Or Obstructive Sleep Apnea Research Articles

The potential role of interleukin-6 in the association between inflammation and cognitive performance in obstructive sleep apnea

BackgroundInterleukin-6 (IL-6) represents one of the main molecules involved in inflammatory responses, which can be altered in either patients with cognitive impairment or obstructive sleep apnea (OSA). The present study aimed to evaluate serum IL-6 levels and cognitive performance in patients with severe OSA (Apnea-Hypopnea Index - AHI >30/h). MethodsThirty patients with severe OSA were compared to 15 controls similar in age, sex, and Body Mass Index. All patients underwent a sleep medicine interview, including the Epworth Sleepiness Scale (ESS), a polygraphic cardiorespiratory recording, the Montreal Cognitive Assessment (MoCA), and a blood sample for serum IL-6 assessment. ResultsOSA patients presented higher IL-6 serum levels (Md = 7.38) than controls (Md = 2.20, p < 0.001). Moreover, OSA patients showed lower MoCA (Md = 27.00) and higher ESS scores (Md = 8.00) than controls (Md = 30.00, p < 0.001; Md = 4.00, p = 0.004, respectively). Higher IL-6 serum levels were associated with lower oxygen saturation parameters and MoCA scores. ConclusionsThis study documented an association between inflammation, featured by higher IL-6 serum levels, and both nocturnal hypoxemia and cognitive impairment in OSA patients. Therefore, the increase in IL-6 levels may represent the result of vascular damage and neuroinflammation due to intermittent nocturnal hypoxia and further causing neurocognitive dysfunction in OSA.

Post-marketing safety profile of solriamfetol: A real-world disproportionality analysis using FDA adverse event reporting system (FAERS) database

Solriamfetol is a selective dopamine and noradrenalin reuptake inhibitor applied in adult patients with excessive daytime sleepiness (EDS) associated with narcolepsy or obstructive sleep apnea (OSA). However, the post-marketing safety profile of solriamfetol in large number of people was unrevealed. The purpose of our study is to unravel solriamfetol's adverse events (AEs) in real-world to refine medication safety using Food and Drug Administration Adverse Event Reporting System (FAERS) database. We derived the data associated with solriamfetol from FAERS between 2019 and 2023, and removed the duplicated entries. We evaluated the disproportionality of solriamfetol's AEs by reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN) and the multi-item gamma Poisson shrinker (MGPS). Among 8,846,085 AE reports, 1659 recorded solriamfetol as the ‘primary suspected (PS)’. 74 significant disproportionality preferred terms (PTs) were retained across 27 organ systems. Moreover, 16 unexpected AEs not mentioned in the FDA label of solriamfetol were identified. Our findings provided the post-marketing safety profile of solriamfetol, highlighting potential solriamfetol's AEs. Further researches are significant to define the causality between solriamfetol and newly identified AEs.

A Review of Current and Future Pharmacologic Treatments for Narcolepsy

IntroductionNarcolepsy is a rare but disabling neurological disorder involving disruption of the sleep-wake cycle that is often under- or misdiagnosed (Barateau L, et al. J Sleep Res. 2022;31(4):e13631). It is characterized by a classical tetrad of excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, and sleep paralysis. Narcolepsy is divided into 3 types: Narcolepsy Type 1 (NT1); Narcolepsy Type 2 (NT2); and Secondary Narcolepsy. The pathophysiology remains unclear but is primarily associated with loss of hypocretin (orexin) neurons involving autoimmune and genetic risk factors, particularly for NT1.ObjectivesTo review the currently available therapies for the treatment of narcolepsy.MethodsThe extant literature was reviewed and discussed in the context of clinical relevance.ResultsTreatment historically has included medications developed for the treatment of other conditions such as psychostimulants (methylphenidate, modafinil/armodafinil, pemoline) and antidepressants (SSRIs,TCAs). These agents are also associated with limiting side effects in practice. In more recent years a variety of specific treatments have been approved that act on diverse pathways. Pitolisant, a histamine H3 receptor inverse agonist, is approved for the treatment of EDS or cataplexy in adult patients with narcolepsy (and children&gt; 6 years in European Union) (Keam SJ.Paediatr Drugs. 2023;25(4):483-488). Solriamfetol, a dopamine and norepinephrine reuptake inhibitor (DNRI) is indicated to improve wakefulness in adult patients with EDS associated with narcolepsy or obstructive sleep apnea (OSA) (Winter Y, et al. Sleep Med. 2023;103:138-143). Sodium oxybate (SXB), a GABAB receptor agonist, is approved for the treatment of cataplexy associated with narcolepsy and (EDS) in patients 7 years or older (Bogan RK, et al. CNS Drugs. 2023;37(4):323-335). Current research focuses on on-peptide hypocretin receptor-2 agonists (Saitoh T, Sakurai T. Peptides. 2023;167:171051).ConclusionsDespite limited understanding of the pathophysiology of narcolepsy there have been substantial advances in the pharmacotherapy, including medications now approved for children. Early diagnosis and treatment are associated with better outcomes. In view of the chronic and disabling morbidity associated with narcolepsy further research and better access to appopriate medications is necessary.Disclosure of InterestNone Declared

SLEEP DISTURBANCE AND DEPRESSIVE SYMPTOMS AMONG OLDER ADULTS: DO GENDER DIFFERENCES EXIST?

