases, Medical University, Military Hospital, Wroclaw, Poland; 5Ludgerus-Kliniken Münster, Clemens Hospital, Münster, Germany; 6University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; 7Bielefeld Medical Center, Bielefeld, Germany; 8Clinic for General and Interventional Cardiology Angiology, Herz- und Diabeteszentrum NRW, Ruhr-Universität Bochum, Bad Oeynhausen, Germany; 9University of Missouri-Kansas City School of Medicine, Saint Luke’s Mid-America Heart Institute, Kansas City, MO, USA; 10Respicardia, Inc., Minnetonka, MN, USACorrespondence: Maria Rosa CostanzoAdvocate Heart Institute, Naperville, IL, 60566, USAEmail mariarosa.costanzo@aah.orgBackground: The remedē System Pivotal Trial was a prospective, multi-center, randomized trial demonstrating transvenous phrenic nerve stimulation (TPNS) therapy is safe and effectively treats central sleep apnea (CSA) and improves sleep architecture and daytime sleepiness. Subsequently, the remedē System was approved by FDA in 2017. As a condition of approval, the Post Approval Study (PAS) collected clinical evidence regarding long-term safety and effectiveness in adults with moderate to severe CSA through five years post implant.Methods: Patients remaining in the Pivotal Trial at the time of FDA approval were invited to enroll in the PAS and consented to undergo sleep studies (scored by a central laboratory), complete the Epworth Sleepiness Scale (ESS) questionnaire to assess daytime sleepiness, and safety assessment. All subjects (treatment and former control group) receiving active therapy were pooled; data from both trials were combined for analysis.Results: Fifty-three of the original 151 Pivotal Trial patients consented to participate in the PAS and 52 completed the 5-year visit. Following TPNS therapy, the apnea-hypopnea index (AHI), central-apnea index (CAI), arousal index, oxygen desaturation index, and sleep architecture showed sustained improvements. Comparing 5 years to baseline, AHI and CAI decreased significantly (AHI baseline median 46 events/hour vs 17 at 5 years; CAI baseline median 23 events/hour vs 1 at 5 years), though residual hypopneas were present. In parallel, the arousal index, oxygen desaturation index and sleep architecture improved. The ESS improved by a statistically significant median reduction of 3 points at 5 years. Serious adverse events related to implant procedure, device or delivered therapy were reported by 14% of patients which include 16 (9%) patients who underwent a pulse generator reposition or lead revision (primarily in the first year). None of the events caused long-term harm. No unanticipated adverse device effects or related deaths occurred through 5 years.Conclusion: Long-term TPNS safely improves CSA, sleep architecture and daytime sleepiness through 5 years post implant.Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT01816776.Keywords: central sleep apnea, phrenic nerve stimulation

Rationale: Obstructive sleep apnea is associated with insulin resistance and liver injury. It is unknown whether apnea contributes to insulin resistance and steatohepatitis in severe obesity.Objectives: To examine whether sleep apnea and nocturnal hypoxemia predict the severity of insulin resistance, systemic inflammation, and steatohepatitis in severely obese individuals presenting for bariatric surgery.Methods: We performed sleep studies and measured fasting blood glucose, serum insulin, C-reactive protein, and liver enzymes in 90 consecutive severely obese individuals, 75 women and 15 men, without concomitant diabetes mellitus or preexistent diagnosis of sleep apnea or liver disease. Liver biopsies (n = 20) were obtained during bariatric surgery.Measurements and Main Results: Obstructive sleep apnea with a respiratory disturbance index greater than 5 events/hour was diagnosed in 81.1% of patients. The median respiratory disturbance index was 15 +/- 29 events/hour and the median oxygen desaturation during apneic events was 4.6 +/- 1.8%. All patients exhibited high serum levels of C-reactive protein, regardless of the severity of apnea, whereas liver enzymes were normal. Oxygen desaturation greater than 4.6% was associated with a 1.5-fold increase in insulin resistance, according to the homeostasis model assessment index. Histopathology data suggested that significant nocturnal desaturation might predispose to hepatic inflammation, hepatocyte ballooning, and liver fibrosis. Fasting blood glucose levels and steatosis scores were not affected by nocturnal hypoxia. There was no relationship between the respiratory disturbance index and insulin resistance or liver histopathology.Conclusions: Hypoxic stress of sleep apnea may be implicated in the development of insulin resistance and steatohepatitis in severe obesity. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea (OSA) is a highly prevalent disease characterized by recurrent episodes of upper airway obstruction that result in recurrent arousals and episodic oxyhemoglobin desaturations during sleep. Significant clinical consequences of the disorder cover a wide spectrum, including daytime hypersomnolence, neurocognitive dysfunction, cardiovascular disease, metabolic dysfunction, and cor pulmonale. The major risk factors for the disorder include obesity, male gender, and age. Current understanding of the pathophysiologic basis of the disorder suggests that a balance of anatomically imposed mechanical loads and compensatory neuromuscular responses are important in maintaining upper airway patency during sleep. OSA develops in the presence of both elevated mechanical loads on the upper airway and defects in compensatory neuromuscular responses. A sleep history and physical examination is important in identification of patients and appropriate referral for polysomnography. Understanding nuances in the spectrum of presenting complaints and polysomnography correlates are important for diagnostic and therapeutic approaches. Knowledge of common patterns of OSA may help to identify patients and guide therapy. [ABSTRACT FROM AUTHOR]

It has been proposed that a titration of the mandibular positioner would be a promising method for predicting the outcome of nasal continuous positive airway pressure (CPAP) therapy. This study was carried out to test the hypothesis that mandible advancement could be evaluated by analysis of inspiratory flow limitation using a titration procedure. To explore its effect, we examined upper airway pressure-flow relationships using a titrated mandible positioner during midazolam sedation. Non-flow limited inspiration occurred when the mandible was advanced 7.1 +/- 1.2 mm from centric occlusion position. In the centric occlusion position (0 mm advancement), Pcrit was -1.9 +/- 2.9 cmH2O and Rua was 23.3 +/- 4.5 cmH2O L(-1) s(-1). In the eMAP position, Pcrit was -7.3 +/- 1.9 cmH2O and Rua was 27.8 +/- 3.3 cmH2O L(-1) s(-1). Essentially no CPAP was required to overcome flow limitation in eMAP position, whereas 3.7 +/- 2.2 cmH2O CPAP was required in centric occlusion position. We conclude that assessing inspiratory flow limitation using a titrated mandible positioner was effective for estimating individual-matched mandible positions. [ABSTRACT FROM AUTHOR]

