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OSA is diagnosed and managed by a metric called the apnea-hypopnea index (AHI). The AHI quantifies the number of respiratory events (apnea or hypopnea), disregarding important information on the characteristics and physiologic consequences of respiratory events, including degrees of ventilatory deficit and associated hypoxemia, cardiac autonomic response, and cortical activity. The oversimplification of the disorder by the AHI is considered one of the reasons for divergent findings on the associations of OSA and cardiovascular disease (CVD) in observational and randomized controlled trial studies. Prospective observational cohort studies have demonstrated strong associations of OSA with several cardiovascular diseases, and randomized controlled trials of CPAP intervention have not been able to detect a benefit of CPAP to reduce the risk of CVD. Over the last several years, novel methodologies have been proposed to better quantify the magnitude of OSA-related breathing disturbance and its physiologic consequences. As a result, stronger associations with cardiovascular and neurocognitive outcomes have been observed. In this review, we focus on the methods that capture polysomnographic heterogeneity of OSA., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: A. A. reports grant support from Somnifix and serves as a consultant for Somnifix, Respicardia, Eli Lilly, Inspire, Cerebra, and Apnimed. Apnimed is developing pharmacological treatments for Obstructive Sleep Apnea. A. A.’s interests were reviewed by Brigham and Women’s Hospital and Mass General Brigham in accordance with their institutional policies. A. W. works as a consultant for Apnimed, Nox, Inspire, and Somnifix International LLC. He has received grants from Sanofi and Somnifix. He also has a financial interest in Apnimed Corp., a company developing pharmacologic therapies for sleep apnea. A. W.’s interests were reviewed and are managed by Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict-of-interest policies. None declared (G. L., Y. K.)., (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Study Objectives: Obstructive sleep apnea (OSA) is associated with cognitive impairment; however, the underlying mechanisms remain incompletely understood. OSA is characterized by periods of interrupted ventilation ("ventilatory burden (VB)"), leading to hypoxemia ("hypoxic burden (HB)") and/or arousal ("arousal burden (AB)") from sleep. While hypoxemia is considered a key mechanism underlying white matter injury, its measurement has been limited. In our primary analysis, we assessed the association of HB, a quantitative measure of hypoxemia, with white matter hyperintensity volume (WMH v ), a marker of small vessel disease, and compared with that of VB and AB (quantitative measures of ventilatory deficit and arousals)., Methods: Data from participants in the Multi-Ethnic Study of Atherosclerosis with full polysomnograms (PSG) and brain MRI were analyzed. HB was defined as the total area under the oxygen desaturation curve per hour of sleep, while VB was defined as the event-specific area under the ventilation signal and AB was defined as the normalized cumulative duration of all arousals. The primary outcome was WMH v , with other MRI measures considered secondary outcomes., Results: The analysis included PSGs from 587 participants (age: 65.5±8.2 years). In the fully adjusted model, each 1 standard deviation (SD) increase in HB was associated with a 0.09 SD increase in WMH v (p=0.023), after adjusting for demographics, study site, and comorbidities. In contrast, VB, AB, and conventional OSA measures were not associated with outcomes., Conclusions: Hypoxic burden was associated with white matter hyperintensity volume in a racially/ethnically diverse cohort of older individuals with a high prevalence of OSA., (© 2024 American Academy of Sleep Medicine.)

Background: With recent advancements in bronchoscopic procedures, data on the best modality to sample peripheral pulmonary lesions (PPLs) is lacking, especially comparing bronchoscopy with computed tomography-guided transthoracic biopsy or needle aspiration (CT-TBNA)., Methods: We performed a meta-analysis, pairwise meta-analysis and network meta-analysis on studies reporting diagnostic yield and complications with the use of CT-TBNA, radial endobronchial ultrasound (rEBUS), virtual bronchoscopy (VB), electromagnetic navigation (EMN) or robot-assisted bronchoscopy (RAB) to sample PPLs. The primary outcome was diagnostic yield and the secondary outcome was complications. We estimated the relative risk ratios using a random-effects model and used the frequentist approach for the network meta-analysis. We performed extensive analysis to assess the heterogeneity including reporting bias, publication bias, subgroup and meta-regressional analysis. We assessed the quality of the studies using Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) and QUADAS-Comparative (QUADAS-C)., Results: We included 363 studies. The overall pooled diagnostic yield was 78.1%, the highest with CT-TBNA (88.9%), followed by RAB (84.8%) and the least with rEBUS (72%). In the pairwise meta-analysis, only rEBUS showed inferiority to CT-TBNA. The network meta-analysis ranked CT-TBNA as likely the most effective approach followed by VB, EMN and RAB, while rEBUS was the least effective, with a low-GRADE certainty. CT-TBNA had the highest rate of complications., Conclusion: Although CT-TBNA is the most effective approach to sample PPLs, RAB has a comparable diagnostic yield with a lesser complication rate. Further prospective studies are needed comparing CT-TBNA and RAB., Competing Interests: Conflict of interest: All authors have nothing to disclose., (Copyright ©The authors 2024.)

Rationale: Multiple mechanisms are involved in the pathogenesis of obstructive sleep apnea (OSA). Elevated loop gain is a key target for precision OSA care and may be associated with treatment intolerance when the upper airway is the sole therapeutic target. Morphological or computational estimation of LG is not yet widely available or fully validated - there is a need for improved phenotyping/endotyping of apnea to advance its therapy and prognosis., Objectives: This study proposes a new algorithm to assess self-similarity as a signature of elevated loop gain using respiratory effort signals and presents its use to predict the probability of acute failure (high residual event counts) of continuous positive airway pressure (CPAP) therapy., Methods: Effort signals from 2145 split-night polysomnography studies from the Massachusetts General Hospital were analyzed for SS and used to predict acute CPAP therapy effectiveness. Logistic regression models were trained and evaluated using 5-fold cross-validation., Results: Receiver operating characteristic (ROC) and precision-recall (PR) curves with AUC values of 0.82 and 0.84, respectively, were obtained. Self-similarity combined with the central apnea index (CAI) and hypoxic burden outperformed CAI alone. Even in those with a low CAI by conventional scoring criteria or only mild desaturation, SS was related to poor therapy outcomes., Conclusions: The proposed algorithm for assessing SS as a measure of expressed high loop gain is accurate, non-invasive, and has the potential to improve phenotyping/endotyping of apnea, leading to more precise sleep apnea treatment strategies.