Abstract Sleep is a key part of a healthy lifestyle, but aging causes sleep problems by decreased melatonin levels. Sleep disturbance includes problems falling or staying asleep, too much sleep, or obstructive sleep apnea (OSA), the most common sleep-related breathing disorder in older adults. Thus, aging-related changes in sleep should be studied in various aspects of elderly’s health such as physical, mental, and cognitive health. As part of that, this study aims to (1) examine the connection between sleep disturbance and depressive symptoms and (2) investigate whether gender differences exist. Participants were Korean adults aged 65 and older (N=1,316) from the 2020 Korean National Health and Nutrition Examination Survey. The survey measured sleep disturbances (OSA, insomnia, hypersomnia), depressive symptoms, and sociodemographic characteristics. Hierarchical multiple regression analysis was conducted to examine whether sleep disturbances influence depressive symptoms and test the interaction between sleep disturbance and gender. Results revealed that after adjusting for covariates, those with more risk factors for OSA (B=1.056, p=.000) or with insomnia (B=1.527, p=.000) were more likely to have greater depressive symptoms than their counterparts. Additionally, the relative influences of OSA (B=1.295, p=.000) or insomnia (B=.965, p=.023) on depressive symptoms were contingent upon gender. However, no correlation was observed between hypersomnia and depressive symptoms. Although both OSA and insomnia are risk factors for depressive symptoms, older women with OSA or insomnia showed more severe depressive symptoms than older men with OSA or insomnia. Findings suggest the need to make sophisticated approaches considering homogeneity and heterogeneity within older adults.

Obstructive Sleep Apnea Is a Distinct Physiological Endotype in Individuals with Comorbid Insomnia and Sleep Apnea (COMISA).

With up to 40% of individuals with either insomnia or obstructive sleep apnea (OSA) demonstrating clinically significant symptoms of the other disorder, the high degree of comorbidity amongst the two most common sleep disorders suggests a bi-directional relationship and/or shared underpinnings. Whilst the presence of insomnia disorder is believed to influence the underlying pathophysiology of OSA, this influence is yet to be examined directly. To investigate whether the four OSA endotypes (upper airway collapsibility, muscle compensation, loop gain, and the arousal threshold) are different in OSA patients with and without comorbid insomnia disorder. Using the ventilatory flow pattern captured from routine polysomnography, the four OSA endotypes were measured in 34 OSA patients who met diagnostic criteria for insomnia disorder (COMISA) and 34 OSA patients without insomnia (OSA-only). Patients demonstrated mild-to-severe OSA (AHI: 25.8±2.0 events/h) and were individually matched according to age (50.2±1.5 years) sex (42M:26F), and body mass index (29.3±0.6 kg/m2). Compared to OSA patients without comorbid insomnia, COMISA patients demonstrated significantly lower respiratory arousal thresholds (128.9 [118.1-137.1] vs. 147.7 [132.3-165.0] %Veupnea, U=261, 95%CI[-38.3, -13.9], d=1.1, p<.001), less collapsible upper airways (i.e., higher Vpassive: 88.2 [85.5-94.6] vs. 72.9 [64.7-79.2] %Veupnea, U=1081, 95%CI[14.0, 26.7], d=2.3, p<.001) and more stable ventilatory control (i.e., lower loop gain: 0.51 [0.44-0.56] vs. 0.58 [0.49-0.70], U=402, 95%CI[-0.2, -0.01], d=.05, p=.03). Muscle compensation was similar between groups. Moderated linear regression revealed the arousal threshold moderated the relationship between collapsibility and OSA severity in COMISA, but not OSA-only patients. A low arousal threshold is an overrepresented endotypic trait in individuals with COMISA and may exhibit a greater relative contribution to OSA pathogenesis in these patients. Contrastingly, the prevalence of a highly collapsible upper airway in COMISA was low, suggesting that anatomical predisposition may contribute less to OSA development in COMISA. Based on our findings we theorise that conditioned hyperarousal perpetuating insomnia may translate to a reduced arousal threshold to respiratory events, thereby increasing the risk or severity of OSA. Therapies which target increased nocturnal hyperarousal (e.g., through CBT-I) may be effective in individuals with COMISA.

1098-P: Association of Sleep with ß-Cell Response and Insulin Sensitivity in Youth

