Kleine-Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci.

Kleine-Levin syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case-control genome-wide association study in 673 KLS cases collected over 14 y, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (rs71947865, Odds Ratio [OR] = 1.48, P = 8.6 × 10-9) within the 3'region of TRANK1 gene locus, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 y, we further stratified our sample by birth years and found that recent cases had a significantly reduced rs71947865 association. While the rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR = 1.54, P = 0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo R2 = 0.15; P < 2.0 × 10-22 at P = 0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, circadian regulation, and bipolar disorder, and indicate that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.

Proteomic Biomarkers of the Apnea Hypopnea Index and Obstructive Sleep Apnea: Insights into the Pathophysiology of Presence, Severity, and Treatment Response.

Obstructive sleep apnea (OSA), a disease associated with excessive sleepiness and increased cardiovascular risk, affects an estimated 1 billion people worldwide. The present study examined proteomic biomarkers indicative of presence, severity, and treatment response in OSA. Participants (n = 1391) of the Stanford Technology Analytics and Genomics in Sleep study had blood collected and completed an overnight polysomnography for scoring the apnea−hypopnea index (AHI). A highly multiplexed aptamer-based array (SomaScan) was used to quantify 5000 proteins in all plasma samples. Two separate intervention-based cohorts with sleep apnea (n = 41) provided samples pre- and post-continuous/positive airway pressure (CPAP/PAP). Multivariate analyses identified 84 proteins (47 positively, 37 negatively) associated with AHI after correction for multiple testing. Of the top 15 features from a machine learning classifier for AHI ≥ 15 vs. AHI < 15 (Area Under the Curve (AUC) = 0.74), 8 were significant markers of both AHI and OSA from multivariate analyses. Exploration of pre- and post-intervention analysis identified 5 of the 84 proteins to be significantly decreased following CPAP/PAP treatment, with pathways involving endothelial function, blood coagulation, and inflammatory response. The present study identified PAI-1, tPA, and sE-Selectin as key biomarkers and suggests that endothelial dysfunction and increased coagulopathy are important consequences of OSA, which may explain the association with cardiovascular disease and stroke.

An improved synthesis of adefovir and related analogues.

An improved synthesis of the antiviral drug adefovir is presented. Problems associated with current routes to adefovir include capricious yields and a reliance on problematic reagents and solvents, such as magnesium tert-butoxide and DMF, to achieve high conversions to the target. A systematic study within our laboratory led to the identification of an iodide reagent which affords higher yields than previous approaches and allows for reactions to be conducted up to 10 g in scale under milder conditions. The use of a novel tetrabutylammonium salt of adenine facilitates alkylations in solvents other than DMF. Additionally, we have investigated how regioselectivity is affected by the substitution pattern of the nucleobase. Finally, this chemistry was successfully applied to the synthesis of several new adefovir analogues, highlighting the versatility of our approach.

Sleep disorders, depression and anxiety are associated with adverse safety outcomes in healthcare workers: A prospective cohort study.

The objective of the study was to determine if sleep disorder, depression or anxiety screening status was associated with safety outcomes in a diverse population of hospital workers. A sample of shift workers at four hospitals participated in a prospective cohort study. Participants were screened for five sleep disorders, depression and anxiety at baseline, then completed prospective monthly surveys for the next 6 months to capture motor vehicle crashes, near-miss crashes, occupational exposures and medical errors. We tested the associations between sleep disorders, depression and anxiety and adverse safety outcomes using incidence rate ratios adjusted for potentially confounding factors in a multivariable negative binomial regression model. Of the 416 hospital workers who participated, two in five (40.9%) screened positive for a sleep disorder and 21.6% screened positive for depression or anxiety. After multivariable adjustment, screening positive for a sleep disorder was associated with 83% increased incidence of adverse safety outcomes. Screening positive for depression or anxiety increased the risk by 63%. Sleep disorders and mood disorders were independently associated with adverse outcomes and contributed additively to risk. Our findings suggest that screening for sleep disorders and mental health screening can help identify individuals who are vulnerable to adverse safety outcomes. Future research should evaluate sleep and mental health screening, evaluation and treatment programmes that may improve safety.

Fatigued but not sleepy? An empirical investigation of the differentiation between fatigue and sleepiness in sleep disorder patients in a cross-sectional study.