Obstructive sleep apnea (OSA) is associated with excessive daytime sleepiness (EDS). Pharmacotherapy offers a potential treatment approach for EDS in OSA patients. This systematic review and meta-analysis aimed to assess the efficacy and safety of pharmacological interventions for alleviating EDS in patients with OSA. Following PRISMA guidelines, we included randomized controlled trials investigating pharmacological treatments for EDS in adult OSA until August 2023. We conducted meta-analysis, subgroup, and meta-regression analyses using a random effects model. Finally, a network meta-analysis synthesized direct and indirect evidence, followed by a comprehensive safety analysis. We included 32 articles in the meta-analysis (n = 3357). Pharmacotherapy showed a significant improvement in the Epworth Sleepiness Scale (ESS) score (Mean Difference (MD) -2.73, (95 % Confidence Interval (CI) [-3.25, -2.20], p < 0.01) and Maintenance of Wakefulness Test (MWT) score (MD 6.00 (95 % CI [2.66, 9.33] p < 0.01). Solriamfetol, followed by Pitolisant and modafinil, exhibited the greatest ESS reduction, while Danavorexton, followed by Solriamfetol and MK-7288, had the strongest impact on MWT. MK-7288 had the most total adverse events (AEs), followed by Danavorexton and armodafinil. Pharmacological Interventions significantly alleviate EDS in OSA patients but with heterogeneity across medications. Treatment decisions should involve a personalized assessment of patient factors and desired outcomes., Competing Interests: Declaration of competing interest Authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: To investigate the sleep and circadian health of critical survivors 12 months after hospital discharge and to evaluate a possible effect of the severity of the disease within this context., Design: Observational, prospective study., Setting: Single-center study., Patients: Two hundred sixty patients admitted to the ICU due to severe acute respiratory syndrome coronavirus 2 infection., Interventions: None., Measurements and Main Results: The cohort was composed of 260 patients (69.2% males), with a median (quartile 1-quartile 3) age of 61.5 years (52.0-67.0 yr). The median length of ICU stay was 11.0 days (6.00-21.8 d), where 56.2% of the patients required invasive mechanical ventilation (IMV). The Pittsburgh Sleep Quality Index (PSQI) revealed that 43.1% of the cohort presented poor sleep quality 12 months after hospital discharge. Actigraphy data indicated an influence of the disease severity on the fragmentation of the circadian rest-activity rhythm at the 3- and 6-month follow-ups, which was no longer significant in the long term. Still, the length of the ICU stay and the duration of IMV predicted a higher fragmentation of the rhythm at the 12-month follow-up with effect sizes (95% CI) of 0.248 (0.078-0.418) and 0.182 (0.005-0.359), respectively. Relevant associations between the PSQI and the Hospital Anxiety and Depression Scale (rho = 0.55, anxiety; rho = 0.5, depression) as well as between the fragmentation of the rhythm and the diffusing lung capacity for carbon monoxide (rho = -0.35) were observed at this time point., Conclusions: Our findings reveal a great prevalence of critical survivors presenting poor sleep quality 12 months after hospital discharge. Actigraphy data indicated the persistence of circadian alterations and a possible impact of the disease severity on the fragmentation of the circadian rest-activity rhythm, which was attenuated at the 12-month follow-up. This altogether highlights the relevance of considering the sleep and circadian health of critical survivors in the long term., Competing Interests: Dr. Labarca received support for article research from the National Research and Development Agency; he acknowledges receiving financial support from the Agencia Nacional de Investigación y Desarrollo (COVID 1005), Chile. Drs. Targa and de Gonzalo-Calvo have received financial support from Instituto de Salud Carlos III (Miguel Servet 2023: CP23/00095 and Miguel Servet 2020: CP20/00041, respectively), co-funded by Fondo Social Europeo Plus. Dr. Barbé is supported by the Institució Catalana de Recerca I Estudis Avançats Academia program. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Rationale: Low arousal threshold and poor muscle responsiveness are common determinants of obstructive sleep apnea (OSA). Hypnotics were hypothesized as an alternative OSA treatment via raising the arousal threshold and possibly genioglossus responsiveness., Objectives: Effect of common hypnotics on arousal threshold, OSA severity and genioglossus responsiveness., Methods: We searched MEDLINE, EMBASE, CENTRAL and ClinicalTrials.gov for randomized clinical trials, and ran meta-analyses to determine the effect of oral hypnotics on arousal threshold, OSA severity and genioglossus responsiveness. GRADE was used to rate the quality of evidence (QoE). The association between post-treatment AHI and arousal threshold percent reductions was explored in individual patient data (IPD) metanalyses (overall sample and low arousal threshold subgroups)., Measurements and Main Results: Based on our analysis (27 studies; 25 for AHI, 11 for arousal threshold, 4 for genioglossus responsiveness), hypnotics minimally raised arousal threshold (mean difference [95% CI]: 2.7 [1.5, 3.8] cmH2O epiglottic pressure swings; moderate QoE), but did not change OSA severity (1.4 [3.5, 0.7] events/h; moderate QoE). IPD meta-analysis (N=114) showed no association between changes in arousal threshold and AHI, independent of low arousal threshold subgrouping. However, people with very-low arousal threshold or those who exhibited 0-25% arousal threshold increase from placebo experienced the greatest-yet still modest-post-treatment AHI reductions (10%). Hypnotics did not affect genioglossus responsiveness (high QoE)., Conclusions: Further research testing or clinical use of hypnotics as OSA alternative treatments should be discouraged, unless in the presence of comorbid insomnia or as part of combination therapy in individuals with very-low arousal threshold.

Study Objectives: Changing the clocks seasonally is potentially harmful because it interferes with normal daytime activities. Studies aimed at quantifying this association are scant. The objective of this study was to determine the effects of 1 year's worth of changing the clocks (fall and spring transitions) on healthy young men located in the Southern Hemisphere in South America., Methods: We performed an observational prospective study. Thirty healthy male university students were evaluated from 2 weeks before to 2 weeks after both the fall and spring transitions. We administered an overall sleep questionnaire, assessed quality of life, recorded 7-day wrist actigraphy, and had participants perform a psychomotor vigilance task. We defined the 1-hour clock change as the primary exposure and the change in psychomotor vigilance task lapses of 500 milliseconds or more in response time as our primary outcome. Changes were evaluated by the Wilcoxon rank test (significance: P < .05)., Results: After the fall transition, we found a significant worsening in psychomotor vigilance task performance (median [interquartile range], 9.9 [6.0-14.3] lapses of ≥ 500 milliseconds in response time at baseline vs 16.8 [8.2-28.0] after transition; P < .002). Additionally, we found a median loss of about 1 hour of total sleep time and time in bed after the fall transition. Furthermore, participants presented with insomnia. Performance on the psychomotor vigilance task was also affected after the spring transition (16.7 [10-23] vs 23 [12.2-32.2]; P < .001)., Conclusions: A decrease in performance in neurocognitive tests was found after both time transitions. The transition led to insomnia and a significant worsening of sleep variables., Citation: Labarca G, Henriquez-Beltrán M, Sanhueza R, et al. Impact on health outcomes associated with changing the clock 1 hour during fall and spring transitions in the Southern Hemisphere. J Clin Sleep Med . 2024;20(6):887-893., (© 2024 American Academy of Sleep Medicine.)

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). Furthermore, we aimed to assess the extent to which a reduction in SBP is explained by a treatment-related reduction in hypoxic burden (HB)., Methods: ΔHR and HB were measured from pretreatment and posttreatment polygraphy, followed by a 24-hour BP assessment in 168 participants treated with continuous positive airway pressure or nocturnal supplemental oxygen from the HeartBEAT study (Heart Biomarker Evaluation in Apnea Treatment). Multiple linear regression models assessed whether high versus mid (reference) ΔHR predicted a larger reduction in SBP (primary outcome) and whether there was an association between treatment-related reductions in SBP and HB., Results: A high versus mid ΔHR predicted improvement in SBP (adjusted estimate, 5.8 [95% CI, 1.0-10.5] mm Hg). Independently, a greater treatment-related reduction in HB was significantly associated with larger reductions in SBP (4.2 [95% CI, 0.9-7.5] mm Hg per 2 SD treatment-related reduction in HB). Participants with substantial versus minimal treatment-related reductions in HB had a 6.5 (95% CI, 2.5-10.4) mm Hg drop in SBP., Conclusions: A high ΔHR predicted a more favorable BP response to therapy. Furthermore, the magnitude of the reduction in BP was partly explained by a greater reduction in HB., Competing Interests: Disclosures A. Azarbarzin receives grant support from Somnifix and serves as a consultant for Somnifix, Respicardia, Eli Lilly, and Apnimed; Apnimed is a developing pharmacological treatment for obstructive sleep apnea. A. Azarbarzin’s interests were reviewed by Brigham and Women’s Hospital and Mass General Brigham in accordance with their institutional policies. S. Sands receives personal fees as a consultant for Nox Medical, Apnimed, Merck, and Inspire outside the submitted work, and he has received grant support from Apnimed, Prosomnus, and Dynaflex. A. Wellman works as a consultant for Apnimed, Somnifix, Inspire, and Nox Medical. He has received grants from Somnifix and Regeneron. He has a financial interest in Apnimed, a company developing pharmacological therapies for sleep apnea. His interests were reviewed and are managed by Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict of interest policies. C. Schmickl reports income from consulting for Verily outside the submitted work. A. Malhotra is funded by the National Institutes of Health. He reports income related to medical education from Livanova, Eli Lilly, Jazz, and Zoll. ResMed provided a philanthropic donation to University of California San Diego. S. Redline received consulting fees from Eli Lilly, Inc, and Jazz Pharma and has consulted for Apnimed, Inc. D.J. Gottlieb has served on scientific advisory boards for Signifier Medical Technologies, Inc, and Wesper, Inc, and as a consultant to Powell-Mansfield, Inc, and Apnimed, Inc, and has received research support from ResMed, Inc. The other authors report no conflicts.