Poor sleep may be associated with reduced β-cell response or decreased insulin sensitivity in youth. We explored whether sleep duration, sleep quality or obstructive sleep apnea (OSA) risk factors were associated with measures of β-cell response or insulin sensitivity in youth. At baseline, 88 youth (10-19 yrs of age) with recently diagnosed T2D or prediabetes completed validated questionnaires (Sleep Disturbances Scale and Cleveland Adolescent Sleepiness) in the Restoring Insulin Secretion (RISE) Study. Hyperglycemic clamps measured insulin sensitivity (steady state glucose infusion rate/insulin [M/I]) and β-cell responses: acute (0-10 min) C-peptide response to glucose (ACPRg), steady-state C-peptide at a glucose of 11.1 mmol/L (SSCP), and arginine-stimulated maximum C-peptide responses at glucose &amp;gt;25 mmol/L (ACPRmax). Linear regression models explored the independent association between sleep variables and clamp measures, adjusted for age, race/ethnicity, sex, Tanner stage, metformin use and BMI. Models including β-cell responses were adjusted for M/I to account for the role of insulin sensitivity in β-cell function. The cohort was 70% female, 28% white, 25% black, 36% Hispanic; age 14.3±2.0 yrs and BMI 36.9±6.4 kg/m2 (mean±SD). Using ADA criteria, 60% had prediabetes and 40% had T2D; 27% reported metformin use. Sleep duration &amp;lt;8 h was reported in 59%; 57% reported daytime sleepiness; 28% reported poor sleep quality; 29% had high risk for OSA. Low sleep duration (&amp;lt;8 h) was associated with a trend for lower ACPRg (p=0.069). No sleep variables (sleep duration or quality, OSA risk) were associated with clamp-derived outcomes in unadjusted or adjusted linear regression models. In youth with prediabetes or T2D, subjective measures of sleep quantity, sleep quality and OSA risk were not independently associated with β-cell response or insulin sensitivity. Further research using objective measures of sleep may better delineate the relationship between sleep and β-cell function in youth. Disclosure K.A.Temple: None. A.H.Tjaden: None. S.Manchanda: Advisory Panel; Inspire. D.Ehrmann: None. K.J.Nadeau: None. S.Edelstein: None. T.S.Hannon: Advisory Panel; Eli Lilly and Company. B.Mokhlesi: None. Rise consortium: n/a. Funding American Diabetes Association (1-20-RISE-01 to S.E.); National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute

0560 Solriamfetol for Excessive Sleepiness in Narcolepsy and Obstructive Sleep Apnea: Effect Sizes and Numbers Needed to Treat or Harm

Abstract Introduction Solriamfetol (Sunosi®), a dopamine/norepinephrine reuptake inhibitor that has been shown to activate TAAR1, is approved (US and EU) to treat excessive daytime sleepiness (EDS) in adults with narcolepsy (75-150mg/day) or obstructive sleep apnea (OSA) (37.5-150mg/day). Effect size, number needed to treat (NNT) and number needed to harm (NNH) are statistical representations of efficacy and tolerability that clinicians may find helpful in guiding treatment decisions. This analysis characterized these statistical parameters from two registrational studies. Methods We conducted a post-hoc analysis of data from two phase 3 studies in adults with excessive daytime sleepiness associated with narcolepsy (TONES 2) or OSA (TONES 3). Effect size compared to placebo, NNT, and NNH were calculated based on previously published endpoints, post-hoc analyses, and adverse events. Results On the Maintenance of Wakefulness Test, effect size compared to placebo (Cohen’s d) was 0.29, 0.82, and 1.13 for 75mg, 150mg, and 300mg doses of solriamfetol in TONES 2 and 0.46, 0.89, 1.08, and 1.28 for 37.5mg, 75mg, 150mg, and 300mg in TONES 3. On the Epworth Sleepiness Scale (ESS), d was 0.47, 0.80, and 1.02 for 75mg, 150mg, and 300mg in TONES 2, and 0.42, 0.37, 0.99, and 1.04 for 37.5mg, 75mg, 150mg, and 300mg doses in TONES 3. NNT for patients achieving an ESS ≤10 was 7, 5, and 3 for 75mg, 150mg, and 300mg doses in TONES 2 and 8, 6, 4, and 3 for 37.5mg, 75mg, 150mg, and 300mg doses in TONES 3. On the Patient Global Impression of Change (PGIc), NNT was 4, 3, and 3 for 75mg,150mg, and 300mg doses in TONES 2 and 16, 5, 3, and 3 for 37.5, 75mg, 150mg, and 300mg in TONES 3. Similar NNT were found for the Clinician Global Impression of Change as for the PGIc. In both TONES 2 and TONES 3, NNH pooled across doses for adverse events occurring in ≥5% of patients and greater than placebo were all &amp;gt;10, with the exception of headache in TONES 2 (NNH=6). Conclusion This post-hoc analysis demonstrates favorable effect size, NNT, and NNH values for solriamfetol in the treatment of EDS associated with narcolepsy and OSA. Support (if any) Axsome Therapeutics

0458 Cardiovascular and sociocultural factors are associated with sleep breathing differences in a diverse Hispanic/Latino cohort

