© 2020, Kuhn et al.Single-molecule approaches provide enormous insight into the dynamics of biomolecules, but adequately sampling distributions of states and events often requires extensive sampling. Although emerging experimental techniques can generate such large datasets, existing analysis tools are not suitable to process the large volume of data obtained in high-throughput paradigms. Here, we present a new analysis platform (DISC) that accelerates unsupervised analysis of single-molecule trajectories. By merging model-free statistical learning with the Viterbi algorithm, DISC idealizes single-molecule trajectories up to three orders of magnitude faster with improved accuracy compared to other commonly used algorithms. Further, we demonstrate the utility of DISC algorithm to probe cooperativity between multiple binding events in the cyclic nucleotide binding domains of HCN pacemaker channel. Given the flexible and efficient nature of DISC, we anticipate it will be a powerful tool for unsupervised processing of high-throughput data across a range of single-molecule experiments. © 2020, White et al.The TMEM175 family constitutes recently discovered K+ channels that are important for autophagosome turnover and lysosomal pH regulation and are associated with the early onset of Parkinson Disease. TMEM175 channels lack a P-loop selectivity filter, a hallmark of all known K+ channels, raising the question how selectivity is achieved. Here, we report the X-ray structure of a closed bacterial TMEM175 channel in complex with a nanobody fusion-protein disclosing bound K+ ions. Our analysis revealed that a highly conserved layer of threonine residues in the pore conveys a basal K+ selectivity. An additional layer comprising two serines in human TMEM175 increases selectivity further and renders this channel sensitive to 4-aminopyridine and Zn2+. Our findings suggest that large hydrophobic side chains occlude the pore, forming a physical gate, and that channel opening by iris-like motions simultaneously relocates the gate and exposes the otherwise concealed selectivity filter to the pore lumen. © 2020, Brunner et al.Axons span extreme distances and are subjected to significant stretch deformations during limb movements or sudden head movements, especially during impacts. Yet, axon biomechanics, and its relation to the ultrastructure that allows axons to withstand mechanical stress, is poorly understood. Using a custom developed force apparatus, we demonstrate that chick dorsal root ganglion axons exhibit a tension buffering or strain-softening response, where its steady state elastic modulus decreases with increasing strain. We then explore the contributions from the various cytoskeletal components of the axon to show that the recently discovered membrane-associated actin-spectrin scaffold plays a prominent mechanical role. Finally, using a theoretical model, we argue that the actin-spectrin skeleton acts as an axonal tension buffer by reversibly unfolding repeat domains of the spectrin tetramers to release excess mechanical stress. Our results revise the current view point that microtubules and their associated proteins are the only significant load-bearing elements in axons. © 2020, Dubey et al.STUDY OBJECTIVES The multiple sleep latency test (MSLT) has limitations when evaluating disorders of hypersomnolence with unknown etiology. Alternative measures of hypersomnolence may objectively identify pathology in patients with complaints of daytime sleepiness that may not be captured by the MSLT alone. This study evaluated the impact of a multimodal hypersomnolence assessment relative to MSLT in patients with unexplained hypersomnolence. METHODS Seventy-five patients with unexplained hypersomnolence were included in the analyzed sample. Polysomnography was performed without prescribed wake time, and the psychomotor vigilance task (PVT) and pupillographic sleepiness test (PST) were completed between MSLT nap opportunities. Presence or absence of hypersomnolence for each assessment was defined using a priori cutpoints. Proportions of patients identified as hypersomnolent using the multimodal assessment relative to MSLT alone were evaluated, as well as the sensitivity and specificity of ancillary hypersomnolence measures relative to MSLT as a gold standard. RESULTS The multimodal assessment more than doubled the proportion of patients identified as having objective deficits relative to MSLT≤8 minutes alone. The combination of excessive sleep duration, lapses on the PVT, and impairments on PST also had perfect sensitivity in identifying all patients identified as sleepy by the MSLT across three different MSLT cutpoints (5, 8, and 10 minutes). CONCLUSIONS These data demonstrate the insufficiency of the MSLT as a singular tool to identify objective pathology in persons with unexplained hypersomnolence. Further efforts to refine and standardize multimodal assessments will likely improve diagnostic acumen and research into the causes of these disorders. © 2020 American Academy of Sleep Medicine.STUDY OBJECTIVES People with obstructive sleep apnea (OSA) remain undiagnosed owing to lack of easy and comfortable screening tools. Through this study, we aimed to compare the diagnostic accuracy of chest wall motion and cyclic variation of heart rate (CVHR) in detecting OSA by using a single-lead electrocardiogram (ECG) patch with a 3-axis accelerometer. METHODS In total, 119 snoring patients simultaneously underwent polysomnography (PSG) with a single-lead ECG patch. Signals of chest wall motion and CVHR from the single-lead ECG patch were collected. The chest effort index (CEI) was calculated using the chest wall motion recorded by a 3-axis accelerometer in the device. The ability of CEI and CVHR indices in diagnosing moderate-to-severe