Background: Novel wireless-based technologies can easily record pulse oximetry at home. One of the main parameters that are recorded in sleep studies is the time under 90% of SpO 2 (T90%) and the oxygen desaturation index 3% (ODI-3%). We assessed the association of T90% and/or ODI-3% in two different scenarios (a community-based study and a clinical setting) with all-cause mortality (primary outcome)., Methods: We included all individuals from the Sleep Heart Health Study (SHHS, community-based cohort) and Santiago Obstructive Sleep Apnea (SantOSA, clinical cohort) with complete data at baseline and follow-up. Two measures of hypoxemia (T90% and ODI-3%) were our primary exposures. The adjusted hazard ratios (HRs) per standard deviation (pSD) between T90% and incident all-cause mortality (primary outcome) were determined by adjusted Cox regression models. In the secondary analysis, to assess whether T90% varies across clinical factors, anthropometrics, abdominal obesity, metabolic rate, and SpO 2 , we conducted linear regression models. Incremental changes in R 2 were conducted to test the hypothesis., Results: A total of 4323 (56% male, median 64 years old, follow-up: 12 years, 23% events) and 1345 (77% male, median 55 years old, follow-up: 6 years, 11.6% events) patients were included in SHHS and SantOSA, respectively. Every 1 SD increase in T90% was associated with an adjusted HR of 1.18 [95% CI: 1.10-1.26] (p value < 0.001) in SHHS and HR 1.34 [95% CI: 1.04-1.71] (p value = 0.021) for all-cause mortality in SantOSA. Conversely, ODI-3% was not associated with worse outcomes. R 2 explains 62% of the variability in T90%. The main contributors were baseline-mean change in SpO 2 , baseline SpO 2 , respiratory events, and age., Conclusion: The findings suggest that T90% may be an important marker of wellness in clinical and community-based scenarios. Although this nonspecific metric varies across the populations, ventilatory changes during sleep rather than other physiological or comorbidity variables explain their variability., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Rationale: 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. Objective: To determine the relationship between airway obstruction and ventilatory drive on snore loudness. Methods: In 40 patients with suspected or diagnosed obstructive sleep apnea (1-98 events/hr), airflow was recorded via a pneumotachometer attached to an oronasal mask, ventilatory drive was recorded using calibrated intraesophageal diaphragm electromyography, and snore loudness was recorded using a calibrated microphone attached over the trachea. "Obstruction" was taken as the ratio of ventilation to ventilatory drive and termed flow:drive, i.e., actual ventilation as a percentage of intended ventilation. Lower values reflect increased flow resistance. Using 165,063 breaths, mixed model analysis (quadratic regression) quantified snore loudness as a function of obstruction, ventilatory drive, and the presence of extreme obstruction (i.e., apneic occlusion). Results: In the presence of obstruction (flow:drive = 50%, i.e., doubled resistance), snore loudness increased markedly with increased drive (+3.4 [95% confidence interval, 3.3-3.5] dB per standard deviation [SD] change in ventilatory drive). However, the effect of drive was profoundly attenuated without obstruction (at flow:drive = 100%: +0.23 [0.08-0.39] dB per SD change in drive). Similarly, snore loudness increased with increasing obstruction exclusively in the presence of increased drive (at drive = 200% of eupnea: +2.1 [2.0-2.2] dB per SD change in obstruction; at eupneic drive: +0.14 [-0.08 to 0.28] dB per SD change). Further, snore loudness decreased substantially with extreme obstruction, defined as flow:drive <20% (-9.9 [-3.3 to -6.6] dB vs. unobstructed eupneic breathing). Conclusions: This study highlights that ventilatory drive, and not simply pharyngeal obstruction, modulates snore loudness. This new framework for characterizing the severity of snoring helps better understand the physiology of snoring and is important for the development of technologies that use snore sounds to characterize sleep-disordered breathing.

Background: Hypoxic burden (HB) has emerged as a strong predictor of cardiovascular risk in obstructive sleep apnoea (OSA). We aimed to assess the potential of HB to predict the cardiovascular benefit of treating OSA with continuous positive airway pressure (CPAP)., Methods: This was a post hoc analysis of the ISAACC trial (ClinicalTrials.gov: NCT01335087) including non-sleepy patients with acute coronary syndrome (ACS) diagnosed with OSA (apnoea-hypopnoea index ≥15 events·h -1 ) by respiratory polygraphy. Patients were randomised to CPAP or usual care and followed for a minimum of 1 year. HB was calculated as the total area under all automatically identified desaturations divided by total sleep time. Patients were categorised as having high or low baseline HB according to the median value (73.1%min·h -1 ). Multivariable Cox regression models were used to assess whether the effect of CPAP on the incidence of cardiovascular outcomes was dependent on the baseline HB level., Results: The population (362 patients assigned to CPAP and 365 patients assigned to usual care) was middle-aged (mean age 59.7 years), overweight/obese and mostly male (84.5%). A significant interaction was found between the treatment arm and the HB categories. In the high HB group, CPAP treatment was associated with a significant reduction in the incidence of cardiovascular events (HR 0.57, 95% CI 0.34-0.96). In the low HB group, CPAP-treated patients exhibited a trend toward a higher risk of cardiovascular outcomes than those receiving usual care (HR 1.33, 95% CI 0.79-2.25). The differential effect of the treatment depending on the baseline HB level followed a dose-response relationship., Conclusion: In non-sleepy ACS patients with OSA, high HB levels were associated with a long-term protective effect of CPAP on cardiovascular prognosis., Competing Interests: Conflict of interest: M.Á. Martinez-Garcia received grants from VitalAire and Philips, Spain, and serves as a consultant for ResMed Inc., Australia, companies that develop products related to sleep apnoea. L. Messineo received a consultancy fee from Apnimed. A. Wellman works as a consultant for Apnimed, SomniFix and Nox, and has received grants from SomniFix and Sanofi; A. Wellman has a financial interest in Apnimed, a company developing pharmacological therapies for sleep apnoea. His interests were reviewed and are managed by Brigham and Women's Hospital and Partners HealthCare in accordance with their conflict of interest policies. S. Redline received grant support and consulting fees from Jazz Pharmaceuticals, and consulting fees from Apnimed and Lilly Pharma. S. Sands receives personal fees as a consultant for Nox Medical and Merck, outside the submitted work, and receives grant support from Apnimed and ProSomnus. F. Barbé received a research grant from ResMed Inc., Australia, a company that develops products related to sleep apnoea. A. Azarbarzin reports grant support from SomniFix and serves as a consultant for SomniFix, Respicardia, Eli Lilly and Apnimed. Apnimed is developing pharmacological treatments for obstructive sleep apnoea. A. Azarbarzin's interests were reviewed by Brigham and Women's Hospital and Mass General Brigham in accordance with their institutional policies. All other authors declare no competing interests., (Copyright ©The authors 2023.)