Abstract Introduction Obesity and or obstructive sleep apnea (OSA) can impact awake breathing patterns, such as increments in the breathing rate. However, little is known about their associations with breathing dysregulations during sleep beyond the apnea-hypopnea events. Understanding this could help elucidate treatment mechanisms or different pathways for disease. Furthermore, there is a strong connection between breathing patterns and cardiovascular disease, thus it is also critical to understand the links between cardiovascular risk factors and disease (CVD) and sleep breathing patterns. Methods The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) is a prospective multicenter study of diverse Latinos. A total of N=16,415 participants from four major metropolitan areas and six different Hispanic/Latino backgrounds were sampled for appropriate generalization to the target population. Participants were given an ARES unirecorder device (Carlsbad, San Diego) for a single night of unsupervised at home recording (N=12,022). Raw data from cannula channel (sampled at 10Hz) was processed using the python Bycycle package. Bycycle is a cycle-by-cycle approach to analyzing time series data. Bycycle finds all peaks and throughs in cycles and allows users to extract time dependent information of cycles. We extracted breathing rate (breaths per minute), breathing variability (interquartile range of breathing rate) and time spent in inhalation phase (percent time). Results In multivariable models (N=10,175), age was linked to decreased breathing rate, breathing variability, and time spent in inhalation phase. Compared to females, males had higher breathing variability and spent more time in the inhalation phase. Compared to Mexicans and? Central Americans, Cubans, Dominicans, and Puerto Ricans had less time spent in inhalation phase. Dominicans and Puerto Ricans also had increased breathing rate compared to Mexicans. Smoking, body mass index, and moderate to severe OSA were associated with increased breathing rate and variability. Systolic, but not diastolic blood pressure, was associated with increased breathing rate. We found no significant associations with cardiovascular disease. Conclusion Factors commonly linked to OSA were associated with increased breathing rate, a compensatory mechanism for optimal oxygenation, and breathing variability. Given cessation or reduced breathing during an apnea-hypopnea event, breathing variability may add more precision to account for varying oxygen demands. Support (if any)

Identification of a real-world clinical model associated with atrial fibrillation in a large french primary care database

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Bristol Myers Squibb and Pfizer. Background Undiagnosed atrial fibrillation (AF) is associated with a higher risk of stroke and mortality. To date, the 2020 European Society of Cardiology (ESC) guidelines recommend opportunistic screening for AF in patients ≥65 years (Class I), or with hypertension (HTN) (Class I), or obstructive sleep apnea (OSA) (IIa), and systematic ECG screening in patients ≥75 years or at high risk of stroke defined by the CHA2DS2-VASc score (Class IIa).1 However, in a primary care practice, these criteria cover a large number of patients. Purpose Evaluate the performance of several clinical markers or combination of clinical markers to identify patients at high-risk of AF in a primary care database. Methods This retrospective national study used patients’ data from the French electronic health records THIN® database of 2 000 General Practitioners (GP). Patients included had visited their GP in 2019 and were followed for ≥ 3 years, were aged ≥ 50 with ≥ 1 risk markers potentially associated with AF (HTN, diabetes, obesity, dyslipidaemia, smoking, alcohol dependence, cardiopathy, heart failure (HF), vascular disease, OSA, chronic obstructive pulmonary disease, inflammatory disease, thyroid or renal dysfunction). Non-AF patients with anticoagulant treatment were excluded. The tested variables and models included the 2020 ESC guidelines criteria for AF screening (age ≥65, age ≥ 75, high stroke risk defined as CHA2DS2-VASc ≥ 2 (male) or ≥ 3 (female), HTN, OSA), the CHA2DS2-VASc taken as a score as well as the multivariate analysis of its components (congestive HF, HTN, age ≥ 75, diabetes, stroke, vascular disease, age 65-74, female sex), and an ad hoc model based on the combination of risk markers associated with AF (15 variables based on cardiovascular and non-cardiovascular comorbidities; Figure 1). Multivariate models were performed with logistical regression. Results Among 573 539 screened patients (mean follow-up 13.5 years), 30 476 had AF (5.3%). The ad hoc model using the 15 variables showed the highest performance with AUC 0.80 (Se 69%, Sp 77%) (Figure 1). In this model, all variables were significantly associated with AF except diabetes, dyslipidaemia, and HIV. Age ≥ 75, HF, age 65-74 and male sex were the most significant risk markers associated with AF (Figure 1). In the CHA2DS2-VASc model, AUC was 0.78 for multivariate analysis (Se 69%; Sp 72%), and 0.71 for the score result (Se 77%, Sp 56%). Regarding the ESC guidelines criteria, age ≥ 75 years had the best performance with AUC 0.69 (Se 62%, Sp 75%), then age ≥65 (AUC 0.67), high stroke risk (AUC 0.66), versus AUC &amp;lt; 0.60 for HTN and OSA. Conclusion In this study on a large primary care database, the ad hoc model had the highest performance, sensitivity and specificity. In the future, it might help GPs to identify patients at high-risk of AF in clinical practice and to propose targeted preventive interventions and screening.

Orofacial myofunctional reeducation assisted by a prefabricated reeducation appliance: a systematic review of the literature