OBJECTIVE: Sleepiness and fatigue are common complaints among individuals with sleep disorders. The two concepts are often used interchangeably, causing difficulty with differential diagnosis and treatment decisions. The current study investigated sleep disorder patients to determine which factors best differentiated sleepiness from fatigue. METHODS: The study used a subset of participants from a multi-site study (n = 606), using a cross-sectional study design. We selected 60 variables associated with either sleepiness or fatigue, including demographic, mental health, and lifestyle factors, medical history, sleep questionnaires, rest-activity rhythms (actigraphy), polysomnographic (PSG) variables, and sleep diaries. Fatigue was measured with the Fatigue Severity Scale and sleepiness was measured with the Epworth Sleepiness Scale. A Random Forest machine learning approach was utilized for analysis. RESULTS: Participants' average age was 47.5 years (SD 14.0), 54.6% female, and the most common sleep disorder diagnosis was obstructive sleep apnea (67.4%). Sleepiness and fatigue were moderately correlated (r = 0.334). The model for fatigue (explained variance 49.5%) indicated depression was the strongest predictor (relative explained variance 42.7%), followed by insomnia severity (12.3%). The model for sleepiness (explained variance 17.9%), indicated insomnia symptoms was the strongest predictor (relative explained variance 17.6%). A post hoc receiver operating characteristic analysis indicated depression could be used to discriminate fatigue (AUC = 0.856) but not sleepiness (AUC = 0.643). CONCLUSIONS: The moderate correlation between fatigue and sleepiness supports previous literature that the two concepts are overlapping yet distinct. Importantly, depression played a more prominent role in characterizing fatigue than sleepiness, suggesting depression could be used to differentiate the two concepts.

Effectiveness and optimization of low-sodium oxybate in participants with narcolepsy switching from a high-sodium oxybate: data from the SEGUE study.

STUDY OBJECTIVES: Low-sodium oxybate (LXB; calcium, magnesium, potassium, and sodium oxybates; Xywav) contains the same active moiety as high-sodium oxybates (sodium oxybate [SXB; Xyrem] and fixed-dose sodium oxybate [Lumryz]), with 92% less sodium, and is approved in the US for treatment of cataplexy or excessive daytime sleepiness in patients 7 years of age and older with narcolepsy, and idiopathic hypersomnia in adults. Patients with narcolepsy have increased cardiovascular risk relative to people without narcolepsy. LXB's lower sodium content is recognized by the US FDA in the narcolepsy population as clinically meaningful in reducing cardiovascular morbidity compared with high-sodium oxybates. The Substitution of Equal Grams of Uninterrupted Xyrem to Xywav (SEGUE) study (NCT04794491) examined the transition experience of patients with narcolepsy switching from SXB to LXB. METHODS: Eligible participants were aged 18 to 80 years with narcolepsy type 1 or 2 on a stable SXB dose/regimen. After 2 weeks, participants transitioned gram-per-gram to LXB for 6 weeks, with opportunity for subsequent titration. Assessments included the Epworth Sleepiness Scale (ESS), Patient Global Impression of Change (PGIc), ease of switching medication scale (EOSMS), and forced preference questionnaire (FPQ). RESULTS: The study enrolled 62 participants at baseline; 60 transitioned to LXB and 54 completed the study. At baseline and end of the LXB intervention/early discontinuation, respectively, mean total doses were 8.0 and 8.0 g/night; mean ESS scores were 9.4 and 8.8. Most participants reported improvement (45%) or no change (48%) in narcolepsy symptoms on the PGIc, reported the transition to LXB was "easy" (easy, extremely easy, not difficult at all; 93%) on the EOSMS, and preferred LXB compared with SXB (79%) on the FPQ, most commonly due to the lower sodium content. CONCLUSIONS: Most participants switched from SXB to LXB with minimal modifications of dose/regimen and reported the transition process was easy. Effectiveness of oxybate treatment was maintained on LXB, and most participants preferred LXB to SXB. No new safety or tolerability issues were identified. CLINICALTRIALREGISTRATION: Registry: ClinicalTrials.gov; Name: An Interventional Safety Switch Study (Segue Study) of XYWAV in Narcolepsy; URL: https://classic.clinicaltrials.gov/ct2/show/NCT04794491; Identifier: NCT04794491.

Dosing and transition characteristics in people with narcolepsy transitioning from sodium oxybate to low-sodium oxybate: Data from the real-world TENOR study.

OBJECTIVE: The Transition Experience of persons with Narcolepsy taking Oxybate in the Real-world (TENOR) study assessed the real-world experience of people with narcolepsy switching from sodium oxybate (SXB) to low-sodium oxybate (LXB; 92 % less sodium than SXB). METHODS: TENOR is a patient-centric, prospective, observational, virtual-format study. Eligible participants included US adults with narcolepsy transitioning from SXB to LXB (±7 days from LXB initiation). Longitudinal data were collected from baseline (taking SXB) through 21 weeks post-transition. RESULTS: TENOR included 85 participants with narcolepsy (type 1, n = 45; type 2, n = 40). Mean (SD) age was 40.3 (13.0) years; the majority (73 %) were female and White (87 %). At study completion, wake-promoting agents were the most common concomitant medications (47 %). Mean (SD) SXB treatment duration was 57.8 (52.1) months; 96 % took SXB twice nightly. After transitioning, 97 % continued on twice-nightly regimens. Mean (SD) dose of both total nightly SXB (n = 85) and baseline LXB (n = 84) was 7.7 (1.5) g; SXB-LXB dose conversions at baseline were gram-for-gram in 87 % of participants. The mean final total nightly dose of LXB was 7.9 g. The most common participant-reported reasons for transitioning included lower sodium content for improved long-term health (93 %), physician recommendation (47 %), to avoid cardiovascular issues (39 %), to avoid side effects (31 %), and to improve control of narcolepsy symptoms (18 %). CONCLUSION: Most participants transitioned from SXB to LXB using a gram-for-gram strategy. The most commonly cited reason for transition was long-term health benefits due to lower sodium.