Abstract Background Researchers who use MEDLINE for text mining, information extraction, or natural language processing may benefit from having a copy of MEDLINE that they can manage locally. The National Library of Medicine (NLM) distributes MEDLINE in eXtensible Markup Language (XML)-formatted text files, but it is difficult to query MEDLINE in that format. We have developed software tools to parse the MEDLINE data files and load their contents into a relational database. Although the task is conceptually straightforward, the size and scope of MEDLINE make the task nontrivial. Given the increasing importance of text analysis in biology and medicine, we believe a local installation of MEDLINE will provide helpful computing infrastructure for researchers. Results We developed three software packages that parse and load MEDLINE, and ran each package to install separate instances of the MEDLINE database. For each installation, we collected data on loading time and disk-space utilization to provide examples of the process in different settings. Settings differed in terms of commercial database-management system (IBM DB2 or Oracle 9i), processor (Intel or Sun), programming language of installation software (Java or Perl), and methods employed in different versions of the software. The loading times for the three installations were 76 hours, 196 hours, and 132 hours, and disk-space utilization was 46.3 GB, 37.7 GB, and 31.6 GB, respectively. Loading times varied due to a variety of differences among the systems. Loading time also depended on whether data were written to intermediate files or not, and on whether input files were processed in sequence or in parallel. Disk-space utilization depended on the number of MEDLINE files processed, amount of indexing, and whether abstracts were stored as character large objects or truncated. Conclusions Relational database (RDBMS) technology supports indexing and querying of very large datasets, and can accommodate a locally stored version of MEDLINE. RDBMS systems support a wide range of queries and facilitate certain tasks that are not directly supported by the application programming interface to PubMed. Because there is variation in hardware, software, and network infrastructures across sites, we cannot predict the exact time required for a user to load MEDLINE, but our results suggest that performance of the software is reasonable. Our database schemas and conversion software are publicly available at http://biotext.berkeley.edu.

Rationale: Ansa cervicalis stimulation (ACS) of the infrahyoid muscles has been proposed as a neurostimulation therapy for obstructive sleep apnea (OSA). ACS stabilizes the pharynx by pulling it caudally, but its specific effects on flow limitation caused by palatal, oropharyngeal lateral wall, tongue base, or epiglottis collapse remains unclear., Objectives: To quantify the effect of ACS on collapsibility of different pharyngeal flow-limiting structures., Methods: Participants with OSA underwent bilateral ACS during drug-induced sleep endoscopy. Maximum inspiratory airflow was assessed over a range of positive airway pressures while ACS was applied. The flow-limiting structure for each breath was classified based on manometric and endoscopic findings and a linear mixed-effects model characterized their response to ACS. The influence of patient characteristics was explored with univariate models., Measurements and Main Results: Forty-one participants yielded 1761 breaths for analysis. On average, bilateral ACS decreased the observed pharyngeal critical closing (P CRIT ) and opening (P OPEN ) pressures by -3.0 [95% confidence interval: [-3.6, -2.3] and -3.7 [-4.4, -3.0] cmH2O, respectively (p<0.001). During tongue base obstruction, modeled ACS effects for P CRIT and P OPEN were -2.0 [-2.7, -1.4] and -3.1 [-3.8, -2.4] cmH 2 O, respectively (p<0.001). Greater reductions were generally observed for other flow-limiting structures. A lower apnea-hypopnea index was associated with a greater decrease in P OPEN (p<0.01). Other patient characteristics, including body mass index, did not influence P CRIT or P OPEN (p>0.05)., Conclusions: Bilateral ACS decreased collapsibility of all airway flow-limiting structures. ACS generally had greater effects on palatal, oropharyngeal lateral wall, and epiglottic collapse than the tongue base., (Copyright ©The authors 2024.)

Introduction: The genioglossus (GG) is known to be the main tongue protrusor, and therefore plays a major role in breathing. However, due to the fan shape of the GG fibers, it could be assumed that contraction of the anterior fibers of the GG do not cause tongue protrusion. In this study, we examined the effect of contraction of the anterior-vertical fibers of the GG (GG V ) on the tongue and their EMG activity during wakefulness and sleep. The findings were compared to those of the longitudinal fibers (GG L ), which, based on their orientation, are responsible for tongue protrusion., Methods: Fine-wire electrode pairs were placed into the GG V and GG L in 11 patients with untreated OSA. Movement of the tongue during electrical stimulation at each site was videoed. The same electrodes were used to record EMG from both sites during respiratory stimulation by inspiratory loading and CO 2 rebreathing during wakefulness. During sleep, repetitive flow limitation events were induced with low-level CPAP to augment GG activity., Results: In all participants, electrical stimulation of GG L and GG V protruded and retracted the tongue, respectively. Respiratory stimulation increased GG activity, but GG V reached only 39 % and 23 % of peak GG L activity during high resistive loading and PCO 2 of 65 mmHg, respectively. Flow limitation during sleep increased GG L to levels that were considerably higher than awake baseline, but GG V activity remained tonic or with minimal phasic activity, reaching on average 15 % of GG L peak activity., Conclusions: Our electrical stimulation findings indicate that GG V is a tongue retractor and depressor. Tongue stimulation for OSA should avoid this area. The EMG results demonstrate that the anterior part of the GG is controlled very differently from the longitudinal protrusive fibers. The GG V responses are similar to those previously found in tongue retractors and peri-pharyngeal muscles other than the GG, in which diminished activation during sleep is likely to be involved in the failure of increasing GG L activity to alleviate flow limitation., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: When navigating the landscape of obstructive sleep apnea (OSA), central sleep apnea (CSA) and intersection of the two diseases (co-existing CSA-OSA), there are significant knowledge gaps. Data are scarce regarding the respective prevalence and differences in clinical presentation of the three conditions. One major issue for characterization of the prevalence of the different sleep apnea entities is the scoring of central versus obstructive hypopneas which is not included in the routine practice of many sleep laboratories., Method: We prospectively assessed multidomain symptoms and collected data on comorbidities, medications and treatment indications in a large monocentric real-life dataset (n > 2400) of patients referred for suspicion of sleep apnea. We have systematically distinguished central versus obstructive hypopneas to define OSA, CSA and co-existing CSA-OSA., Results: When CSA was defined by the proportion of central apneas (and hypopneas were considered obstructive by default), the prevalence of CSA was 4.59 % (co-existing CSA-OSA: 11.03 %, and OSA: 84.37 %). When the distinction between obstructive and central hypopneas was used to classify the sleep disordered breathing, the prevalence of CSA was fourfold higher at 19.69 % (co-existing: 19.16 %, OSA: 61.16 %). The burden of cardiovascular and metabolic comorbidities was the highest in the CSA and co-existing sleep apnea subgroups. The three sleep apnea groups exhibited different constellations of symptoms but most of the patients with CSA, co-existing and OSA were symptomatic after comprehensive evaluation. The CSA group exhibited the most severe disturbances in sleep architecture on polysomnography. Therapeutic indications differed depending on the subtype of respiratory events., Conclusion: Our findings imply that not differentiating between central and obstructive hypopneas will underestimate the severity of central sleep disordered breathing abnormalities that mislead therapeutic decisions and might limit improvements in quality of life and sleepiness that are expected in appropriately treated patients with CSA., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jean-Louis Pepin reports financial support was provided by ZOLLRespicardia Inc. Scott McKane reports a relationship with ZOLLRespicardia Inc that includes: employment. Robin Germany reports a relationship with ZOLLRespicardia Inc that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Importance: Drug-induced sleep endoscopy (DISE) is used to guide therapeutic management of obstructive sleep apnea (OSA), depending on the levels and patterns of pharyngeal collapse. However, the collapsibility of specific pharyngeal sites remains unknown., Objective: To assess collapse sites in patients with OSA undergoing DISE and whether number and location are associated with differences in airway collapsibility; and to quantify differences in collapsibility between primary and secondary sites in multilevel collapse., Design, Setting, and Participants: This cohort study assessed adult patients (≥18 years) with OSA undergoing DISE with manometry and positive airway pressure (PAP) titration at a tertiary care center from November 2021 to November 2023. Patients with an AHI score greater than 5 were included; those with less than 1 apnea event during DISE or incorrect catheter placement were excluded. Data were analyzed from September 28, 2022, to March 31, 2024., Exposure: DISE with manometry and PAP titration., Main Outcomes and Measures: Active pharyngeal critical pressure (Pcrit-A) and pharyngeal opening pressure (PhOP) were used to quantify airway collapsibility, adjusted for covariates (age, sex, race, and body mass index [BMI])., Results: Of 94 screened, 66 patients (mean [SD] age, 57.4 [14.3] years; BMI, 29.2 [3.9]; 51 [77.3%] males) with a mean (SD) apnea-hypopnea index (AHI) of 31.6 (19.0) were included in the analysis. Forty-seven patients (71.2%) had multilevel collapse, 10 (15.2%) had single-level nasopalatal collapse, and 9 (13.6%) had single-level infrapalatal collapse. Groups did not differ in demographic characteristics or established measures of OSA severity. The single-level nasopalatal group had substantially elevated levels of airway collapsibility (Pcrit-A and PhOP covariate adjusted mean, 2.4; 95% CI, 1.1 to 3.8; and 8.2; 95% CI, 6.4 to 9.9 cmH2O) compared to the single-level infrapalatal group (-0.9; 95% CI, -2.4 to 0.5 cmH2O; and 4.9; 95% CI, 3.0 to 6.8 cmH2O, respectively) and similar to the level among the multilevel group (1.3; 95% CI, 0.7 to 2.0; and 8.5; 95% CI, 7.7 to 9.3 cmH2O). The multilevel group had more negative inspiratory pressure (-24.2; 95% CI, -28.1 to -20.2 cmH2O) compared to the single-level nasopalatal group (-9.8; 95% CI, -18.3 to -1.28 cmH2O). In patients with multilevel collapse, airway collapsibility was significantly higher at the primary nasopalatal compared to secondary infrapalatal site (mean difference, 13.7; 95% CI, 11.3 to 16.1 cmH2O)., Conclusions and Relevance: The findings of this cohort study suggest that intervention should target the primary site of pharyngeal collapse, and secondary sites only if they are nearly as collapsible as the primary site. Future work is needed to precisely define the difference in primary and secondary collapsibility that necessitates multilevel treatment.