Several cross-sectional studies have shown the association of a dysfunctional orofacial environment with a greater prevalence of malocclusions. Orofacial myofunctional reeducation (OFMR) is the rehabilitation of the muscles, functions and resting postures of the orofacial complex. It is used in the therapeutic management of orofacial dysfunction in patients of all ages and with a wide range of disorders and comorbidities. RMOF mainly uses isotonic and isometric exercises targeting the oral and oropharyngeal structures, combined with specific exercises for ventilation, swallowing and mastication. It may involve the use of prefabricated reeducation appliances (PRAs), which may also be prescribed to modify the shape and relationship of the dental arches. The primary objective of this systematic review of the literature was to describe and evaluate the efficacy of prefabricated reeducation appliance-assisted OFMR in orthodontics, occlusodontics and dental sleep medicine. Its secondary objective was to assess whether the use of currently available PRAs is associated with adverse effects. The systematic literature review was undertaken using five electronic databases: Medline (via PubMed), Web of Science, Cochrane Library, Embase, and Google Scholar, to identify studies evaluating the efficacy of PRA-assisted OFMR in the treatment of orofacial dysfunctions and parafunctions, temporo-mandibular dysfunction (TMD) or obstructive sleep apnea (OSA) in children, adolescents and adults, published until 20 March 2023. The primary outcome of interest was the therapeutic efficacy of PRA-assisted OFMR. In patients with obstructive sleep apnoea (OSA), efficacy was assessed primarily by a decrease in the apnoea/hypopnoea index (AHI) of at least five episodes per hour from baseline, improvement in subjective sleep quality, sleep quality measured by nocturnal polysomnography and subjectively measured quality of life. In patients with orofacial dysfunctions, parafunctions or TMD, efficacy was assessed mainly by electromyography (EMG), history and clinical examination. Secondary outcomes were dentoalveolar or skeletal improvements, and possible adverse effects of the PRAs used, including adverse effects on occlusion. Only fourteen studies met all inclusion criteria: two randomised controlled trials, one non-randomised controlled trial, five prospective case-control studies, two retrospective case-control studies, two prospective case series and two retrospective case series. The two randomised controlled trials were assessed as "low risk of bias" according to the Cochrane Back Review Group's 12 risk of bias criteria. The methodological quality of the remaining 12 included studies was assessed using the ROBINS-I tool, according to the recommendations of the Cochrane Handbook. One was judged to have a measured risk of bias, eight a significant risk of bias and three a critical risk of bias. Based on the available evidence, PRA-assisted OFMR results in a statistically significant (p=0.0425) reduction in AHI in children with mild to moderate obstructive sleep apnea. In children with obstructive sleep apnoea undergoing adenoid and/or tonsil surgery, postoperative OFMR combined with a flexible PRA leads to a greater reduction in AHI compared to a control group and an improvement in SaO2 at 6 months and 12 months after surgery (p<0.01). It also contributes to greater improvement in sleep disturbance, physical fitness, daytime lethargy in the treated group than in the control group 6 months and 12 months after surgery (p<0.05). PRA-assisted OFMR provides correction of atypical swallowing and improvement in orofacial muscle balance. GRPs are generally less effective than activators for the treatment of Class II Division 1 malocclusions and appear to cause more adverse effects, mainly vestibuloversion of the mandibular incisors. The use of PRA-assisted OFMR for the management of TMD is not validated by current evidence. Published data, albeit of uneven methodological quality, appear to show the superiority of OFMR combined with the use of a PRA, compared with the implementation of OFMR without PRA. Prospective studies with large sample sizes would be useful to better evaluate the new therapeutic possibilities brought by the combination of OFMR with a PRA. Continued attention should be paid to the monitoring of possible adverse effects of PRA-assisted OFMR on the dental arches, especially the vestibuloversion of the mandibular incisors. It might be useful to reflect on the relevance of the arguments put forward by manufacturers about the particularities of their devices and their supposed effects. PRA-assisted OFMR appears to be a necessary paradigm shift, which it seems useful to bring to our patients. This protocol was registered on March 02, 2023 in the International Prospective Register of Systematic Review (PROSPERO) and received the CRD number: CRD42023400421.

Psychomotor Vigilance Performance in Participants with Excessive Daytime Sleepiness in Obstructive Sleep Apnea or Narcolepsy Compared withSAFTE-FAST Model Predictions.

Excessive daytime sleepiness (EDS) associated with narcolepsy or obstructive sleep apnea (OSA) can impair vigilance/attention. Solriamfetol, a dopamine/norepinephrine reuptake inhibitor, is approved to treat EDS associated with narcolepsy (75-150mg/day) or OSA (37.5-150mg/day). The analysis reported here explored the use of the Sleep, Activity, Fatigue, and Task Effectiveness (SAFTE) model (used in transport industries to model performance based on accumulated sleep and circadian variability) as a substitute for healthy controls using psychomotor vigilance task (PVT) data collected during clinical studies. Data were analyzed from two phase 2 studies of solriamfetol in adults with OSA (NCT02806895, EudraCT 2015-003930-28) or narcolepsy (NCT02806908, EudraCT 2015-003931-36). Participants were randomly assigned 1:1 to solriamfetol 150mg/day (3days) followed by 300mg/day (4days), or placebo (7days), then crossed over to the other treatment. Actual task effectiveness scores were calculated from average PVT inverse reaction time (pre-dose; 2h post-dose; 6h post-dose). Actigraphy-derived sleep intervals were used in SAFTE to determine modeled healthy control task effectiveness scores. In participants with OSA (N = 31) on placebo or solriamfetol, actual and modeled healthy control task effectiveness did not differ at any time point. In participants with narcolepsy (N = 20) on placebo, actual task effectiveness at 2h post-dose was lower than modeled healthy control task effectiveness (nominal P = 0.03), a difference not present with solriamfetol. There was no main effect of solriamfetol on actual or modeled healthy control task effectiveness across time points. This study represents a novel application of the SAFTE biomathematical model to approximate healthy controls in sleep disorder research and provides valuable lessons that may optimize future research. Future studies should perform a priori power analyses for model-tested outcomes and use sleep measures that capture sleep fragmentation characteristic of sleep disorders for sleep input (e.g., total sleep time rather than time in bed). NCT02806895, EudraCT 2015-003930-28: A Randomized, Double-Blind, Placebo-Controlled, Crossover On-Road Driving Study Assessing the Effect of JZP-110 on Driving Performance in Subjects With Excessive Sleepiness Due to Obstructive Sleep Apnea. NCT02806908, EudraCT 2015-003931-36: A Randomized, Double-Blind, Placebo-Controlled, Crossover On-Road Driving Study Assessing the Effect of JZP-110 on Driving Performance in Subjects With Excessive Sleepiness Due to Narcolepsy.