Proteomic insights into the pathophysiology of periodic limb movements and restless legs syndrome.

OBJECTIVES: We used a high-throughput assay of 5000 plasma proteins to identify biomarkers associated with periodic limb movements (PLM) and restless legs syndrome (RLS) in adults. METHODS: Participants (n = 1410) of the Stanford Technology Analytics and Genomics in Sleep (STAGES) study had blood collected, completed a sleep questionnaire, and underwent overnight polysomnography with the scoring of PLMs. An aptamer-based array (SomaScan) was used to quantify 5000 proteins in plasma. A second cohort (n = 697) that had serum assayed using a previous iteration of SomaScan (1300 proteins) was used for replication and in a combined analysis (n = 2107). A 5% false discovery rate was used to assess significance. RESULTS: Multivariate analyses in STAGES identified 68 proteins associated with the PLM index after correction for multiple testing (ie, base model). Most significantly decreased proteins were iron-related and included Hepcidin (LEAP-1), Ferritin, and Ferritin light chain. Most significantly increased proteins included RANTES, Cathepsin A, and SULT 1A3. Of 68 proteins significant in the base model, 17 were present in the 1300 panel, and 15 of 17 were replicated. The most significant proteins in the combined model were Hepcidin (LEAP-1), Cathepsin A, Ferritin, and RANTES. Exploration of proteins in RLS versus non-RLS identified Cathepsin Z, Heme oxygenase 2 (HO-2), Interleukin-17A (upregulated in the combined cohort), and Megalin (upregulated in STAGES only) although results were less significant than for proteins associated with PLM index. CONCLUSIONS: These results confirm the association of PLM with low iron status and suggest the involvement of catabolic enzymes in PLM/RLS.

Health-related impact of illness associated with excessive daytime sleepiness in patients with obstructive sleep apnea.

OBJECTIVES: This real-world study aimed to characterize the impact of illness of excessive daytime sleepiness (EDS) in patients with obstructive sleep apnea (OSA) who are adherent to continuous positive airway pressure (CPAP). METHODS: This cross-sectional study surveyed participants in Evidation Health's Achievement app (November 2020-January 2021), a mobile consumer platform that encourages users to develop healthy habits and provides incentives to participate in research. Participants were US-resident adults who self-reported a physician diagnosis of OSA and adherence to CPAP (≥4 hours/night, ≥5 nights/week) for≥6 months. The survey included the Functional Outcomes of Sleep Questionnaire-Short Version (FOSQ-10), Epworth Sleepiness Scale (ESS), and questions regarding comorbidities, CPAP use, caffeine consumption, and physical activity. EDS was defined as ESS score >10. There were more female than male participants; therefore, data were reported separately for females/males. RESULTS: In total, 476 participants (female, n = 283 [59%]; mean [SD] age, 49.7 [10.8] years; obese, 74.4%) completed the survey; 209 had EDS (mean [SD] ESS, 13.8 [2.5]) and 267 did not (mean [SD] ESS, 6.3 [2.5]). Self-reported duration of CPAP use was consistent between the EDS/no EDS cohorts, with most participants using CPAP for 7 to 9 hours/night, 7 nights/week. Participants with EDS commonly reported anxiety ([EDS/no EDS] males: 31.5%/20.0%; females: 53.7%/39.5%), depression (males: 35.6%/24.2%; females: 55.9%/44.9%), and insomnia (males: 19.2%/6.7%; females: 25.7%/12.9%) and showed impairment on the FOSQ-10 ([EDS/no EDS] males: 80.8%/35.0%; females: 91.9%/53.1%). Participants with EDS reported that sleepiness 'very often' prevented physical activity and influenced dietary choices. CONCLUSION: EDS influences choices related to physical activity, caffeine consumption, and diet in patients who are adherent with CPAP. More research is needed to understand the association between EDS and choices of CPAP-adherent patients. Future research should explore the health-related consequences of residual EDS associated with OSA and whether they can be mitigated by improving EDS.

Approximately 1 billion people worldwide have a sleep disorder called obstructive sleep apnea (OSA). People with OSA experience a blockage in their upper airway during sleep, which can lead to snoring, gasping for air, difficulty breathing, and disturbed sleep. As a result, 50%­80% of people with OSA experience excessive daytime sleepiness (EDS) ­ the irresistible need to sleep during the daytime. Many people (9%­22%) who are treated for OSA using continuous positive airway pressure (CPAP) still experience EDS. Previous studies have described the negative impact EDS has on people, such as decreased work productivity and increased risk of motor vehicle accidents. However, it is unclear if EDS impacts health, behavioral choices, and lifestyle in the real world. This study surveyed people with OSA and collected their Fitbit data using Evidation's Achievement app. People with OSA and EDS reported having anxiety, depression, insomnia, and other health problems more often than people with OSA without EDS. Also, people with OSA and EDS reported having more impairments in daytime functioning than people with OSA without EDS. Furthermore, people with OSA and EDS reported that sleepiness 'very often' prevented them from engaging in physical activity. Women with OSA and EDS said that sleepiness 'very often' influenced their food choices. People with OSA and EDS also used caffeine and 'sometimes' used physical activity to stay awake during the daytime. Findings from this study show people with OSA alter their lifestyle and behavioral choices because of EDS.