A 47-year-old male patient diagnosed with severe obstructive sleep apnea (OSA) sought alternatives to positive airway pressure, prompting evaluation with drug-induced sleep endoscopy (DISE). He underwent a specialized DISE with nasal airflow and pharyngeal pressure monitoring. During obstructive apneas, airflow and pressure signals demonstrated dynamic, multilevel upper airway collapse, with shifting sites of airflow obstruction as respiratory effort increased. This case report illustrates how quantitative airflow and pressure measurements can complement the standard DISE exam and aid in surgical decision-making. Laryngoscope, 134:4418-4420, 2024., (© 2024 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Purpose: To examine factors accounting for differences in hyoid motion during obstructive breathing events amongst obstructive sleep apnea (OSA) patients., Methods: This was a prospective cohort study from June 2022 to October 2022. Patients with OSA undergoing evaluation for PAP alternative therapies with drug-induced sleep endoscopy with positive airway pressure titration (DISE-PAP). All patients underwent DISE-PAP and concurrent hyoid-focused ultrasound. DISE-PAP enabled measurement of airway physiology (flow, respiratory effort) and airway collapsibility (pharyngeal opening pressure, PhOP). Hyoid-ultrasound enabled hyoid bone movement during obstructive breathing. Respiratory effort was measured using a retro-epiglottic pressure-sensitive catheter. Hyoid position was measured using a standardized, awake, CT protocol. Regression analyses adjusted for age, race, sex, and BMI were performed to associate indices of respiratory effort and CT data with hyoid motion., Results: On average, the 26 patients in this cohort were older (63.9 ± 10.5 years), male (69%), overweight (29.6 ± 3.99 kg/m 2 ), and with moderate-to-severe OSA (26.8 ± 10.4 events/hour). Greater respiratory effort was associated with increased hyoid motion (β [95% CI] = 0.034 [0.016,0.052], standardized β = 0.261,p = 0.0003). Higher hyoid position was associated with greater hyoid displacement (β [95% CI] = -0.20 [-0.38,-0.01], Standardized β = -0.57, p = 0.036)., Conclusion: Our data demonstrate that greater respiratory effort, higher hyoid position, and higher airway collapsibility, but not airflow, are associated with greater hyoid motion during obstructive breathing in DISE. These findings suggest that downward hyoid movement represents a compensatory response to upper airway obstruction. Further studies should investigate the vectors of hyoid motion to better understand its role in sleep-related airway collapse., (© 2024. The Author(s).)

A 71-year-old male with severe obstructive sleep apnea and nasal septal deviation presented to a positive airway pressure (PAP) alternatives clinic due to persistent obstructive events on both continuous PAP and bilevel PAP therapy delivered via oronasal mask. He underwent drug-induced sleep endoscopy with PAP titration to determine the mechanism of oronasal mask failure. A nasal mask was also applied and titrated for comparison. Drug-induced sleep endoscopy with PAP showed tongue base collapse which resolved at low pressure using a nasal mask. Application of an oronasal mask increased minimum therapeutic PAP level. Tightening the mask worsened tongue base collapse, which was not resolved by increasing the PAP level. Following nasal surgery, the patient was able to tolerate nasal continuous PAP at low therapeutic pressure, which resulted in both objective and self-reported improvement is his obstructive sleep apnea. This case highlights the ability of drug-induced sleep endoscopy with PAP to determine the mechanistic cause of oronasal mask failure., Citation: Harkins TR, Seay E, Schwartz AR, Thuler E, Dedhia RC. Mechanistic insights from sleep endoscopy related to oronasal mask failures: a case report. J Clin Sleep Med . 2024;20(9):1551-1554., (© 2024 American Academy of Sleep Medicine.)

Gender-affirming hormone therapy (GAHT) can help transgender and/or gender diverse (TGD) individuals achieve emobidment goals that align with their transition needs. Clinical evidence from estradiol (E)-GAHT patients indicate widespread changes in tissues sensitive to E and testosterone (T), particularly in the reproductive system. Notably, E-GAHTs effects on hormones and reproduction vary greatly between patients. With the goal of informing clinical research and practice for TGD individuals taking E, this study examines intact male mice implanted with capsules containing one of three different E doses (low 1.25 mg; mid 2.5 mg; high 5 mg), or a blank control capsule. All E-GAHT doses suppress T and follicle stimulating hormone levels while elevating E levels. Only the high E-GAHT dose significantly supresses luteinizing hormone levels. All E-GAHT doses affect epididymis tubule size similarly while seminiferous tubule morphology and bladder weight changes are dose-dependent. E-GAHT does not alter the presence of mature sperm, though E-exposed sperm have altered motility. These data represent the first evidence that mouse models offer an effective tool to understand E-GAHTs impact on reproductive health and the dose-dependent effects of this model permit examinations of diverse patient outcomes., (© 2023 The Authors. Advanced Biology published by Wiley‐VCH GmbH.)