Association of a History of Sleep Disorder With Risk of Mild Cognitive Impairment and Alzheimer's Disease Dementia.

We explored whether a history of sleep disorder affected a current diagnosis of cognitive impairment and clinical conversion in a non-demented elderly population. Comprehensive clinical data collected as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI) was analyzed. A history of sleep disorder was recorded in the recent ADNI medical database. Standard clinical and neuropsychological tests were performed both at baseline and follow-up visit. Multiple logistic regression analysis was performed after adjusting for age, sex, education, apolipoprotein E ε4 status, vascular risk score, body mass index, Geriatric Depression Scale score, and use of sleeping pills. A total of 391 cognitively normal individuals, 303 with early mild cognitive impairment (MCI) and 364 with late MCI were included. Sleep disorder history was significantly associated with an increased risk of MCI but not with clinical conversion. A history of insomnia or obstructive sleep apnea (OSA) significantly increased the risk of MCI, but only an OSA history predicted progression to Alzheimer's disease (AD) dementia. Our findings suggest that a sleep disorder history usefully aids early detection of cognitive impairment and emphasize that such sleep disorder, particularly OSA, is important as potential target for AD prevention.

All-Cause Mortality in People with Co-Occurring Insomnia Symptoms and Sleep Apnea: Analysis of the Wisconsin Sleep Cohort.

PurposeInsomnia symptoms and sleep apnea frequently co-occur and are associated with worse sleep, daytime function, mental health and quality of life, compared to either insomnia or obstructive sleep apnea (OSA) alone. This study aimed to investigate the association of symptoms of co-morbid insomnia and sleep apnea (COMISA) with all-cause mortality.Patients and MethodsWisconsin Sleep Cohort data were analysed to assess potential associations between COMISA symptoms and all-cause mortality. Nocturnal insomnia symptoms were defined as difficulties initiating sleep, maintaining sleep, and/or early morning awakenings “often” or “almost always”, and/or regular sedative-hypnotic medicine use. OSA was defined as an apnea-hypopnea index ≥5/hr sleep. Participants were classified as having neither insomnia symptoms nor OSA, insomnia symptoms alone, OSA alone, or COMISA symptoms. Associations between the four groups and all-cause mortality over 20 years of follow-up were examined via multivariable adjusted Cox regression models.ResultsAmong 1115 adult participants (mean ± SD age 55 ± 8 years, 53% males), 19.1% had COMISA symptoms. After controlling for sociodemographic and behavioral factors, COMISA symptoms were associated with an increased risk of all-cause mortality compared to no insomnia symptoms or OSA (HR [95% CI]; 1.71 [1.00–2.93]). OSA alone (0.91 [0.53, 1.57]) and insomnia symptoms alone (1.04 [0.55, 1.97]) were not associated with increased mortality risk.ConclusionCo-morbid insomnia symptoms and sleep apnea is associated with increased all-cause mortality risk. Future research should investigate mechanisms underpinning COMISA and the effectiveness of different treatment approaches to reduce mortality risk for this common condition.

Solriamfetol Titration & AdministRaTion (START) in Patients With Narcolepsy

PurposeSolriamfetol, a dopamine/norepinephrine reuptake inhibitor, is approved (in the United States and European Union) to treat excessive daytime sleepiness (EDS) in adults with narcolepsy (75–150 mg/d) or obstructive sleep apnea (OSA) (37.5–150 mg/d). This study characterized real-world titration strategies for patients with narcolepsy (with or without comorbid OSA) initiating solriamfetol therapy. MethodsThis virtual, descriptive study included a retrospective medical record review and qualitative survey. US-based physicians prescribing solriamfetol for EDS associated with narcolepsy or OSA participated. Data are reported for patients with narcolepsy with or without comorbid OSA (OSA alone reported separately). On the basis of medical record review, titration strategies were classified de novo (EDS medication naive), transition (switched or switching from existing EDS medication[s] to solriamfetol), or add-on (adding solriamfetol to current EDS medication[s]). The survey included open-ended questions regarding a hypothetical patient—a 32-year-old woman with narcolepsy (Epworth Sleepiness Scale score of 8) treated with 35 mg/d of amphetamine and 6 g per night of sodium oxybate who experiences non–use-limiting adverse events from amphetamine. FindingsTwenty-six physicians participated: 23 provided data from 70 patients with narcolepsy (type 1, n = 24; type 2, n = 46; mean [SD] age, 40 [11] years; 57% female; 6 with comorbid OSA), and 26 responded to the hypothetical patient scenario. From the medical record review, solriamfetol therapy initiation was de novo for 19 of 70 patients (27%), transition for 31 of 70 patients (44%), and add-on for 20 of 70 patients (29%). Efficacy profile of solriamfetol was the primary reason for de novo (12 of 19 [63%]), transition (18 of 31 [58%]), and add-on (19 of 20 [95%]) initiation. Most (86%) initiated use of solriamfetol at 75 mg/d and were stable at 150 mg/d (76%). Most (67%) had 1 dose adjustment, reaching a stable dose over a median (range) of 14 (1–60) days. Physicians most often considered EDS severity (44%) when titrating. Among transitioning patients, 14 of 22 (64%) using wake-promoting agents discontinued their use abruptly, and 5 of 9 (56%) using stimulants were tapered off. At data collection, 90% continued to take solriamfetol. Regarding the hypothetical patient scenario, most physicians (81%) thought solriamfetol was appropriate, highlighting tolerability issues with current treatment and lack of symptom control as drivers for switching; however, 3 physicians (12%) did not think solriamfetol was appropriate, noting current symptoms were not severe enough and/or symptoms could be managed by increasing sodium oxybate dose; 2 (8%) thought it would depend on other factors. Physicians emphasized managing withdrawal symptoms while maintaining EDS symptom control when titrating off a stimulant and starting solriamfetol therapy. ImplicationsIn a real-world study, physicians initiated solriamfetol therapy at 75 mg/d for most patients with narcolepsy, adjusted dosages once, tapered stimulants, and abruptly discontinued therapy with wake-promoting agents.