Effectiveness and tolerability in people with narcolepsy transitioning from sodium oxybate to low-sodium oxybate: Data from the real-world TENOR study.

OBJECTIVES: The Transition Experience of persons with Narcolepsy taking Oxybate in the Real-world (TENOR) study was conducted to provide real-world insight into the experience of people with narcolepsy switching from sodium oxybate (SXB) to low-sodium oxybate (LXB; 92% less sodium than SXB). METHODS: TENOR is a patient-centric, prospective, observational, virtual-format study. Participants were adults with narcolepsy (type 1 or 2) who were transitioning from SXB to LXB treatment (±7 days from LXB initiation). Effectiveness and tolerability data were collected online from baseline (taking SXB) through 21 weeks (taking LXB) via daily and weekly diaries and questionnaires, including the Epworth Sleepiness Scale (ESS), the Functional Outcomes of Sleep Questionnaire, short version (FOSQ-10), and the British Columbia Cognitive Complaints Inventory (BC-CCI). RESULTS: TENOR participants (N = 85) were 73% female with a mean (SD) age of 40.3 (13.0) years. Mean (SD) ESS scores decreased numerically throughout the transition from SXB to LXB (baseline: 9.9 [5.2]; week 21: 7.5 [4.7]), with 59.5% and 75.0% of participants having scores in the normal range (≤10) at baseline and week 21, respectively. Mean (SD) FOSQ-10 scores (baseline: 14.4 [3.4]; week 21: 15.2 [3.2]) and BC-CCI scores (baseline: 6.1 [4.4]; week 21: 5.0 [4.3]) also remained stable. The most common symptoms related to tolerability reported by participants at baseline were sleep inertia, hyperhidrosis, and dizziness (45.2%, 40.5%, and 27.4%, respectively), which decreased in prevalence by week 21 (33.8%, 13.2%, and 8.8%, respectively). CONCLUSIONS: Findings from TENOR confirm maintenance of effectiveness and tolerability when transitioning from SXB to LXB treatment.

Persistent pediatric obstructive sleep apnea treated with skeletally anchored transpalatal distraction / SAOS pédiatrique persistant traité par distraction transpalatine à ancrage squelettique

Introduction: The aim of this study was to evaluate the impact of nasomaxillary expansion using skeletally anchored transpalatal distraction (TPD) in children without transverse maxillary deficiency that were previously treated by rapid palatal expansion (RPE). Materials and Methods: Twenty-nine consecutive children were treated by TPD. Twenty-five children, aged 10-16 years completed pre- and post-operative clinical evaluations, questionnaires (OSA-18), cone beam computed tomography (CBCT), and polysomnography (PSG). The pre- and post-operative CBCT data were used to reconstruct the 3-dimensional shape of the upper airway. Two measures of airflow function (pressure and velocity) were simulated by using computational fluid dynamics (CFD) at four different airway segments (nasal, nasopharyngeal, oropharyngeal and hypopharyngeal). Results: Twenty-three patients (92%) experienced improvement based on PSG. The apnea hypopnea index (AHI) improved from 6.72 ± 4.34 to 3.59 ± 5.11 (p<0.001) events per hour. Clinical symptoms based on OSA-18 scores were improved in all patients. Twenty-five patients (100%) had successful expansion defined as separation of the midpalatal suture at least 1mm from anterior nasal spine (ANS) to posterior nasal spine (PNS). The nasal sidewall widening was 2.59 ± 1,54 mm at canine, 2.91 ± 1,23 mm at first molar and 2.30 ± 1,29 mm at PNS. The ratio of dental expansion to nasal expansion was 1.12:1 (2.90mm:2.59mm) at canine and 1.37:1 (3.98mm:2.91mm) at first molar. The nasal airflow pressure reduced by 76% (-275.73 to -67.28 Pa) and the nasal airflow velocity reduced by over 50% (18.60 to 8.56 m/s). Conclusions: Nasomaxillary expansion by skeletally anchored TPD improves OSA in children without transverse maxillary deficiency that were previously treated by RPE. A nearly parallel anterior-posterior opening of the mid-palatal suture achieves enlargement of the entire nasal passage with improvement of the airflow characteristics in the nasal and pharyngeal airway. The improved airflow characteristic is significantly correlated with the improved polysomnographic findings, thus demonstrating that nasomaxillary expansion in previously expanded patients is a viable treatment option.