Objective  To evaluate the clinical utility of the Baveno classification in predicting incident cardiovascular mortality after five years of follow-up in a clinic-based cohort of patients with obstructive sleep apnea (OSA). Materials and Methods  We evaluated the reproducibility of the Baveno classification using data from the Santiago Obstructive Sleep Apnea (SantOSA) study. The groups were labeled Baveno A (minor symptoms and comorbidities), B (severe symptoms and minor comorbidities), C (minor symptoms and severe comorbidities), and D (severe symptoms and comorbidities). Within-group comparisons were performed using analysis of variance (ANOVA) and post hoc tests. The associations between groups and incident cardiovascular mortality were determined through the Mantel-Cox and Cox proportional hazard ratios (HRs) adjusted by covariables. Results  A total of 1,300 OSA patients were included (Baveno A: 27.7%; B: 28%; C: 16.8%; and D: 27.5%). The follow-up was of 5.4 years. Compared to Baveno A, the fully-adjusted risk of cardiovascular mortality with Baveno B presented an HR of 1.38 (95% confidence interval [95%CI]: 0.14-13.5; p  = 0.78); with Baveno C, it was of 1.71 (95%CI: 0.18-16.2; p  = 0.63); and, with Baveno D, of 1.04 (95%CI: 0.12-9.2; p  = 0.98). We found no interactions involving Baveno group, sex and OSA severity. Discussion  Among OSA patients, the Baveno classification can describe different subgroups. However, its utility in identifying incident cardiovascular mortality is unclear. Long-term follow-up studies and the inclusion of demographic variables in the classification could improve its ability to detect a high-risk phenotype associated with cardiovascular mortality. Conclusion  The Baveno classification serves as a valuable method for categorizing varying groups of patients afflicted with OSA. Nevertheless, its precision in identifying occurrence of cardiovascular mortality is still unclear., Competing Interests: Conflict of Interests The authors have no conflict of interests to declare., (Brazilian Sleep Association. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Rationale: 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. Objective: To validate a novel method to quantify the HB that is based on automatically scored desaturations. Methods: The sample included 5,655 middle-aged or older adults from the Sleep Heart Health Study (52.8% women; age, 63.2 ± 11.3 yr). The original HB method was based on a subject-specific search window obtained from an ensemble average of oxygen saturation signals (as measured by pulse oximetry) and synchronized with respect to the termination of scored respiratory events. In this study, however, the search window was obtained from ensemble average of oxygen saturation signals that synchronized with respect to the minimum of all automatically identified desaturations (⩾2% and other thresholds, including 3% and 4%, in sensitivity analyses). The time interval between the two maxima around the minimum saturation was defined as the search window. The oximetry-derived HB (HB Oxi ) was defined as the total area under all desaturation curves (restricted by the search window) divided by the total sleep time. Logistic and Cox regression models assessed the adjusted odds ratio (aOR)/hazard ratio of excessive daytime sleepiness (EDS), hypertension (HTN), and CVD mortality per 1-standard deviation increase in HB Oxi after adjusting for several covariates and confounders. Results: The Spearman's rank correlation between HB (median [interquartile range], 34.4 [18.4-59.8] % min/h) and HB Oxi (median [interquartile range], 34.5 [21.6-53.8] % min/h) was 0.81 ( P  < 0.001). Similar to HB, HB Oxi was significantly associated with EDS (aOR [95% confidence interval (CI)], 1.17 [1.09-1.26] per standard deviation), HTN (aOR [95% CI], 1.13 [1.05-1.21]), and CVD mortality (adjusted hazard ratio [95% CI], 1.15 [1.01-1.30]) in fully adjusted models. Conclusions: The HB Oxi was highly correlated with the HB based on manually scored apneas and hypopneas and was associated with EDS, HTN, and CVD mortality with similar effect sizes as previously reported. This method could be incorporated into wearable technology that accurately records oxygen saturation signals.

Current studies agree on the impact of sleep and circadian rest-activity rhythm alterations in acute respiratory distress syndrome (ARDS) survivors. However, research on the duration of this impact is scarce. In this study, we evaluate the impact of ARDS on the sleep and circadian rest-activity rhythm of COVID-19 survivors twelve months after hospital discharge. This is a prospective study including COVID-19 survivors with and without ARDS during hospitalization. Data was collected four and twelve months after hospital discharge. The interventions included one-week wrist actigraphy and a home sleep apnea test (HSAT), and evaluations were conducted according to the Pittsburgh sleep quality index (PSQI), Epworth sleepiness scale (ESS), and insomnia severity index (ISI). Fifty-two patients were evaluated (ARDS = 31 and non-ARDS = 21); they had a median age of 49.0 [39.0;57.2] years and 53.8% were male. After twelve months, 91.3% presented poor sleep quality, 58.7% presented insomnia, 50% presented daytime somnolence, and 37% presented comorbid insomnia and obstructive sleep apnea (COMISA). No significant improvement was observed in relation to sleep or the circadian rest-activity rhythm between four and twelve months. A tendency of poor sleep quality, insomnia, daytime somnolence, and COMISA was observed. Finally, there was no significant impact on the circadian rest-activity rhythm between four and twelve months or between the groups.

Background: Chylothorax is an uncommon medical condition for which limited data are available regarding the contemporary aetiology, management and outcomes. The goal of this study was to better define these poorly characterised features., Methods: The medical records of adult patients diagnosed with chylothorax at 12 centres across Europe, America and South Africa from 2009-2021 were retrospectively reviewed. Descriptive and inferential statistics were performed., Results: 77 patients (median age 69 years, male to female ratio 1.5) were included. Subacute dyspnoea was the most typical presenting symptom (66%). The commonest cause of chylothorax was malignancy (68.8%), with lymphoma accounting for 62% of these cases. Other aetiologies were trauma (13%), inflammatory/miscellaneous conditions (11.7%) and idiopathic cases (6.5%). At the initial thoracentesis, the pleural fluid appeared milky in 73%, was exudative in 89% and exhibited triglyceride concentrations >100 mg·dL -1 in 88%. Lymphangiography/lymphoscintigraphy were rarely ordered (3%), and demonstration of chylomicrons in pleural fluid was never ascertained. 67% of patients required interventional pleural procedures. Dietary measures were infrequently followed (36%). No patient underwent thoracic duct ligation or embolisation. Morbidity included infections (18%), and thrombosis in malignant aetiologies (16%). The 1-year mortality was 47%. Pleural fluid protein >3.5 mg·dL -1 (sub-distribution hazard ratio (SHR) 4.346) or lactate dehydrogenase <500 U·L -1 (SHR 10.21) increased the likelihood of effusion resolution. Pleural fluid protein ≤3.5 mg·dL -1 (HR 4.047), bilateral effusions (HR 2.749) and a history of respiratory disease (HR 2.428) negatively influenced survival., Conclusion: Chylothoraces have a poor prognosis and most require pleural interventions. Despite the standard recommendations, lymphatic imaging is seldom used, nor are dietary restrictions followed., Competing Interests: Conflict of interest: J.M. Porcel has received consultancy fees from Becton Dickinson and Suministros Hospitalarios SA (SH Medical Group), and is an associate editor of this journal. Conflict of interest: The remaining authors declare that they have no relevant conflicts of interest., (Copyright ©The authors 2023.)