Objective: There are disparities between Black and White patients in the utilization of positive airway pressure (PAP) alternatives for obstructive sleep apnea (OSA). Given low utilization rates among Black patients, there is limited knowledge of PAP alternative outcomes in this group. Therapeutic PAP levels are clinically accessible measures that have been shown to predict PAP alternative outcomes. Herein, we examined differences in PAP requirements between Black and White patients in a large clinical sample., Study Design: Cross-sectional., Setting: Academic sleep center., Methods: We included OSA patients prescribed autoadjusting PAP between January 2018 and 2020 with baseline apnea-hypopnea index (AHI) ≥ 10. Mean and 90th percentile PAP levels were compared between White and Black patients who used PAP for ≥1 hour daily using linear regression controlling for age, sex, body mass index (BMI), AHI, oxygen saturation nadir, and mask type., Results: There were 157 Black and 234 White patients who were generally obese (BMI, 37.3 ± 8.7) with severe OSA (AHI, 36.9 ± 25.6). Black patients had a 0.68 cm higher (95% confidence interval [CI]: 0.36, 1.35) mean PAP level and 0.85 cm H 2 O higher (95% CI: 0.36, 1.35) 90th percentile PAP level than white patients. Although statistically significant, differences were small and not clinically meaningful., Conclusion: Black and White OSA patients had clinically insignificant differences in PAP requirements, suggesting comparable upper airway collapsibility. Considering the predictive value of therapeutic PAP levels, our findings suggest Black and White patients may have comparable PAP alternative responses from a collapsibility standpoint. Future studies should explore reasons for low utilization of PAP alternatives among Black patients., (© 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Background: Norepinephrine reuptake inhibitors such as atomoxetine (ato) can improve OSA by increasing pharyngeal muscle activity. Mineralocorticoid antagonists such as spironolactone, may potentiate the reduction of OSA severity and reduce blood pressure. We evaluated whether adding spironolactone to atomoxetine (ato-spiro) improved responses in hypertensive OSA patients., Methods: Twenty-one patients with an apnea-hypopnea index (AHI) between 10 and 50 events/h and a history of hypertension were recruited and crossed-over in random order to ato 80 mg and ato-spiro 80/50 mg for 1 week after a 3-day low dose run-in period. Two dropped out due to drug related side effects. Polysomnography and 24-hour blood pressure (BP) monitoring were performed at baseline and after each treatment period., Results: AHI decreased on both ato and ato-spiro from a baseline median(IQR) of 20.3(18.8 to 28.5) to 8.2(7 to 13.1) and 6.2(5.7 to 14.1), respectively (p < 0.001 for both). Systolic BP (mmHg) fell by mean(95%CI) -4.5(-13.8 to 4.8, p = 0.33) on ato and - 10.3(-19.2 to -1.5, p = 0.02) on ato-spiro, and diastolic BP dropped by -3.0(-8.0 to 2.0, p = 0.23) on ato and - 5.0(-9.1 to -0.9; p = 0.02) on ato-spiro. Both ato and ato-spiro led to a significant shift from apnea to hypopnea predominance (p < 0.001), and significant reductions in hypoxic burden (p ≤ 0.001) and REM sleep (p ≤ 0.001)., Conclusions: Both ato-spiro and ato alone decreased OSA severity similarly, but ato-spiro led to even greater, statistically significant and clinically meaningful falls in systolic and diastolic BP. BP reductions were likely due to ato-related improvements in upper airway patency and hypoxemia, and to spiro-related reduced fluid retention. These findings show promise for ato-spiro as an oral treatment for hypertensive OSA patients. REGISTERED AT CLINICALTRIALS.GOV: NCT04905979., Competing Interests: Declarations Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the (place name of institution and/or national research committee) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Name of the ethic committee Advarra, 6100 Merriweather Dr. Ste 600, Columbia, MD 21044. Conflict of interest Within the past two years, AS reports sponsored research from NIH/NHLBI, Apnimed, Itamar/Zoll, and Periodic Breathing LLC. AS provided consultancy for Apnimed, Humannity Foundation, Invicta Medical, Itamar/Zoll, LivaNova, Lunair, Nyxoah, Periodic Breathing, Respicardia/Zoll, Sonosa. RB reports sponsored research for Apnimed, Avadel, Axsome, Bresotec, Bayer, Idorsia, Suven, Jazz, Balance, NLS, Vanda, Merck, Eisai, Philips, Fresca, Takeda, Liva Nova, Roche, Sanofi, Sommetrics, Noctrix, Oura. RB provided consultancy to Jazz Pharmaceuticals, Harmony Biosciences, Avadel Pharmaceuticals, Takeda, Oventus, Axsome. He provided consultancy for Jazz Pharmaceuticals, Harmony Biosciences, Avadel Pharmaceuticals, Takeda, Oventus, Axsome. Speakers Bureau for Jazz, Eisai, Harmony, Axsome, Idorsia. RB is a shareholder of WaterMark Medical, Healthy Humming, LLC and sits on the board of directors of WaterMark Medical. BC reports sponsored research from Apnimed, Avadel, Axsome, Harmony, Jazz, NLS, Takeda, Zefra Therapeutics. BC has been consultant for Avadel and speaker for Axsome and Jazz Pharmaceuticals. HP and LT-M are Apnimed employees. LH has no conflict to disclose., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Obstructive sleep apnea (OSA) is a chronic disorder characterized by recurrent episodes of upper airway collapse during sleep, which can lead to serious health issues like cardiovascular disease and neurocognitive impairments. While positive airway pressure serves as the standard treatment, intolerance in some individuals necessitates exploration of alternative therapies. Hypoglossal nerve stimulation (HGNS) promises to mitigate OSA morbidity by stimulating the tongue muscles to maintain airway patency. However, its effectiveness varies, prompting research for optimization. This review summarizes the effects of HGNS on upper airway obstruction from human and animal studies. It examines physiological responses including critical closing pressure, maximal airflow, nasal and upper airway resistance, compliance, stiffness, and geometry. Interactions among these parameters and discrepant findings in animal and human studies are explored. Additionally, the review summarizes the impact of HGNS on established OSA metrics, such as the apnea-hypopnea index, oxygen desaturation index, and sleep arousals. Various therapeutic modalities, including selective unilateral or bilateral HGNS, targeted unilateral HGNS, and whole unilateral or bilateral HGNS, are discussed. This review consolidates our understanding of HGNS mechanisms, fostering exploration of under-investigated outcomes and approaches to drive advancements in HGNS therapy., Competing Interests: Declaration of competing interest No potential conflicts of interest related to this manuscript are reported by MMS and JA. CH reports grants and personal fees from Inspire Medical Systems (Maple Grove, MN, USA) and Nyxoah (Mt. St. Gilbert, Belgium) and grants and personal fees for consultancy from both companies. CH is also a consultant for Resmed. ARS Potential Conflicts include AE Mann Foundation, Deerfield Catalyst, Invicta Medical, LivaNova, Nyxoah, Respicardia/Zoll., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: Positive airway pressure (PAP) titration during drug-induced sleep endoscopy (DISE) provides objective measures of upper airway collapsibility. While skeletal measurements relate to collapsibility measures on DISE, the influence of soft tissue dimensions on upper airway collapsibility is not known. We analyzed the relationship of measures of upper airway soft tissue volumes, specifically soft palate, pharyngeal lateral walls, and tongue, with metrics of collapsibility., Study Design: Cross-sectional analysis from a prospective cohort., Setting: Academic medical center., Methods: Patients seeking PAP alternative therapies for obstructive sleep apnea (OSA) underwent standardized supine computed tomography (CT) acquisition and DISE protocols. The CT analysis primarily focused on soft tissue volumes and, secondarily, on airway and skeletal volumetric measures. DISE with PAP administration (DISE-PAP) enabled the determination of the pressure at which inspiratory airflow first commenced (pharyngeal critical pressure, Pcrit A ) and the pressure at which inspiratory flow limitation was abolished (pharyngeal opening pressure, PhOP). Both unadjusted and adjusted correlation analyses were performed to understand the relationship between upper airway anatomy and either Pcrit A or PhOP., Results: One hundred thirty-nine subjects completed both CT and DISE-PAP. On average, patients were male (70.5%), white (84.2%), middle-aged (56.6 ± 13.5 years), and overweight (29.6 ± 4.7 kg/m 2 ), with moderate-severe apnea-hypopnea index (29.7 ± 21.3 events/h). Adjusted for age, sex, body mass index, and skeletal volumes, soft palate, and lateral pharyngeal wall volumes were not associated with PhOP or Pcrit A , but a larger tongue was associated with more positive PhOP (⍴ = 0.20, P = .02), and more positive Pcrit A (⍴ = 0.16, P = .07). Exploratory analyses revealed smaller minimum cross-sectional retropalatal area and intramandibular volume were also associated with increased collapsibility measures., Conclusion: After controlling for clinical factors and skeletal volume, greater tongue volume was associated with more severe collapsibility during DISE. These results, in concert with previous work, suggest that greater tongue volume in a smaller skeletal dimensions contribute to the severity of airway collapsibility, a key driver of OSA pathogenesis., (© 2024 The Authors. Otolaryngology–Head and Neck Surgery published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Objective: With the recent addition of airflow and respiratory effort channels, our group has observed central and mixed apnea events during drug-induced sleep endoscopy (DISE). We measured the frequency and timing of sentinel central and/or mixed events (SCents), as well as assessed for differences in velum, oropharynx, tongue, and epiglottis (VOTE) classification compared to obstructive events., Study Design: Prospective single-cohort study., Setting: Tertiary Care Academic Medical Center., Methods: Patients underwent DISE between June 2020 and November 2022. Nasal airflow, thoracoabdominal effort belt signals, and videoendoscopy were simultaneously captured. Demographics, sleep study, and DISE data were compared among patients with and without SCents using Student's T tests or χ 2 tests., Results: On average, the cohort (n = 103) was middle-aged (53.5 ± 12.1 years), overweight (body mass index of 29.7 ± 5.3 kg/m 2 ), and had severe obstructive sleep apnea (apnea-hypopnea index of 30.7 ± 18.7 events/h). Forty-seven patients (46%) were found to have at least 1 SCent. Among those with SCent, 45 (95.7%) transitioned to obstructive pathology after an average of 7.91 ± 2.74 minutes, with at least 95% of patients expected to do so within 12.57 minutes. Twenty-nine out of 47 patients (61.2% [95% confidence interval: 46.4.9%, 75.5%]) with SCent had meaningful differences between central/mixed and