Introduction: L'objectif de cette étude était d'évaluer l'impact de l'expansion nasomaxillaire à l'aide d'une distraction transpalatine (DTP) à ancrage squelettique chez des enfants sans insuffisance maxillaire transversale et qui ont été précédemment traités par expansion palatine rapide (EPR). Matériels et méthodes: Vingt-neuf enfants enrôlés consécutivement ont été traités par DTP. Vingt-cinq enfants, âgés de 10 à 16 ans, ont été soumis à des évaluations cliniques pré- et postopératoires, des questionnaires (OSA-18), une tomographie à faisceau conique (CBCT) et une polysomnographie (PSG). Les données CBCT pré- et postopératoires ont été utilisées pour reconstruire la forme tridimensionnelle des voies aériennes supérieures. Deux mesures des caractéristiques d'écoulement de l'air (pression et vitesse) ont été simulées en utilisant la dynamique des fluides computationnelle (DFC) dans quatre segments différents des voies aériennes (nasal, nasopharyngé, oropharyngé et hypopharyngé). Résultats: Vingt-trois patients (92 %) ont bénéficié d'une rapide amélioration objectivée par la PSG. L'indice d'apnée-hypopnée (IAH) est passé de 6,72 ± 4,34 à 3,59 ± 5,11 (p<0,001) événements par heure. Les symptômes cliniques évalués avec les scores du questionnaire OSA-18 se sont améliorés chez tous les patients. Pour les vingt-cinq patients (100 %), l'expansion a été réussie, selon le critère d'une séparation de la suture médiopalatine d'au moins 1 mm, de l'épine nasale antérieure (ENA) jusqu'à l'épine nasale postérieure (ENP). L'élargissement de la distance entre les parois nasales latérales était de 2,59 ± 1,54 mm au niveau de la canine, de 2,91 ± 1,23 mm au niveau de la première molaire et de 2,30 ± 1,29 mm à l'épine nasale postérieure. Le rapport entre l'expansion dentaire et l'expansion nasale était de 1,12:1 (2,90 mm:2,59 mm) au niveau de la canine et de 1,37:1 (3,98 mm:2,91 mm) au niveau de la première molaire. La pression du flux d'air nasal a diminué de 76 % (-275,73 à -67,28 Pa) et la vitesse du flux d'air nasal a diminué de plus de 50 % (18,60 à 8,56 m/s). Conclusions: L'expansion nasomaxillaire à l'aide d'une distraction transpalatine à ancrage squelettique améliore le SAOS chez les enfants sans déficit maxillaire transverse et qui ont été auparavant traités par EPR. Une ouverture antéro-postérieure et presque parallèle de la suture médiopalatine permet d'élargir l'ensemble du passage nasal et d'améliorer les caractéristiques du flux d'air dans les voies aériennes nasales et pharyngées. L'amélioration des caractéristiques de l'écoulement d'air est significativement corrélée à l'amélioration des résultats polysomnographiques, démontrant ainsi que l'expansion nasomaxillaire chez des patients précédemment traités par EPR est une option thérapeutique viable.

Nasomaxillary Expansion by Endoscopically-Assisted Surgical Expansion (EASE): An airway centric approach / Expansion nasomaxillaire chirurgicale assistée par endoscopie (EASE) : une approche centrée surles voies respiratoires

Introduction: The aim of this study was to analyze the skeletal, dental and airway changes with endoscopically assisted surgical expansion (EASE) to widen the nasomaxillary complex for the treatment of sleep apnea in adults. Methods: One hundred and five consecutive patients underwent EASE. Cone beam computed tomography (CBCT) was conducted preoperatively and within four weeks after the completion of the expansion process. Computational fluid dynamic (CFD) analysis was performed on 20 randomly selected patients to assess airway flow changes. Results: One hundred patients (67 males) with the mean age of 35.0±13.5 years (17-64 years) had completed pre- and post-expansion imaging. Ninety-six patients (96%) had successful expansion defined as separation of the midpalatal suture at least 1 mm from anterior nasal spine (ANS) to posterior nasal spine (PNS). The nasal cavity expansion was 3.12±1.11 mm at ANS, 3.64±1.06 mm at first molar and 2.39±1.15 mm at PNS. The zygoma expansion was 2.17±1.11 mm. The ratio of dental expansion to skeletal expansion was 1.23:1 (3.83 mm:3.12 mm) at canine and 1.31:1 (4.77 mm:3.64 mm) at first molar. CFD airway simulation showed a dynamic change following expansion throughout the airway. The mean negative pressure improved in the nasal airway (from -395.5±721.0 to -32.7±19.2 Pa), nasopharyngal airway (from -394.2±719.4 to -33.6±18.5 Pa), oropharyngeal airway (from -405.9±710.8 to -39.4±19.3 Pa) and hypopharyngeal airway (from -422.6±704.9 to -55.1±33.7 Pa). The mean airflow velocity within the nasal airway decreased from 18.8±15.9 to 7.6±2.0 m/s and the oropharyngeal airway decreased from 4.2±2.9 to 3.2±1.2 m/s. The velocity did not change significantly in the nasopharyngeal and hypopharyngeal regions. Conclusions: EASE results in expansion of the midpalatal suture from the ANS to PNS with a nearly pure skeletal movement of minimal dental effect. The expansion of the nasomaxillary complex resulted in the widening of the nasal sidewall throughout the nasal cavity. The improved air flow dynamics was demonstrated by CFD simulation.