Solriamfetol treatment of excessive daytime sleepiness in participants with narcolepsy or obstructive sleep apnea with a history of depression

Given the high rate of depression associated with narcolepsy or obstructive sleep apnea (OSA), this analysis compared effects of solriamfetol treatment of excessive daytime sleepiness (EDS) in participants with/without a history of depression (DHx+/DHx-). This secondary analysis included data from two randomized, controlled trials in which participants were randomized to 12 weeks placebo or solriamfetol 37.5 (OSA only), 75, 150, or 300 mg/day. Efficacy/safety (combined solriamfetol doses) was summarized for DHx+/DHx-subgroups. 27.5% (65/236) with narcolepsy and 23.4% (111/474) with OSA were DHx+. In narcolepsy (DHx+ and DHx-), 40-min Maintenance of Wakefulness Test (MWT40) mean sleep latency increased (5.4 and 7.0 min), Epworth Sleepiness Scale (ESS) score decreased (3.8 and 3.5 points), and percentage of participants improved on Patient Global Impression of Change (PGI-C) was higher (31.7% and 39.4%) relative to placebo. In OSA (DHx+ and DHx-), MWT40 mean sleep latency increased (7.7 and 10.7 min), ESS decreased (3.5 and 3.7 points), and percentage of participants improved on PGI-C was higher (41.1% and 29.4%) relative to placebo. Common treatment-emergent adverse events (headache, decreased appetite, nausea, anxiety) were similar in DHx+/DHx-. This study suggests that safety and efficacy of solriamfetol for treating EDS in narcolepsy and OSA are not affected by depression history. Moreover, the findings emphasize the high prevalence of depression in people with sleep disorders and suggest that increased awareness of this association may have clinical significance.

124-LB: Incidence and Risk Factors of Erythrocytosis following Initiation of Sodium–Glucose Cotransporter 2 Inhibitors in Men with Type 2 Diabetes in Real-World Setting

Background: Analyses of prospective trials consistently demonstrated that therapy with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) in type 2 diabetes (T2D) results in mild but significant increase in hematocrit (Hct) . We sought to determine if SGLT-2i therapy poses risk of erythrocytosis (ERY) in routine clinical practice. Methods: This was a retrospective study of T2D US Veterans who were prescribed an SGLT-2i and had adequate adherence based on the proportion of days covered &amp;gt;80% during 3/2013-12/2019 and baseline Hct&amp;lt;50%. ERY incidence was defined as first Hct&amp;gt;54% within 180 days of an SGLT-2i initiation. The detailed patient data were obtained using the VA Informatics and Computing Infrastructure (VINCI) database. Odds ratio (OR) of ERY risk was calculated by logistic regression models adjusted for case-mix. Results: We identified 9402 patients (76.0% Whites/14.7% Blacks) with baseline mean±SD age 65.0±8.9 yrs, BMI 34.1±6.3 kg/m2, Hct 41.5±4.1 % and hemoglobin A1c 8.5±1.2 %. By the end of observation period, mean Hct increased from the baseline by 1.74% [95% CI 1.68-1.80] in the entire cohort and 61 patients (0.65% of the cohort) developed ERY. We found that BMI, tobacco use, or obstructive sleep apnea (OSA) were not associated with risk of developing ERY. However, concomitant use of testosterone replacement therapy (TRT) was associated with significant ERY risk compared with SGLT-2i users not on TRT in both unadjusted analyses (OR 12.28 [95% CI 5.29-25.10]) and after adjustments for age, race, BMI, OSA, and tobacco use (OR 7.26 [95% CI 2.95-16.04]) . The risk of ERY was independent of baseline Hct or modality of TRT (topical vs. injectable) . Conclusions: For the first time, we demonstrated that SGLT-2i initiation in men with T2D in real world clinical setting can result in detectable risk of erythrocytosis. It appears that concomitant TRT can significantly influence that risk. We recommend monitoring for Hct changes following SGLT-2i initiation and, particularly, in those persons who receive testosterone therapy. Disclosure A. R. Gosmanov: Research Support; AbbVie Inc., Kowa Research Institute, Inc., Speaker’s Bureau; AstraZeneca. D. E. Gemoets: None. M. A. Green: None. K. Schumacher: None.