obstructive VOTE scores., Conclusion: Central events were present in almost half of our cohort. At least 95% of patients were expected to transition to obstructive events within 12 to 13 minutes of propofol initiation. In addition, over half of patients demonstrate significantly different VOTE scores between central and obstructive events. These factors should raise awareness of central events and scoring passive apneas during DISE and consider delaying VOTE scoring., (© 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Introduction: Increased pharyngeal collapsibility leads to obstructive sleep apnea (OSA). Positive airway pressure titration during drug-induced sleep endoscopy (DISE-PAP) provides objective collapsibility metrics, the pharyngeal opening pressure (PhOP), and active pharyngeal critical pressure (Pcrit A ). We examined the interrelationships between risk factors of OSA, airway collapsibility measures, and clinical manifestations of the disease., Methods: This is a cross-sectional analysis of consecutive OSA patients undergoing DISE-PAP. Nasal PAP was increased stepwise until inspiratory flow limitation was abolished, signifying PhOP. Pcrit A was derived from the resulting titration pressure-flow relationships. Clinical data including demographics, anthropometrics, sleep studies, and patient-symptom questionnaires were obtained from the electronic medical record. Multivariate regression was used to evaluate the relationship between risk factors, airway collapsibility, and clinical data., Results: On average, the 164 patients meeting inclusion criteria were middle-aged (54.2 ± 14.7 years), overweight/obese (BMI 29.9 ± 4.5 kg/m 2 ), male (72.6%), White (79.3%) and had severe OSA (AHI 32.0 ± 20.5 events/hour). Mean PhOP was 7.5 ± 3.3 cm H 2 O and mean Pcrit A was 0.80 ± 3.70 cm H 2 O. Younger age (Standardized β = -0.191, p = 0.015) and higher BMI (Standardized β = 0.176, p = 0.028) were associated with higher PhOP, but not Pcrit A . PhOP and Pcrit A were both associated with AHI, supine AHI, and SpO 2 nadir. Higher PhOP was associated with higher snoring scores (Standardized β = 0.246, p = 0.008), but not other patient-reported outcomes., Conclusion: Objective assessment of passive and active airway mechanics during DISE relates with clinical risk factors for OSA. Quantitative measures of collapsibility provide accessible and meaningful data, enhancing the standard sleep surgery evaluation., Level of Evidence: 4 Laryngoscope, 134:1978-1985, 2024., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: Buprenorphine is effective for chronic pain and safer than full-agonist opioids; however, limited education about and support for buprenorphine can result in under-prescribing in primary care and reduced access in specialty pain clinics. The purpose of this quality improvement initiative was to optimize and evaluate procedures for transferring patients stable on buprenorphine for chronic pain from a specialty pain clinic back to primary care., Setting: Eight primary care clinics within a Veterans Health Administration health care system., Methods: A standard operating procedure for facilitated transfer of prescribing was developed after a needs assessment and was introduced during an educational session with primary care providers, and providers completed a survey assessing attitudes about buprenorphine prescribing. Success of the initiative was measured through the number of patients transferred back to primary care over the course of 18 months., Results: Survey results indicated that primary care providers with previous experience prescribing buprenorphine were more likely to view buprenorphine prescribing for pain as within the scope of their practice and to endorse feeling comfortable managing a buprenorphine regimen. Providers identified systemic and educational barriers to prescribing, and they identified ongoing support from specialty pain care and primary care as a facilitator of prescribing. Metrics suggested that the standard operating procedure was generally successful in transferring and retaining eligible patients in primary care., Conclusion: This quality improvement initiative suggests that a facilitated transfer procedure can be useful in increasing buprenorphine prescribing for pain in primary care. Future efforts to increase primary care provider comfort and address systemic barriers to buprenorphine prescribing are needed., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: The significance of hyoid dynamics in OSA pathophysiology remains unclear. Drug-induced sleep endoscopy (DISE) is often used for evaluating patients intolerant to positive airway pressure (PAP) therapy. We performed DISE with concurrent hyoid-focused ultrasonography to quantify hyoid dynamics during obstructive and non-obstructive breathing., Methods: A cross-sectional analysis from a prospective cohort of patients undergoing DISE with PAP titration (DISE-PAP) and hyoid-focused ultrasound was conducted. Hyoid ultrasound was performed during obstructive breathing, and non-obstructive breathing after PAP administration. Motion was quantified by generating displacement curves based on echo-tracking hyoid movement. The image analysis protocol for quantifying hyoid displacement was performed independently by two researchers, and reliability of measures was assessed. Univariate and multivariate regressions were performed for various clinical data and hyoid displacement during obstructive breathing., Results: Twenty patients met inclusion criteria. On average, the cohort was male (75%), elderly (65.9 ± 10 years), overweight (29.3 ± 3.99 kg/m 2 ), and with moderate-to-severe OSA (29.3 ± 12.5 events/h). Mean hyoid displacement during obstructive breathing was 5.81 mm (±3.48). In all patients, hyoid displacement decreased after PAP administration (-3.94 mm [95% CI: -5.10, -2.78]; p < 0.0001). Inter-rater reliability for measures of hyoid displacement was excellent. After multivariate regression, hyoid displacement at baseline was associated with higher AHI (β [95% CI] = 0.18 [0.03, 0.33], p = 0.020)., Conclusion: During DISE, hyoid displacement is greater during obstructive breathing with significant variability amongst patients. Further, these ultrasonographic measurements had excellent intra- and inter-rater reliability. Additional, larger studies are needed to understand contributors to hyoid mobility., Level of Evidence: 4 Laryngoscope, 133:3221-3227, 2023., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: The impact of gender-affirming testosterone on fertility is poorly understood, with ovarian histopathologic studies showing variable results, some with a detrimental effect on reproductive capacity and uncertain reversibility. Assisted reproductive outcome data are restricted to small case series that lack the ability to inform clinical practice guidelines and limit fertility preservation counseling for transgender and nonbinary individuals., Objective: This study aimed to determine the impact of current testosterone and testosterone washout on in vitro fertilization outcomes in a mouse model for gender-affirming hormone treatment. We hypothesized that current or previous testosterone treatment would not affect in vitro fertilization outcomes., Study Design: C57BL/6N female mice (n=120) were assigned to 4 treatment groups: (1) current control, (2) current testosterone, (3) control washout, and (4) testosterone washout. Testosterone implants remained in situ for 6 or 12 weeks, representing the short- and long-term treatment arms, respectively. Current treatment groups underwent ovarian stimulation with implants in place, and washout treatment groups were explanted and had ovarian stimulation after 2 weeks. Oocytes were collected, fertilized, and cultured in vitro, with one arm continuing to the blastocyst stage and the other having transfer of cleavage-stage embryos. Statistical analysis was performed using GraphPad Prism, version 9.0 and R statistical software, version 4.1.2, with statistical significance defined by P<.05., Results: Current long-term testosterone treatment impaired in vitro fertilization outcomes, with fewer mature oocytes retrieved (13.7±5.1 [standard deviation] vs 28.6±7.8 [standard deviation]; P<.0001) leading to fewer cleavage-stage embryos (12.1±5.1 vs 26.5±8.2; P<.0001) and blastocysts (10.0±3.2 vs 25.0±6.5; P<.0001). There was recovery of in vitro fertilization outcomes following washout in the short-term treatment cohort, with incomplete reversibility in the long-term cohort. Testosterone did not negatively affect maturity, fertilization, or blastulation rates., Conclusion: In a mouse model of gender-affirming hormone treatment, testosterone negatively affected oocyte yield without affecting oocyte quality. Our findings suggest that testosterone reversibility is duration-dependent. These results demonstrate the feasibility of in vitro fertilization without testosterone discontinuation while supporting a washout period for optimization of mature oocyte yield., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To examine the relationship between craniofacial skeletal anatomy and objective measures of pharyngeal collapse obtained during drug-induced sleep endoscopy. We hypothesized that transverse maxillary deficiency and an increased pharyngeal length will be associated with higher levels of pharyngeal collapsibility., Study Design: Cross-sectional analysis in a prospective cohort., Setting: University Hospital., Methods: A cross-sectional analysis was conducted in a cohort of consecutive patients from the positive airway pressure (PAP) alternatives clinic who underwent computed tomography (CT) analysis and drug-induced sleep endoscopy for characterization of upper airway collapsibility. PAP titration was used to determine pharyngeal critical pressure (P CRIT ) and pharyngeal opening pressure (PhOP). CT metrics included: Transverse maxillary dimensions (interpremolar and intermolar distances) and pharyngeal length (posterior nasal spine to hyoid distance)., Results: The cohort (n = 103) of severe obstructive sleep apnea (Apnea and Hipopnea Index 32.1 ± 21.3 events/h) was predominantly male (71.8%), Caucasian (81.6%), middle-aged (54.4 ± 14.3 years), and obese (body mass index [BMI] = 30.0 ± 4.9 kg/m 2 ). Reduced transverse maxillary dimensions were associated with higher P CRIT (intermolar distance: β [95% confidence interval, CI] = -.25 [-0.14, -0.36] cmH 2 O/mm; p = .03) and PhOP (Interpremolar distance: β = -.25 [-0.14, -0.36] cmH 2 O/mm; p = .02). Longer pharyngeal length was also associated with higher P CRIT (β = .11 [0.08, 0.14] cmH 2 O/mm, p = .04) and PhOP (β [95% CI] = .06 [0.03, 0.09] cmH 2 O/mm, p = .04). These associations persisted after adjustments for sex, age, height, and BMI., Conclusion: Our results further the concept that skeletal restriction in the transverse dimension and hyoid descent are associated with elevations in pharyngeal collapsibility during sleep, suggesting a role of transverse deficiency in the pathogenesis of airway obstruction., (© 2023 American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