COVID-19 continues to affect an unprecedented number of people with the emergence of new variants posing a serious challenge to global health. There is an expansion of knowledge in understanding the pathogenesis of Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the impact of the acute disease on multiple organs. In addition, growing evidence reports that the impact of COVID-19 on different organs persists long after the recovery phase of the disease, leading to long-term consequences of COVID-19. These long-term consequences involve pulmonary as well as extra-pulmonary sequelae of the disease. Noteably, recent research has shown a potential association between COVID-19 and change in the molecular cargo of extracellular vesicles (EVs). EVs are vesicles released by cells and play an important role in cell communication by transfer of bioactive molecules between cells. Emerging evidence shows a strong link between EVs and their molecular cargo, and regulation of metabolism in health and disease. This review focuses on current knowledge about EVs and their potential role in COVID-19 pathogenesis, their current and future implications as tools for biomarker and therapeutic development and their possible effects on long-term impact of COVID-19., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Introduction: Long-term pulmonary dysfunction (L-TPD) is one of the most critical manifestations of long-COVID. This lung affection has been associated with disease severity during the acute phase and the presence of previous comorbidities, however, the clinical manifestations, the concomitant consequences and the molecular pathways supporting this clinical condition remain unknown. The aim of this study was to identify and characterize L-TPD in patients with long-COVID and elucidate the main pathways and long-term consequences attributed to this condition by analyzing clinical parameters and functional tests supported by machine learning and serum proteome profiling., Methods: Patients with L-TPD were classified according to the results of their computer-tomography (CT) scan and diffusing capacity of the lungs for carbon monoxide adjusted for hemoglobin (DLCOc) tests at 4 and 12-months post-infection., Results: Regarding the acute phase, our data showed that L-TPD was favored in elderly patients with hypertension or insulin resistance, supported by pathways associated with vascular inflammation and chemotaxis of phagocytes, according to computer proteomics. Then, at 4-months post-infection, clinical and functional tests revealed that L-TPD patients exhibited a restrictive lung condition, impaired aerobic capacity and reduced muscular strength. At this time point, high circulating levels of platelets and CXCL9, and an inhibited FCgamma-receptor-mediated-phagocytosis due to reduced FcγRIII (CD16) expression in CD14+ monocytes was observed in patients with L-TPD. Finally, 1-year post infection, patients with L-TPD worsened metabolic syndrome and augmented body mass index in comparison with other patient groups., Discussion: Overall, our data demonstrated that CT scan and DLCOc identified patients with L-TPD after COVID-19. This condition was associated with vascular inflammation and impair phagocytosis of virus-antibody immune complexes by reduced FcγRIII expression. In addition, we conclude that COVID-19 survivors required a personalized follow-up and adequate intervention to reduce long-term sequelae and the appearance of further metabolic diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Sanhueza, Vidal, Hernandez, Henriquez-Beltran, Cabrera, Quiroga, Antilef, Aguilar, Castillo, Llerena, Fraga Figueroa, Nazal, Castro, Lagos, Moreno, Lastra, Gajardo, Garcés, Riffo, Buchert, Sanhueza, Ormazába, Saldivia, Vargas, Nourdin, Koch, Zuñiga, Lamperti, Bustos, Guzmán-Gutiérrez, Tapia, Ferrada, Cerda, Woehlbier, Riquelme, Yuseff, Muñoz Ramirez, Lombardi, De Gonzalo-Calvo, Salomon, Verdugo, Quiñones, Colombo, Barría, Labarca and Nova-Lamperti.)

Importance: The effect of continuous positive airway pressure (CPAP) on secondary cardiovascular disease prevention is highly debated., Objective: To assess the effect of CPAP treatment for obstructive sleep apnea (OSA) on the risk of adverse cardiovascular events in randomized clinical trials., Data Sources: PubMed (MEDLINE), EMBASE, Current Controlled Trials: metaRegister of Controlled Trials, ISRCTN Registry, European Union clinical trials database, CENTRAL (Cochrane Central Register of Controlled Trials), and ClinicalTrials.gov databases were systematically searched through June 22, 2023., Study Selection: For qualitative and individual participant data (IPD) meta-analysis, randomized clinical trials addressing the therapeutic effect of CPAP on cardiovascular outcomes and mortality in adults with cardiovascular disease and OSA were included., Data Extraction and Synthesis: Two reviewers independently screened records, evaluated potentially eligible primary studies in full text, extracted data, and cross-checked errors. IPD were requested from authors of the selected studies (SAVE [NCT00738179], ISAACC [NCT01335087], and RICCADSA [NCT00519597])., Main Outcomes and Measures: One-stage and 2-stage IPD meta-analyses were completed to estimate the effect of CPAP treatment on risk of recurrent major adverse cardiac and cerebrovascular events (MACCEs) using mixed-effect Cox regression models. Additionally, an on-treatment analysis with marginal structural Cox models using inverse probability of treatment weighting was fitted to assess the effect of good adherence to CPAP (≥4 hours per day)., Results: A total of 4186 individual participants were evaluated (82.1% men; mean [SD] body mass index, 28.9 [4.5]; mean [SD] age, 61.2 [8.7] years; mean [SD] apnea-hypopnea index, 31.2 [17] events per hour; 71% with hypertension; 50.1% receiving CPAP [mean {SD} adherence, 3.1 {2.4} hours per day]; 49.9% not receiving CPAP [usual care], mean [SD] follow-up, 3.25 [1.8] years). The main outcome was defined as the first MACCE, which was similar for the CPAP and no CPAP groups (hazard ratio, 1.01 [95% CI, 0.87-1.17]). However, an on-treatment analysis by marginal structural model revealed a reduced risk of MACCEs associated with good adherence to CPAP (hazard ratio, 0.69 [95% CI, 0.52-0.92])., Conclusions and Relevance: Adherence to CPAP was associated with a reduced MACCE recurrence risk, suggesting that treatment adherence is a key factor in secondary cardiovascular prevention in patients with OSA.

Rationale: Obstructive sleep apnea is characterized by frequent reductions in ventilation, leading to oxygen desaturations and/or arousals. Objectives: 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. Methods: Hypoxic, ventilatory, and arousal burdens were measured from baseline polysomnograms in the Multi-Ethnic Study of Atherosclerosis (MESA) and the Osteoporotic Fractures in Men (MrOS) studies. Ventilatory burden was defined as event-specific area under ventilation signal (mean normalized, area under the mean), and arousal burden was defined as the normalized cumulative duration of all arousals. The adjusted hazard ratios for incident CVD and mortality were calculated. Exploratory analyses quantified contributions to hypoxic burden of ventilatory burden, baseline oxygen saturation as measured by pulse oximetry, visceral obesity, and spirometry parameters. Measurements and Main Results: Hypoxic and ventilatory burdens were significantly associated with incident CVD (adjusted hazard ratio [95% confidence interval] per 1 SD increase in hypoxic burden: MESA, 1.45 [1.14, 1.84]; MrOS, 1.13 [1.02, 1.26]; ventilatory burden: MESA, 1.38 [1.11, 1.72]; MrOS, 1.12 [1.01, 1.25]), whereas arousal burden was not. Similar associations with mortality were also observed. Finally, 78% of variation in hypoxic burden was explained by ventilatory burden, whereas other factors explained only <2% of variation. Conclusions: Hypoxic and ventilatory burden predicted CVD morbidity and mortality in two population-based studies. Hypoxic burden is minimally affected by measures of adiposity and captures the risk attributable to ventilatory burden of obstructive sleep apnea rather than a tendency to desaturate.