Introduction: L'objectif de cette étude était d'analyser les modifications obtenues au niveau du squelette, des dents et des voies respiratoires lors d'une expansion nasomaxillaire chirurgicale assistée par endoscopie (EASE), visant à élargir le complexe nasomaxillaire pour le traitement de l'apnée du sommeil chez des adultes. Méthodes: Cent cinq patients consécutifs ont subi une EASE. Une tomographie à faisceau conique (CBCT) a été réalisée en préopératoire et dans les quatre semaines suivant la fin du processus d'expansion. Une analyse de la dynamique des fluides computationnelle (DFC) a été réalisée sur vingt patients sélectionnés au hasard pour évaluer les modifications du débit de leurs voies respiratoires. Résultats: Un bilan d'imagerie pré- et post-expansion a été réalisé chez cent patients (dont 67 hommes) d'un âge moyen de 35,0 ± 13,5 ans (17-64 ans). Quatre-vingt-seize patients (96 %) ont bénéficié d'une expansion réussie, définie comme une séparation de la suture médiopalatine d'au moins 1 mm, de l'épine nasale antérieure (ENA) à l'épine nasale postérieure (ENP). L'expansion de la cavité nasale était de 3,12 ± 1,11 mm au niveau de l'ENA, de 3,64 ± 1,06 mm au niveau de la première molaire et de 2,39 ± 1,15 mm au niveau de l'ENP. L'expansion zygomatique était de 2,17 ± 1,11 mm. Le rapport entre l'expansion dentaire et l'expansion squelettique était de 1,23 : 1 (3,83 mm : 3,12 mm) au niveau de la canine et de 1,31 : 1 (4,77 mm : 3,64 mm) au niveau de la première molaire. Après l'expansion, la simulation des voies respiratoires par DFC a montré un changement dynamique au niveau de l'ensemble des voies respiratoires. La pression négative moyenne s'est améliorée dans les voies nasales (de -395,5 ± 721,0 à -32,7 ± 19,2 Pa), les voies nasopharyngiennes (de -394,2 ± 719,4 à -33,6 ± 18,5 Pa), les voies aériennes oropharyngées (de -405,9 ± 710,8 à -39,4 ± 19,3 Pa) et les voies aériennes hypopharyngées (de -422,6 ± 704,9 à -55,1 ± 33,7 Pa). La vitesse moyenne du flux d'air dans les voies nasales a diminué de 18,8 ± 15,9 à 7,6 ± 2,0 m/s et de 4,2 ± 2,9 à 3,2 ± 1,2 m/s dans les voies oropharyngées. La vitesse n'a pas changé de manière significative dans les régions nasopharyngienne et hypopharyngienne. Conclusions: L'EASE entraîne une expansion de la suture médiopalatine, de l'ENA jusqu'à l'ENP avec un mouvement squelettique presque pur et un effet dentaire minimal. L'expansion du complexe nasomaxillaire a entraîné l'écartement des parois nasales latérales dans toute la cavité nasale. L'amélioration de la dynamique du flux d'air a été démontrée par une simulation DFC.

Persistent pediatric obstructive sleep apnea treated with skeletally anchored transpalatal distraction

Introduction: The aim of this study was to evaluate the impact of nasomaxillary expansion using skeletally anchored transpalatal distraction (TPD) in children without transverse maxillary deficiency that were previously treated by rapid palatal expansion (RPE). Materials and Methods: Twenty-nine consecutive children were treated by TPD. Twenty-five children, aged 10-16 years completed pre- and post-operative clinical evaluations, questionnaires (OSA-18), cone beam computed tomography (CBCT), and polysomnography (PSG). The pre- and post-operative CBCT data were used to reconstruct the 3-dimensional shape of the upper airway. Two measures of airflow function (pressure and velocity) were simulated by using computational fluid dynamics (CFD) at four different airway segments (nasal, nasopharyngeal, oropharyngeal and hypopharyngeal). Results: Twenty-three patients (92%) experienced improvement based on PSG. The apnea hypopnea index (AHI) improved from 6.72±4.34 to 3.59±5.11 (p<0.001) events per hour. Clinical symptoms based on OSA-18 scores were improved in all patients. Twenty-five patients (100%) had successful expansion defined as separation of the midpalatal suture at least 1 mm from anterior nasal spine (ANS) to posterior nasal spine (PNS). The nasal sidewall widening was 2.59±1.54 mm at canine, 2.91±1.23 mm at first molar and 2.30±1.29 mm at PNS. The ratio of dental expansion to nasal expansion was 1.12:1 (2.90 mm:2.59 mm) at canine and 1.37:1 (3.98 mm:2.91 mm) at first molar. The nasal airflow pressure reduced by 76% (-275.73 to -67.28 Pa) and the nasal airflow velocity reduced by over 50% (18.60 to 8.56 m/s). Conclusions: Nasomaxillary expansion by skeletally anchored TPD improves OSA in children without transverse maxillary deficiency that were previously treated by RPE. A nearly parallel anterior-posterior opening of the mid-palatal suture achieves enlargement of the entire nasal passage with improvement of the airflow characteristics in the nasal and pharyngeal airway. The improved airflow characteristic is significantly correlated with the improved polysomnographic findings, thus demonstrating that nasomaxillary expansion in previously expanded patients is a viable treatment option.