Importance: Evidence is lacking from randomized clinical trials of hypoglossal nerve stimulation in obstructive sleep apnea (OSA)., Objective: To evaluate the safety and effectiveness of targeted hypoglossal nerve stimulation (THN) of the proximal hypoglossal nerve in patients with OSA., Design, Setting, and Participants: This randomized clinical trial (THN3) was conducted at 20 centers and included 138 patients with moderate to severe OSA with an apnea-hypopnea index (AHI) of 20 to 65 events per hour and body mass index (calculated as weight in kilograms divided by height in meters squared) of 35 or less. The trial was conducted from May 2015 through June 2018. Data were analyzed from January 2022 through January 2023., Intervention: Implant with THN system; randomized 2:1 to activation at month 1 (treatment) or month 4 (control). All received 11 months of THN with follow-up at months 12 and 15, respectively., Main Outcomes and Measures: Primary effectiveness end points comprised AHI and oxygen desaturation index (ODI) responder rates (RRs). Treatment responses at months 4 and 12/15 were defined as a 50% or greater reduction in AHI to 20 or less per hour and an ODI decrease of 25% or greater. Coprimary end points comprised (1) month 4 AHI and ODI RR in the treatment greater than the control group and (2) month 12/15 AHI and ODI RR in the entire cohort exceeding 50%. Secondary end points included sleep apnea severity (AHI and ODI) and patient-reported outcomes (Epworth Sleepiness Scale, Functional Outcomes of Sleep Questionnaire, and EQ-5D visual analog scale)., Results: Among 138 participants, the mean (SD) age was 56 (9) years, and 19 (13.8%) were women. Month 4 THN RRs were substantially greater in those in the treatment vs control group (AHI, 52.3% vs 19.6%; ODI, 62.5% vs 41.3%, respectively) with treatment-control standardized mean differences of 0.725 (95% CI, 0.360-1.163) and 0.434 (95% CI, 0.070-0.843) for AHI and ODI RRs, respectively. Months 12/15 RRs were 42.5% and 60.4% for AHI and ODI, respectively. Improvements in AHI, ODI, Epworth Sleepiness Scale, Functional Outcomes of Sleep Questionnaire, and EQ-5D visual analog scale scores were all clinically meaningful (medium to large effect size). Two serious adverse events and 100 nonserious related adverse events were observed from the implant procedure or study protocol., Conclusions and Relevance: This randomized clinical trial found that THN demonstrated improvements in sleep apnea, sleepiness, and quality of life in patients with OSAs over an extended AHI and body mass index range without prior knowledge of pharyngeal collapse pattern. Clinically meaningful improvements in AHI and patient-reported responses compared favorably with those of distal hypoglossal nerve stimulation trials, although clinically meaningful differences were not definitive for ODI., Trial Registration: ClinicalTrials.gov Identifier: NCT02263859.