Background: Although a proven relationship exists between the blood eosinophil count (BEC) and the severity of both asthma and COPD, its relationship with bronchiectasis has not been well established. The objective of this study was to analyze the relationship between BEC and the number and severity of exacerbations, and patients' responses to inhaled corticosteroid (IC) treatment in bronchiectasis RESEARCH QUESTION: Does an association exist among BEC, the number of exacerbations and severity of bronchiectasis, and IC treatment?, Study Design and Methods: This was a multicenter (43 centers) prospective observational study derived from the Spanish Bronchiectasis Registry. Patients with proven bronchiectasis and a known BEC were included, whereas those with asthma or antieosinophilic treatments were excluded. Patients were divided into four groups according to the BEC at the time of inclusion in the study in a steady-state situation: (1) eosinopenic bronchiectasis (< 50 eosinophils/μL), (2) low number of eosinophils (51-100/μL), (3) normal number of eosinophils (101-300/μL), and (4) eosinophilic bronchiectasis (> 300 eosinophils/μL)., Results: Nine hundred twenty-eight patients finally were included: 123 patients (13.3%) with < 50 eosinophils/μL (eosinopenic group), 164 patients (17.7%) with 50-100 eosinophils/μL, 488 patients (52.6%) with 101-300 eosinophils/μL, and 153 patients (16.5%) with > 300 eosinophils/μL (eosinophilic group). BEC showed a significant U-shaped relationship with severity, exacerbations, lung function, microbiologic profile, and IC treatment (these being higher in the eosinopenic group compared with the eosinophilic group). IC treatment significantly decreased the number and severity of exacerbations only in the group of bronchiectasis patients with > 300 eosinophils/μL., Interpretation: A significant U-shaped relationship was found between BEC and severity and exacerbations in bronchiectasis that was more pronounced in the eosinopenic group. IC treatment decreased the number and severity of exacerbations only in the eosinophilic group., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Rationale: 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. Objectives: For the first time, we critically test whether the loss of drive could explain the loss of genioglossus activity observed within events in OSA. Methods: We examined the time course of genioglossus activity (EMGgg; intramuscular electromyography), ventilatory drive (intraesophageal diaphragm electromyography), and esophageal pressure during spontaneous respiratory events (using the ensemble-average method) in 42 patients with OSA (apnea-hypopnea index 5-91 events/h). Results: Multivariable regression demonstrated that the falling-then-rising time course of EMGgg may be well explained by falling-then-rising drive and rising negative pressure stimuli (model R  = 0.91 [0.88-0.98] [95% confidence interval]). Overall, EMGgg was 2.9-fold (0.47-∞) more closely associated with drive than pressure stimuli (ratio of standardized coefficients, β drive :β pressure ; ∞ denotes absent pressure contribution). However, individual patient results were heterogeneous: approximately one-half ( n  = 22 of 42) exhibited drive-dominant responses (i.e., β drive :β pressure  > 2:1), and one-quarter ( n  = 11 of 42) exhibited pressure-dominant EMGgg responses (i.e., β drive :β pressure  < 1:2). Patients exhibiting more drive-dominant EMGgg responses experienced greater event-related EMGgg declines (12.9 [4.8-21.0] % baseline /standard deviation of β drive :β pressure ; P  = 0.004, adjusted analysis). Conclusions: Loss of genioglossus activity precipitating events in patients with OSA is strongly associated with a contemporaneous loss of drive and is greatest in those whose activity tracks drive rather than pressure stimuli. These findings were upheld for events without prior arousal. Responding to falling drive rather than rising negative pressure during events may be deleterious; future therapeutic strategies whose aim is to sustain genioglossus activity by preferentially enhancing responses to rising pressure rather than falling drive are of interest.

Study Objectives: There is uncertainty on best approaches for defining apnea-hypopnea events. To clarify the contributions of desaturation vs arousal to defining hypopneas, we examined the associations of events with desaturation (≥ 3%) but not arousal (apnea-hypopnea index [AHI] ≥3%Only ) vs events with arousals but no desaturation (AHI ArOnly ) with obstructive sleep apnea-related comorbidities and incident cardiovascular disease across multiple cohorts., Methods: In the Sleep Heart Health Study (n = 5,473), the Multi-Ethnic Study of Atherosclerosis (n = 1,904), and the Osteoporotic Fractures in Men Study (n = 2,685), we examined the independent associations of AHI ≥3%Only and AHI ArOnly with hypertension, diabetes, and daytime sleepiness, and incident cardiovascular disease., Results: After adjusting for covariates and AHI based on events with electroencephalogram arousal (regardless of desaturation), AHI ≥3%Only was associated with hypertension in Sleep Heart Health Study (odds ratio: 1.12; 95% confidence interval: 1.04,1.21), per 1 standard deviation increase). Similar associations were observed in the Multi-Ethnic Study of Atherosclerosis and Osteoporotic Fractures in Men Study, as well as for associations with diabetes (odds ratio: 1.30; 1.09,1.54, and 1.25; 1.07,1.47, respectively), sleepiness (odds ratio: 1.19; 1.00,1.41; and 1.17; 1.01-1.35), and incident cardiovascular disease (hazard ratio: 1.37; 1.05,1.77 and 1.14; 1.00,1.29). In contrast, after adjusting for events with desaturation (regardless of arousal), AHI ArOnly was unassociated with these outcomes. In Sleep Heart Health Study, greater baseline obstructive sleep apnea severity was associated with a reduction in arousal frequency over 5 years ( P < .0001)., Conclusions: In middle-aged and older individuals, addition of events with arousals does not improve the strength of associations with comorbidities or incident cardiovascular disease. Research is needed to understand generalizability to younger individuals and the mechanistic role of arousals in obstructive sleep apnea., Citation: Azarbarzin A, Sands SA, Han S, et al. Relevance of cortical arousals for risk stratification in sleep apnea: a 3 cohort analysis. J Clin Sleep Med . 2023;19(8):1475-1484., (© 2023 American Academy of Sleep Medicine.)

Sleep is essential for life, and inappropriate sleep duration patterns may lead to chronic consequences regarding human health. Several studies have confirmed the presence of a U-shaped association between sleep duration and mortality. Moreover, many consequences related to cardiometabolic aspects have been suggested in patients with abnormal sleep durations. In this study, we analyzed the associations between sleep duration, total sleep time (TST), the risk of all-cause mortality, and 10-year cardiovascular risk in a cohort of patients at a sleep medicine center in Santiago, Chile. We conducted a prospective cohort study of patients (SantOSA). A short TST was defined as ≤6 h, a normal TST as 6 to 9 h, and a long TST as ≥9 h. Adjusted hazard ratios (aHRs) for all-cause mortality were calculated. A cross-sectional analysis between TST and 10-year cardiovascular risk (calculated using the Framingham 2008 formula) was determined using logistic regression models. A total of 1385 subjects were included in the results (78% male; median age: 53, interquartile range (IQR): 42-64 years; median BMI: 29.5, IQR: 16.7-33.1). A total of 333 subjects (24%) reported short TSTs, 938 (67.7%) reported normal TSTs, and 114 (8.3%) reported long TSTs. In the fully adjusted model, the association remained significant for short (aHR: 2.51 (1.48-4.25); p -value = 0.01) and long TSTs (aHR: 3.97 (1.53-10.29); p -value = 0.04). Finally, a U-shaped association was found between short and long TSTs, with an increase in cardiovascular risk at 10 years. Compared with normal TSTs, short (≤6 h) and long (≥9 h) TSTs were significantly associated with all-cause mortality and increased 10-year cardiovascular risk.