Nasomaxillary Expansion by Endoscopically-Assisted Surgical Expansion (EASE): An airway centric approach

Introduction: The aim of this study was to analyze the skeletal, dental and airway changes with endoscopically assisted surgical expansion (EASE) to widen the nasomaxillary complex for the treatment of sleep apnea in adults. Methods: One hundred and five consecutive patients underwent EASE. Cone beam computed tomography (CBCT) was conducted preoperatively and within four weeks after the completion of the expansion process. Computational fluid dynamic (CFD) analysis was performed on 20 randomly selected patients to assess airway flow changes. Results: One hundred patients (67 males) with the mean age of 35.0±13.5 years (17-64 years) had completed pre- and post-expansion imaging. Ninety-six patients (96%) had successful expansion defined as separation of the midpalatal suture at least 1 mm from anterior nasal spine (ANS) to posterior nasal spine (PNS). The nasal cavity expansion was 3.12±1.11 mm at ANS, 3.64±1.06 mm at first molar and 2.39±1.15 mm at PNS. The zygoma expansion was 2.17±1.11 mm. The ratio of dental expansion to skeletal expansion was 1.23:1 (3.83 mm:3.12 mm) at canine and 1.31:1 (4.77 mm:3.64 mm) at first molar. CFD airway simulation showed a dynamic change following expansion throughout the airway. The mean negative pressure improved in the nasal airway (from -395.5±721.0 to -32.7±19.2 Pa), nasopharyngal airway (from -394.2±719.4 to -33.6±18.5 Pa), oropharyngeal airway (from -405.9±710.8 to -39.4±19.3 Pa) and hypopharyngeal airway (from -422.6±704.9 to -55.1±33.7 Pa). The mean airflow velocity within the nasal airway decreased from 18.8±15.9 to 7.6±2.0 m/s and the oropharyngeal airway decreased from 4.2±2.9 to 3.2±1.2 m/s. The velocity did not change significantly in the nasopharyngeal and hypopharyngeal regions. Conclusions: EASE results in expansion of the midpalatal suture from the ANS to PNS with a nearly pure skeletal movement of minimal dental effect. The expansion of the nasomaxillary complex resulted in the widening of the nasal sidewall throughout the nasal cavity. The improved air flow dynamics was demonstrated by CFD simulation.

Age estimation from sleep studies using deep learning predicts life expectancy.

Sleep disturbances increase with age and are predictors of mortality. Here, we present deep neural networks that estimate age and mortality risk through polysomnograms (PSGs). Aging was modeled using 2500 PSGs and tested in 10,699 PSGs from men and women in seven different cohorts aged between 20 and 90. Ages were estimated with a mean absolute error of 5.8 ± 1.6 years, while basic sleep scoring measures had an error of 14.9 ± 6.29 years. After controlling for demographics, sleep, and health covariates, each 10-year increment in age estimate error (AEE) was associated with increased all-cause mortality rate of 29% (95% confidence interval: 20-39%). An increase from -10 to +10 years in AEE translates to an estimated decreased life expectancy of 8.7 years (95% confidence interval: 6.1-11.4 years). Greater AEE was mostly reflected in increased sleep fragmentation, suggesting this is an important biomarker of future health independent of sleep apnea.

Deletion of cytosolic phospholipase A2 promotes striated muscle growth.

Generation of arachidonic acid by the ubiquitously expressed cytosolic phospholipase A2 (PLA2) has a fundamental role in the regulation of cellular homeostasis, inflammation and tumorigenesis. Here we report that cytosolic PLA2 is a negative regulator of growth, specifically of striated muscle. We find that normal growth of skeletal muscle, as well as normal and pathologic stress-induced hypertrophic growth of the heart, are exaggerated in Pla2g4a-/- mice, which lack the gene encoding cytosolic PLA2. The mechanism underlying this phenotype is that cytosolic PLA2 negatively regulates insulin-like growth factor (IGF)-1 signaling. Absence of cytosolic PLA2 leads to sustained activation of the IGF-1 pathway, which results from the failure of 3-phosphoinositide-dependent protein kinase (PDK)-1 to recruit and phosphorylate protein kinase C (PKC)-zeta, a negative regulator of IGF-1 signaling. Arachidonic acid restores activation of PKC-zeta, correcting the exaggerated IGF-1 signaling. These results indicate that cytosolic PLA2 and arachidonic acid regulate striated muscle growth by modulating multiple growth-regulatory pathways.