Among sleep-related disordered breathing events, hypopneas are the most frequent. Like obstructive and central apneas, hypopneas may be obstructive or central (reduced drive) in origin. Nevertheless, unlike apneas, categorizing hypopneas as either "obstructive" or "central" is often difficult or ambiguous. It has been suggested that hypopneas could be categorized as obstructive when associated with snoring, inspiratory flow limitation, or paradoxical thoraco-abdominal excursions. This approach, however, has not been extensively tested and misclassification of hypopneas is unavoidable. Yet, much rides on the accurate distinction of these events to guide therapy with medical devices or pharmacological therapy in each patient. Additionally, accurate hypopnea classification is critical for design of clinical trials, because therapeutic responses differ depending on the subtype of hypopnea. Correctly classifying hypopneas can also allay concerns about obtaining coverage for therapies that specifically target either central or obstructive sleep-disordered breathing events. The present paper expands on the current criteria for differentiating obstructive from central hypopneas and provides illustrative tracings that can help classify these events., Citation: Javaheri S, Rapoport DM, Schwartz AR. Distinguishing central from obstructive hypopneas on a clinical polysomnogram. J Clin Sleep Med . 2023;19(4):823-834., (© 2023 American Academy of Sleep Medicine.)

Objective: To examine the accuracy and interrater reliability of a visually assessed vs airflow-based measure of pharyngeal collapsibility obtained in patients with obstructive sleep apnea undergoing drug-induced sleep endoscopy (DISE)., Study Design: Prospective observational study., Setting: Academic tertiary care practice., Methods: Patients underwent DISE with airflow monitoring and nasal positive airway pressure titration to determine visual and airflow-based levels of pharyngeal opening pressure (PhOP). Visual DISE-PhOP was assessed by 2 blinded independent raters and defined as the pressure at which visual confirmation of airway collapse, including snoring, was abolished. Airflow-based DISE-PhOP was defined as the minimally effective positive airway pressure that abolished inspiratory flow limitation. Equivalence testing between visual and airflow DISE-PhOP of each rater was performed with the two one sided T-test (TOST) with an a priori equivalence bound of ±1 cm H 2 O. Interrater reliability was evaluated with the intraclass correlation coefficient., Results: One hundred patients were enrolled in the study and 77 completed the full evaluation. The population was predominantly male (74%) with an average age of 54.8 years, body mass index of 30.1 kg/m 2 , and apnea-hypopnea index of 30.7 events/h. Equivalence testing showed that both raters were within ±1 cm H 2 O of airflow-based DISE-PhOP (-0.43 to 0.09 cm H 2 O and -0.32 to 0.48 cm H 2 O). Interrater reliability of visual DISE-PhOP between the raters was also good to excellent with an intraclass correlation coefficient of 0.895 (95% CI, 0.84-0.932)., Conclusion: DISE-PhOP, a measure of upper airway collapsibility, was equivalent between airflow-based and visual assessments with strong interrater reliability, supporting its adoption as a standardized objective parameter in clinical DISE., (© 2022 American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

Obstructive sleep apnea (OSA) affects nearly 1 billion people worldwide, including approximately 35 million US residents. OSA has detrimental cardiovascular and neurocognitive consequences. Positive airway pressure corrects sleep disordered breathing but is not always tolerated or used sufficiently. Oral appliances and surgery provide alternatives in select populations but are variably effective. Hypoglossal nerve stimulation can effectively treat obstructive sleep apnea. Targeted hypoglossal nerve stimulation (THN) is simpler than incumbent technology with no sensor and an easier, proximal electrode implantation. The third clinical study of THN, THN3, was the first randomized, controlled trial of hypoglossal nerve stimulation to demonstrate significant improvement of sleep disordered breathing in OSA. The present investigation reports the design of a novel trial of targeted stimulation to provide additional Level 1 evidence in moderate to severe obstructive apnea. OSPREY is a randomized, parallel-arm, 13-month trial wherein all subjects are implanted, 2/3 are activated at Month 1 ("Treatment") and 1/3 are activated at Month 7 ("Control"). The primary endpoint is the difference in apnea-hypopnea index response rates between Treatment and Control groups at Month 7. Secondary endpoints include quality of life and oximetry metrics. OSPREY follows an adaptive "Goldilocks" design which optimizes the number of subjects with the need for high-confidence results. A maximum of 150 subjects is allowed, at which study power of >95% is predicted. Interim analyses begin once 50 patients are randomized and recur after each 20 additional randomizations to detect early success or futility. OSPREY is a unique, efficient trial that should provide high-confidence confirmation of the safety and efficacy of targeted hypoglossal nerve stimulation for moderate to severe obstructive sleep apnea., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Data are steadily accruing that demonstrate that intestinal tumors are frequently derived from multiple founding cells, resulting in tumors comprised of distinct ancestral clones that might cooperate or alternatively compete, thereby potentially impacting different phases of the disease process., Aim: We sought to determine whether tumors with a multi-ancestral architecture involving at least two distinct clones show increased tumor number, growth, progression, or resistance to drug intervention., Methods: Mice carrying the Min allele of Apc were generated that were mosaic with only a subset of cells in the intestinal epithelium expressing an activated form of PI3K, a key regulatory kinase affecting several important cellular processes. These cells were identifiable as they fluoresced green, whereas all other cells fluoresced red., Results: Cell lineage tracing revealed that many intestinal tumors from our mouse model were derived from at least two founding cells, those expressing the activated PI3K (green) and those which did not (red). Heterotypic tumors with a multi-ancestral architecture as evidenced by a mixture of green and red cells exhibited increased tumor growth and invasiveness. Clonal architecture also had an impact on tumor response to low-dose aspirin. Aspirin treatment resulted in a greater reduction of heterotypic tumors derived from multiple founding cells as compared to tumors derived from a single founding cell., Conclusion: These data indicate that genetically distinct tumor-founding cells can contribute to early intratumoral heterogeneity. The coevolution of the founding cells and their progeny enhances colon tumor progression and impacts the response to aspirin. These findings are important to a more complete understanding of tumorigenesis with consequences for several distinct models of tumor evolution. They also have practical implications to the clinic. Mouse models with heterogenous tumors are likely better for predicting drug efficacy as compared to models in which the tumors are highly homogeneous. Moreover, understanding how interactions among different populations in a single heterotypic tumor with a multi-ancestral architecture impact response to a single agent and combination therapies are necessary to fully develop personalized medicine., (© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Alternatives to positive airway pressure therapy, including surgery, represent an important area of research. Specifically, predictors of response to surgical therapy remain underdeveloped. Drug-induced sleep endoscopy (DISE) holds promise as a diagnostic tool to identify patient-specific causes of airway collapse. Herein, we present a novel, standardized approach which combines anatomic and physiologic measurements during DISE. Our DISE platform measures airflow, airway compliance, airway collapsibility, and structural drivers of collapse. Taken together, these inputs provide a comprehensive framework to further inform the surgeon in providing personalized care of the patient with obstructive sleep apnea., (© 2021 S. Karger AG, Basel.)