Sleepiness is one of the outcomes most used in randomized clinical trials (RCT) on the effect of treatments for obstructive sleep apnea (OSA). Furthermore, it is known that there is a placebo effect, especially in subjective measures. Therefore, given that sleepiness is a subjective measure, the objective of this systematic review with meta-analysis and three-level meta-regression was to assess the response to different placebos (pills and sham-CPAP) used in RCTs in OSA, both on subjective (Epworth Sleepiness Scale [ESS]) and objective (Multiple Sleep Latency Test [MSLT], Maintenance Wake Test [MWT], the Osler test and the Psychomotor Vigilance Task [PVT]). We observed a statistically significant placebo effect in both subjective and objective measures of hypersomnia, and in both sham-CPAP and pills. This placebo effect was greater, even clinically significant, in subjective measures (ESS: -2.84 points) and in those RCTs that used pills as a placebo. In the meta-regression, only a higher baseline value of the ESS and Osler test was related to the placebo effect., Competing Interests: Declaration of competing interest The authors 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 © 2022 Elsevier Ltd. All rights reserved.)

Purpose: Robust biomarkers that predict disease outcomes amongst COVID-19 patients are necessary for both patient triage and resource prioritisation. Numerous candidate biomarkers have been proposed for COVID-19. However, at present, there is no consensus on the best diagnostic approach to predict outcomes in infected patients. Moreover, it is not clear whether such tools would apply to other potentially pandemic pathogens and therefore of use as stockpile for future pandemic preparedness., Methods: We conducted a multi-cohort observational study to investigate the biology and the prognostic role of interferon alpha-inducible protein 27 ( IFI27 ) in COVID-19 patients., Results: We show that IFI27 is expressed in the respiratory tract of COVID-19 patients and elevated IFI27 expression in the lower respiratory tract is associated with the presence of a high viral load. We further demonstrate that the systemic host response, as measured by blood IFI27 expression, is associated with COVID-19 infection. For clinical outcome prediction (e.g., respiratory failure), IFI27 expression displays a high sensitivity (0.95) and specificity (0.83), outperforming other known predictors of COVID-19 outcomes. Furthermore, IFI27 is upregulated in the blood of infected patients in response to other respiratory viruses. For example, in the pandemic H1N1/09 influenza virus infection, IFI27- like genes were highly upregulated in the blood samples of severely infected patients., Conclusion: These data suggest that prognostic biomarkers targeting the family of IFI27 genes could potentially supplement conventional diagnostic tools in future virus pandemics, independent of whether such pandemics are caused by a coronavirus, an influenza virus or another as yet-to-be discovered respiratory virus., Competing Interests: FS-F-G is a consultant for Biotheus Inc. KS is a consultant for Sanofi, Roche and NovoNordisk. The opinions and data presented in this manuscript are of the authors and are independent of these relationships. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shojaei, Shamshirian, Monkman, Grice, Tran, Tan, Teo, Rodrigues Rossi, McCulloch, Nalos, Raei, Razavi, Ghasemian, Gheibi, Roozbeh, Sly, Spann, Chew, Zhu, Xia, Wells, Senegaglia, Kuniyoshi, Franck, dos Santos, Noronha, Motamen, Valadan, Amjadi, Gogna, Madan, Alizadeh-Navaei, Lamperti, Zuñiga, Nova-Lamperti, Labarca, Knippenberg, Herwanto, Wang, Phu, Chew, Kwan, Kim, Teoh, Pelaia, Kuan, Jee, Iredell, O’Byrne, Fraser, Davis, Belz, Warkiani, Gallo, Souza-Fonseca-Guimaraes, Nguyen, Mclean, Kulasinghe, Short and Tang.)

Background and Objective: Currently, computed tomography-guided transthoracic biopsy (CTTB) is the most accurate diagnostic approach for pulmonary nodules suspected of malignancy. Traditional bronchoscopy has shown suboptimal diagnostic sensitivity, but the emergence of robotic-assisted bronchoscopy (RAB) has the potential to improve diagnostic accuracy, maximize diagnostic yield and complete mediastinal and hilar staging in a single procedure. We aim to assess the efficacy and diagnostic performance of RAB compared to CTTB for diagnosing pulmonary nodules suspected of lung cancer., Methods: A multicenter retrospective review of consecutive patients who underwent RAB and CTTB for evaluating pulmonary nodules from January 2019 to March 2021 at Mayo Clinic Florida and Mayo Clinic Rochester, United States. Clinical and demographic information, nodule characteristics, outcomes and complications were compared between RAB and CTTB., Results: A total of 225 patients were included: 113 in the RAB group and 112 in the CTTB group. Overall diagnostic yield was 87.6% for RAB and 88.4% for CTTB. For malignant disease, RAB had a sensitivity of 82.1% and a specificity of 100%, CTTB had a sensitivity of 88.5% and a specificity of 100%. Complication rate was significantly higher for CTTB compared to RAB (17% vs. 4.4%; p = 0.002)., Conclusion: RAB, when available, can be as accurate as CTTB for sampling pulmonary nodules with similar or reduced complications and should be considered as a means for nodule biopsy, particularly when mediastinal staging is also clinically warranted., (© 2022 Asian Pacific Society of Respirology.)

Rationale: A low respiratory arousal threshold is a key endotype responsible for obstructive sleep apnea (OSA) pathogenesis. Pimavanserin is an antiserotoninergic capable of suppressing CO 2 -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. Objectives: We measured the effect of pimavanserin on arousal threshold (primary outcome), OSA severity, arousal index, and other OSA endotypes (secondary outcomes). Methods: A total of 18 OSA participants were studied in a randomized, double-blind, crossover study. Patients received a single dose of placebo or pimavanserin 34 mg 4 hours before in-lab polysomnography. Airflow was measured with an oronasal mask attached to a pneumotachograph, and ventilatory drive was recorded with an intraesophageal electromyography catheter. Results are presented as mean or median changes (Δ) and 95% confidence intervals (CIs). Results: Pimavanserin did not increase the arousal threshold, nor did it decrease OSA severity or arousal index. It, however, prolonged total sleep time (Δ[confidence interval (CI)], 39.5 [95%CI, -1.2 to 80.1] min). In an exploratory analysis, a subgroup of seven patients who had a 10% or more increase in arousal threshold on pimavanserin exhibited a decrease in AHI 4 (hypopneas associated with 4% desaturation) (Δ[CI], 5.6 [95%CI, 3.6-11.1] events/h) and hypoxic burden (Δ[CI], 22.3 [95%CI, 6.6-32.3] %min/h). Conclusions: A single dose of pimavanserin did not have a significant effect on arousal threshold or OSA severity. However, in a post hoc analysis, a subset of patients who exhibited an increase in arousal threshold on pimavanserin showed a small decrease in OSA severity. Thus, if the arousal threshold could be increased with pimavanserin, perhaps with longer dosing to reach higher drug blood concentrations, then the desired effect on OSA severity might be achievable. Clinical trial registered with ClinicalTrials.gov (NCT04538755).