Estimation of Apnea-Hypopnea Index Using Deep Learning On 3-D Craniofacial Scans.

Obstructive sleep apnea (OSA) is characterized by decreased breathing events that occur through the night, with severity reported as the apnea-hypopnea index (AHI), which is associated with certain craniofacial features. In this study, we used data from 1366 patients collected as part of Stanford Technology Analytics and Genomics in Sleep (STAGES) across 11 US and Canadian sleep clinics and analyzed 3D craniofacial scans with the goal of predicting AHI, as measured using gold standard nocturnal polysomnography (PSG). First, the algorithm detects pre-specified landmarks on mesh objects and aligns scans in 3D space. Subsequently, 2D images and depth maps are generated by rendering and rotating scans by 45-degree increments. Resulting images were stacked as channels and used as input to multi-view convolutional neural networks, which were trained and validated in a supervised manner to predict AHI values derived from PSGs. The proposed model achieved a mean absolute error of 11.38 events/hour, a Pearson correlation coefficient of 0.4, and accuracy for predicting OSA of 67% using 10-fold cross-validation. The model improved further by adding patient demographics and variables from questionnaires. We also show that the model performed at the level of three sleep medicine specialists, who used clinical experience to predict AHI based on 3D scan displays. Finally, we created topographic displays of the most important facial features used by the model to predict AHI, showing importance of the neck and chin area. The proposed algorithm has potential to serve as an inexpensive and efficient screening tool for individuals with suspected OSA.

PSG Validation of minute-to-minute scoring for sleep and wake periods in a consumer wearable device.

BACKGROUND: Actigraphs are wrist-worn devices that record tri-axial accelerometry data used clinically and in research studies. The expense of research-grade actigraphs, however, limit their widespread adoption, especially in clinical settings. Tri-axial accelerometer-based consumer wearable devices have gained worldwide popularity and hold potential for a cost-effective alternative. The lack of independent validation of minute-to-minute accelerometer data with polysomnographic data or even research-grade actigraphs, as well as access to raw data has hindered the utility and acceptance of consumer-grade actigraphs. METHODS: Sleep clinic patients wore a consumer-grade wearable (Huami Arc) on their non-dominant wrist while undergoing an overnight polysomnography (PSG) study. The sample was split into two, 20 in a training group and 21 in a testing group. In addition to the Arc, the testing group also wore a research-grade actigraph (Philips Actiwatch Spectrum). Sleep was scored for each 60-s epoch on both devices using the Cole-Kripke algorithm. RESULTS: Based on analysis of our training group, Arc and PSG data were aligned best when a threshold of 10 units was used to examine the Arc data. Using this threshold value in our testing group, the Arc has an accuracy of 90.3%±4.3%, sleep sensitivity (or wake specificity) of 95.5%±3.5%, and sleep specificity (wake sensitivity) of 55.6%±22.7%. Compared to PSG, Actiwatch has an accuracy of 88.7%±4.5%, sleep sensitivity of 92.6%±5.2%, and sleep specificity of 60.5%±20.2%, comparable to that observed in the Arc. CONCLUSIONS: An optimized sleep/wake threshold value was identified for a consumer-grade wearable Arc trained by PSG data. By applying this sleep/wake threshold value for Arc generated accelerometer data, when compared to PSG, sleep and wake estimates were adequate and comparable to those generated by a clinical-grade actigraph. As with other actigraphs, sleep specificity plateaus due to limitations in distinguishing wake without movement from sleep. Further studies are needed to evaluate the Arc's ability to differentiate between sleep and wake using other sources of data available from the Arc, such as high resolution accelerometry and photoplethysmography.

Prediction of Patient Demographics using 3D Craniofacial Scans and Multi-view CNNs.

3D data is becoming increasingly popular and accessible for computer vision tasks. A popular format for 3D data is the mesh format, which can depict a 3D surface accurately and cost-effectively by connecting points in the (x, y, z) plane, known as vertices, into triangles that can be combined to approximate geometrical surfaces. However, mesh objects are not suitable for standard deep learning techniques due to their non-euclidean structure. We present an algorithm which predicts the sex, age, and body mass index of a subject based on a 3D scan of their face and neck. This algorithm relies on an automatic pre-processing technique, which renders and captures the 3D scan from eight different angles around the x-axis in the form of 2D images and depth maps. Subsequently, the generated data is used to train three convolutional neural networks, each with a ResNet18 architecture, to learn a mapping between the set of 16 images per subject (eight 2D images and eight depth maps from different angles) and their demographics. For age and body mass index, we achieved a mean absolute error of 7.77 years and 4.04 kg/m2 on the respective test sets, while Pearson correlation coefficients of 0.76 and 0.80 were obtained, respectively. The prediction of sex yielded an accuracy of 93%. The developed framework serves as a proof of concept for prediction of more clinically relevant variables based on 3D craniofacial scans stored in mesh objects.