OSA (apnea hypopnea index ≥ 15) was compared using the area under the curve (AUC) by using the DeLong test. RESULTS CVHR detected moderate-to-severe OSA with 52.9% sensitivity and 94.1% specificity (AUC 0.76, 95% confidence interval [CI] 0.67-0.84, optimal cutoff 21.2 events/h). By contrast, CEI identified moderate-to-severe OSA with 80% sensitivity and 79.4% specificity (AUC 0.87, 95% CI 0.80-0.94, optimal cutoff 7.1 events/h). CEI significantly outperformed CVHR with regard to the discrimination ability for moderate-to-severe OSA (delta AUC 0.11, 95% CI 0.009-0.21, P = 0.032). For determining severe OSA, the performance of discrimination ability was greater (AUC = 0.90, 95% CI 0.85-0.95) when combining these two signals. CONCLUSIONS Both CEI and CVHR recorded from a patch-type device with ECG and a 3-axis accelerometer can be used to detect moderate-to-severe OSA. Thus, incorporation of CEI is helpful in the detection of sleep apnea by using a single-lead ECG with a 3-axis accelerometer. © 2020 American Academy of Sleep Medicine.STUDY OBJECTIVES The variable efficacy of mandibular advancement device (MAD) treatment necessitates both accessible and accurate methods for patient selection. The role of awake nasopharyngoscopy for this purpose, however, remains dubious. We introduced an assessment method based on anatomical upper airway features during tidal breathing for nasopharyngoscopy. The current study aimed to relate these features to MAD treatment outcome. METHODS One hundred patients diagnosed with obstructive sleep apnea were prospectively recruited for MAD treatment in a fixed 75% degree of maximal protrusion. Nasopharyngoscopic observations during Müller’s maneuver and tidal breathing were recorded both with and without MAD. Treatment outcome, confirmed by three-month follow-up polysomnography with MAD, was classified as (1) apnea-hypopnea index (AHI) reduction ≥50%, (2) treatment AHI less then 5 events/h, and (3) ≥10% increase in AHI compared to baseline (treatment deterioration). RESULTS A complete dataset was obtained in 65 patients. After adjusting for baseline AHI, body mass index and supine dependency, the position of the soft palate [odds ratio (OR) 4.0 (1.3-11.8); P=0.013] and crowding of the oropharynx [OR 7.7 (1.4-41.4); P=0.017] were related to treatment deterioration. Addition of both features significantly (P=0.031) improved the accuracy of baseline models based on clinical measurements alone. Moreover, with the MAD in situ, a posteriorly located soft palate [OR 9.8 (1.7-56.3); P=0.010] and a posteriorly located tongue base [OR 7.4 (1.5-35.9); P=0.013] were associated with treatment deterioration. CONCLUSIONS Awake nasopharyngoscopy might be a valuable office-based examination to exclude the risk of treatment deterioration and improve patient selection for MAD treatment. © 2020 American Academy of Sleep Medicine.STUDY OBJECTIVES Thermistors, nasal cannulas and respiratory inductance plethysmography (RIP) are the reference sensors (AASM recommendations) for the detection and characterization of apneas and hypopneas. However, these sensors are not well tolerated by patients and have a poor scorability. We evaluated the performance of an alternative method using a combination of tracheal sounds and RIP signals. METHODS Consecutive recordings of 70 adult patients from the Pays de la Loire Sleep Cohort were manually scored in a random order using the AASM standard signals and the combination tracheal sound (TS) and RIP signals, TS-RIP, without respiratory sensors placed on the patient’s face. The TS-RIP scoring used the TS and RIP-Flow signals for detection of apneas and hypopneas respectively, and the suprasternal pressure (SSP) and RIP belts signals for the characterization of apneas. RESULTS Sensitivity (Se) and specificity (Sp) of the TS-RIP combination were 96.21% and 91.34% for apnea detection, and 89.94% and 93.25% for detecting hypopneas, respectively, with a Kappa coefficient of 0.87. For the characterization of apneas, Se and Sp were 98.67% and 96.17% for obstructive apneas, 92.66% and 99.36% for mixed apneas, and 96.14% and 98.89% for central apneas, respectively, with a Kappa coefficient of 0.94. The TS-RIP scoring revealed a high agreement for classifying obstructive sleep apnea (OSA) into severity classes (no OSA, mild, moderate and severe OSA) with a Cohen’s Kappa coefficient of 0.96. CONCLUSIONS Compared to the AASM reference sensors, the TS-RIP combination allows reliable non-invasive detection and characterization of respiratory events with a high degree of sensitivity and specificity. TS-RIP combination could be used for OSA diagnosis, in adults, either as an alternative or in combination with the recommended AASM sensors. © 2020 American Academy of Sleep Medicine.STUDY OBJECTIVES To undertake a meta-analysis of literatures comparing the prevalence of cardio- and cerebrovascular comorbidities between overlap syndrome (OS) patients and chronic obstructive pulmonary disease (COPD) or obstructive sleep apnea (OSA) patients. METHODS Studies about the cardio- and cerebrovascular disease of OS were searched among several electronic databases from the time of database construction to June, 2019. Two independent reviewers performed the process of study screening, quality assessment and data extraction. Meta-analysis of odds ratios was carried out by RevMan5.3 under either fixed- or random- effects models. Sensitivity analysis was conducted to examine the robustness of pooled outcome. RESULTS A total of 17 articles were included. Compared with COPD/OSA, OS significantly increased the risk of developing hypertension (OS vs. COPD OR=1.94, 95% CI [1.49, 2.52]; OS vs. OSA OR=2.05, 95% CI [1.57, 2.68]) and pulmonary hypertension (OS vs. COPD OR=2.96, 95% CI [1.30, 6.77]; OS vs. OSA OR=5.