There is a limited understanding of the pathophysiology of postacute pulmonary sequelae in severe COVID-19. The aim of current study was to define the circulating microRNA (miRNA) profiles associated with pulmonary function and radiologic features in survivors of SARS-CoV-2-induced ARDS. The study included patients who developed ARDS secondary to SARS-CoV-2 infection (n = 167) and a group of infected patients who did not develop ARDS (n = 33). Patients were evaluated 3 months after hospital discharge. The follow-up included a complete pulmonary evaluation and chest computed tomography. Plasma miRNA profiling was performed using RT-qPCR. Random forest was used to construct miRNA signatures associated with lung diffusing capacity for carbon monoxide (D LCO ) and total severity score (TSS). Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses were conducted. D LCO  < 80% predicted was observed in 81.8% of the patients. TSS showed a median [P 25 ;P 75 ] of 5 [2;8]. The miRNA model associated with D LCO comprised miR-17-5p, miR-27a-3p, miR-126-3p, miR-146a-5p and miR-495-3p. Concerning radiologic features, a miRNA signature composed by miR-9-5p, miR-21-5p, miR-24-3p and miR-221-3p correlated with TSS values. These associations were not observed in the non-ARDS group. KEGG pathway and GO enrichment analyses provided evidence of molecular mechanisms related not only to profibrotic or anti-inflammatory states but also to cell death, immune response, hypoxia, vascularization, coagulation and viral infection. In conclusion, diffusing capacity and radiological features in survivors from SARS-CoV-2-induced ARDS are associated with specific miRNA profiles. These findings provide novel insights into the possible molecular pathways underlying the pathogenesis of pulmonary sequelae. Trial registration: ClinicalTrials.gov identifier: NCT04457505.. Trial registration: ISRCTN.org identifier: ISRCTN16865246..

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., Methods: Twelve subjects with OSA underwent a randomized, double-blind, crossover trial comparing one night of atomoxetine plus fesoterodine (80-4 mg) to placebo. Parameters of OSA severity (e.g., apnoea-hypopnoea index [AHI], nadir oxygen desaturation and hypoxic burden) were calculated from two clinical, in-lab polysomnographic studies. OSA endotypes (including collapsibility per V MIN and arousal threshold) were derived from validated algorithms., Results: Compared to placebo, Ato-Feso did not reduce the AHI (34.2 ± 19.1 vs. 30.1 ± 28.2 events/h, p = 0.493), but reduced the apnoea index (12.9 [28.8] vs. 1.8 [9.1] events/h, median [interquartile range], p = 0.027) and increased nadir desaturation (76.8 [8.0] vs. 82.2 [8.8] %, p = 0.003); a non-significant trend for improved hypoxic burden was observed (52.4 [50.5] vs. 29.7 [78.9] %min/h, p = 0.093). Ato-Feso lowered collapsibility (raised V MIN ; 43.7 [29.8-55.7] vs. 56.8 [43.8-69.8] %V EUPNOEA , mean [CI], p = 0.002), but reduced the arousal threshold (129.3 [120.1-138.6] vs. 116.7 [107.5-126] %V EUPNOEA , p = 0.038). In post hoc analysis, 6/6 patients with milder collapsibility (V MIN  > 43%) exhibited OSA resolution (drop in AHI > 50% and residual AHI < 10 events/h) and improved hypoxaemia., Conclusion: While inefficacious in unselected patients, Ato-Feso administered for one night suppressed OSA in patients with milder collapsibility. Ato-Feso may hold some promise as an alternative OSA treatment in certain subgroups of individuals., (© 2022 Asian Pacific Society of Respirology.)

Rationale: 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). Objectives: Here, in this post hoc 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. Methods: ΔHR was measured from baseline polysomnography of the RICCADSA (Randomized Intervention with CPAP in CAD and OSA) randomized controlled trial (patients with coronary artery disease [CAD] and OSA [apnea-hypopnea index ⩾ 15 events/h] with Epworth Sleepiness Scale score < 10; n CPAP : n control  = 113:113; male, 85%; age, 66 ± 8 [mean ± SD] yr). The primary outcome was a composite of repeat revascularization, myocardial infarction, stroke, and cardiovascular mortality. Multivariable Cox regression assessed whether the effect of CPAP was moderated by ΔHR (treatment-by-ΔHR interaction). Measurements and Main Results: The CPAP-related reduction in risk increased progressively with increasing pretreatment ΔHR (interaction hazard ratio [95% confidence interval], 0.49 [0.27 to 0.90] per SD increase in ΔHR; P  < 0.05). This means that in patients with a ΔHR of 1 SD above the mean (i.e., 10 beats/min), CPAP was estimated to reduce cardiovascular risk by 59% (6% to 82%) ( P  < 0.05), but no significant risk reduction was estimated in patients with a mean ΔHR (6 beats/min; CPAP risk reduction, 16% [-53% to 54%]; P  = 0.6). Conclusions: The protective effect of CPAP in patients with CAD and OSA without excessive sleepiness was modified by the ΔHR. Specifically, patients with higher ΔHR exhibit greater cardiovascular benefit from CPAP therapy.

The long-term clinical management and evolution of a cohort of critical COVID-19 survivors have not been described in detail. We report a prospective observational study of COVID-19 patients admitted to the ICU between March and August 2020. The follow-up in a post-COVID consultation comprised symptoms, pulmonary function tests, the 6-minute walking test (6MWT), and chest computed tomography (CT). Additionally, questionnaires to evaluate the prevalence of post-COVID-19 syndrome were administered at 1 year. A total of 181 patients were admitted to the ICU during the study period. They were middle-aged (median [IQR] of 61 [52;67]) and male (66.9%), with a median ICU stay of 9 (5-24.2) days. 20% died in the hospital, and 39 were not able to be included. A cohort of 105 patients initiated the follow-up. At 1 year, 32.2% persisted with respiratory alterations and needed to continue the follow-up. Ten percent still had moderate/severe lung diffusion (DLCO) involvement (<60%), and 53.7% had a fibrotic pattern on CT. Moreover, patients had a mean (SD) number of symptoms of 5.7 ± 4.6, and 61.3% met the criteria for post-COVID syndrome at 1 year. During the follow-up, 46 patients were discharged, and 16 were transferred to other consultations. Other conditions, such as emphysema (21.6%), COPD (8.2%), severe neurocognitive disorders (4.1%), and lung cancer (1%) were identified. A high use of health care resources is observed in the first year. In conclusion, one-third of critically ill COVID-19 patients need to continue follow-up beyond 1 year, due to abnormalities on DLCO, chest CT, or persistent symptoms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 González, Zuil, Benítez, de Gonzalo-Calvo, Aguilar, Santisteve, Vaca, Minguez, Seck, Torres, de Batlle, Gómez, Barril, Moncusí-Moix, Monge, Gort-Paniello, Ferrer, Ceccato, Fernández, Motos, Riera, Menéndez, Garcia-Gasulla, Peñuelas, Labarca, Caballero, Barberà, Torres and Barbé.)

Rationale: 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. Objectives: To evaluate the efficacy of MAD + AMT in comparison with MAD alone. Methods: A prospective crossover pilot study was designed to test this hypothesis. Briefly, adult participants with an apnea-hypopnea index (AHI) between 10 and 50 events/h at the screening visit were randomized to no treatment (baseline), MAD treatment, AMT treatment, and MAD + AMT treatment. As a primary analysis, absolute AHI was compared between MAD and MAD + AMT arms. Secondary analyses included quantifying the percent change in AHI, percentage of complete (AHI < 5 events/h) and incomplete (5-10 events/h) responders, and the efficacy of AMT alone in comparison with other treatment arms. Results: A total of 21 participants were included (baseline AHI = 24.3 ± 9.9 events/h). The median AHI (interquartile range) in the MAD and MAD + AMT arms were 10.5 (5.4-19.6) events/h and 5.6 (2.2-11.7) events/h ( P  = 0.02), respectively. A total of 76% of individuals achieved an AHI of <10 events/h in the MAD + AMT arm versus 43% in the MAD arm ( P  < 0.01). Finally, the observed effect was similar in moderate to severe OSA (AHI ⩾ 15 events/h) in terms of absolute reduction and treatment responders, and AMT alone did not significantly reduce the AHI compared with baseline. Conclusions: A combination of an adhesive mouthpiece and MAD is a more effective therapy than MAD alone. These findings may help improve clinical decision making in sleep apnea.