Study Objective: Positive airway pressure (PAP) therapy for central sleep apnea (CSA) is often poorly tolerated, ineffective, or contraindicated. Transvenous phrenic nerve stimulation (TPNS) offers an alternative, although its impact on previously PAP-treated patients with CSA has not been examined., Methods: TPNS responses among PAP-naïve and prior PAP-treated patients from the remedē ® System Pivotal Trial were assessed. Of 151, 56 (37%) used PAP therapy before enrolling in the trial. Patients were implanted with a TPNS device and randomized to either active or deferred (control) therapy for 6 months before therapy activation. Apnea-hypopnea index (AHI) and patient-reported outcomes (PRO) were assessed at baseline, and 6 and 12 months following active therapy., Results: Patients had moderate-severe CSA at baseline, which was of greater severity and more symptomatic in the PAP-treated vs. PAP-naïve group (median AHI 52/h vs. 38, central apnea index (CAI) 32/h vs. 18, Epworth Sleepiness Scale 13 vs. 10, fatigue severity scale 5.2 vs. 4.5). Twelve months of TPNS decreased AHI to <20/h and CAI to ≤2/h. Both groups showed reductions in daytime sleepiness and fatigue, improved well-being by patient global assessment, and high therapeutic acceptance with 98% and 94% of PAP-treated and PAP-naïve patients indicating they would undergo the implant again. Stimulation produced discomfort in approximately one-third of patients, yet <5% of prior PAP-treated participants discontinued therapy., Conclusion: Polysomnographic and clinical responses to TPNS were comparable in PAP-naïve and prior PAP-treated CSA patients. TPNS is a viable therapy across a broad spectrum of CSA patients., Trial Registration: ClinicalTrials.gov Identifier NCT01816776; March 22, 2013., (© 2021. The Author(s).)

Study Objectives: Lower therapeutic positive airway pressure (PAP) levels are associated with improved response to non-PAP therapies in the treatment of obstructive sleep apnea. The aim of this study was to evaluate the prevailing notion that patients with apnea-predominant obstructive sleep apnea require higher therapeutic PAP levels compared to patients with hypopnea-predominant obstructive sleep apnea., Methods: An institutional review board-approved retrospective review was performed using strict inclusion criteria: presence of type I or III sleep study, apnea-hypopnea index > 10 events/h, and adherence to auto-adjusting continuous positive airway pressure. Patients were stratified by apnea (> 50% apneas) or hypopnea (≤ 50% apneas) predominance, and PAP data were compared. Statistical analyses were performed using Student's t test and linear regression modeling., Results: Between January 1, 2018 and January 1, 2020, 500 patients met inclusion criteria. Two hundred twenty-one (44.1%) patients were apnea-predominant and 279 (55.8%) were hypopnea-predominant. Apnea-predominant patients had a slightly greater mean PAP (9.01 vs 8.36, P = .002) than hypopnea-predominant patients. Univariable and multivariable linear regression of 7 variables (obstructive apnea percentage, age, sex, body mass index, apnea-hypopnea index, O 2 nadir, mask type) showed obstructive apnea percentage was the weakest predictor of therapeutic PAP levels., Conclusions: Apnea-predominant individuals demonstrated a clinically insignificant difference in PAP level compared to hypopnea-predominant individuals; moreover, obstructive apnea percentage was not a strong predictor of therapeutic PAP levels. Of the modeled variables, the strongest predictor of PAP level was apnea-hypopnea index. Further studies are needed to explore these relationships as well as additional variables that may contribute to predicting therapeutic PAP levels., Citation: Yu JL, Liu Y, Tangutur A, et al. Influence of apnea vs hypopnea predominance in predicting mean therapeutic positive airway pressures among patients with obstructive sleep apnea. J Clin Sleep Med . 2021;17(11):2171-2178., (© 2021 American Academy of Sleep Medicine.)

Background: Marfan syndrome (MFS) is a connective tissue disorder characterised by complex aortic pathology and a high prevalence of obstructive sleep apnoea (OSA). OSA produces intrathoracic transmural stresses that may accelerate aortic injury. The current study was designed to examine the associations between OSA risk and markers of aortic enlargement in MFS., Method: Consecutive patients with MFS were recruited at Johns Hopkins if they completed a STOP-BANG survey. Composite survey scores were categorised into those with low OSA risk (STOP-BANG <3) and high OSA risk (STOP-BANG ≥3). Participants' aortic data were collated to ascertain aortic root diameter, dilatation and prior aortic root replacement. Regression analyses were used to examine associations between OSA risk strata and these aortic parameters., Results: Of the 89 participants studied, 28% had a high OSA risk and 32% had aortic grafts. Persons with high OSA risk had greater aortic root diameter (mm) (ß=4.13, SE=1.81, p=0.027) and aortic root dilatation (ß=2.80, SE=1.34, p=0.046) compared with those with low OSA risk . In addition, the odds of prior aortic root replacement was three times greater in those with high OSA risk compared with those with low OSA risk., Conclusion: In MFS, high OSA risk is associated with aortic enlargement and a threefold increased risk of having had prior aortic root replacement. These findings invite further exploration of the relationship between OSA and aortic disease in MFS, and studies to clarify whether targeted interventions for OSA might mitigate aortic disease progression in MFS., Registration Number: IRB00157483., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)