Predictive Factors for Concurrent Tegmen Dehiscence in Superior Canal Dehiscence Syndrome.

To describe factors predictive of tegmen dehiscence in subjects with superior semicircular canal dehiscence syndrome (SCDS). Retrospective case series. Tertiary referral center. Subjects with SCDS who underwent middle fossa craniotomy (MFC) for plugging/resurfacing. Operative and radiographic findings of tegmen dehiscences, preoperative low frequency air-bone gaps (LF-ABGs), ocular vestibular evoked myogenic potential (oVEMP) amplitudes, size of superior semicircular canal dehiscence (SCD), and history of obesity or obstructive sleep apnea (OSA). One hundred thirty six patients (avg. age, 50.6 yr, 55.1% female) underwent MFC for repair of SCDS. Tegmen dehiscences were commonly found intraoperatively (tegmen tympani dehiscence [TTD] in 19.9% [11% with dural contact of ossicles], tegmen mastoideum dehiscence [TMD] in 28.7%). There were no differences in preoperative LF-ABGs and preoperative oVEMP amplitudes with respect to tegmen status. The sensitivity and specificity of computed tomography (CT) for predicting an intraoperatively confirmed TTD was 85 and 74%, respectively, and 44 and 79% for TMD. History of obesity and OSA did not differ between those with and without tegmen dehiscences. The presence of contralateral SCD and increasing cross-sectional area of SCD were both significantly associated with concurrent tegmen defects. Obesity, OSA, preoperative oVEMP, and LF-ABG do not differ between those with SCD alone and those with SCD and concurrent tegmen dehiscences. Likewise, CT scans have relatively low sensitivity for identifying tegmen dehiscences. The presence of concurrent tegmen defects is more common in subjects with larger SCD cross-sectional areas and contralateral SCD.

단순 코골이 또는 폐쇄성 수면 무호흡증이 있는 후기 남자 청소년에서 다면적 인성 검사 결과

Objectives The purpose of this study was to quantitatively assess the degree of Simple Snoring(SS) or Obstructive Sleep Apnea (OSA) affecting mental health through the results of multiphasic military personality inventory. Method We collected and analyzed the results of the military personality inventory(MPI) for healthy controls and SS or OSA patients among the 19-year-old men who visited the Military Manpower Administration from January 2008 to January 2013. MPI invented for Korean military test has similar system to Minnesota multiphasic personality inventory. Results Among demographic data, education level was lower in SS or OSA group (χ2=69.49, p<0.001). Socio-economic status and parents-relationship were not statistically different between two groups (χ2=2.94, p=0.401; χ2=2.01, p=0.570). BMI was higher in SS or OSA group (t=-8.24, p<0.001). Among validity scale, the score of faking good subscale was lower in SS or OSA group (t=3.157, p=0.002). Each score of faking bad and infrequency subscale was higher in SS or OSA group (t=-3.741, p<0.001; t=-2.766, p=0.006). Among neurosis scale, each score of anxiety, depression, somatization and personality disorder subscale was higher in SS or OSA group, respectively (t=-4.060, p<0.001; t=-3.977, p<0.001; t=-4.293, p<0.001; t=-3.499, p=0.001). Among psychopath scale, each score of schizophrenia and paranoia subscales were not statistically different between two groups (t=-1.669, p=0.096; t=-2.012, p=0.045). Conclusion According to MPI results, we can confirm that SS or OSA patients may appear feature such as anxiety, depression, somatization and personality tendency (introversion or impulsivity) than the control group.

482 Solriamfetol Titration &amp; AdministRaTion (START): dosing and titration strategies in patients with narcolepsy starting solriamfetol

Abstract Introduction Solriamfetol (Sunosi®), a dopamine/norepinephrine reuptake inhibitor, is approved (US and EU) to treat excessive daytime sleepiness (EDS) in adults with narcolepsy (75–150 mg/day) or obstructive sleep apnea (OSA) (37.5–150 mg/day). Previous research examined the use of solriamfetol in clinical trial settings but research in real-world settings was not previously conducted. This study characterized real-world dosing and titration with solriamfetol. Methods This virtual, descriptive study included a quantitative retrospective patient chart review among US-based physicians prescribing solriamfetol. Target enrollment was 25 physicians treating patients with EDS associated with OSA or narcolepsy. Titration strategies were classified as de novo (no prior EDS medication), transition (switched/switching from existing EDS medications onto solriamfetol), or add-on (adding solriamfetol to current EDS medication). Results Twenty-six physicians participated. Seventy patients with narcolepsy were analyzed (type 1, n=24; type 2, n=46; mean±SD age, 40±11 years; 57% female; 6 also had OSA); EDS was primarily moderate (59%) or severe (36%). Solriamfetol initiation was de novo for 19 (27%) patients, transition for 31 (44%), and add-on for 20 (29%). Most patients (86%) started solriamfetol at 75 mg; 11% and 3% started at 37.5 mg and 150 mg, respectively. The final/stable dose was 150 mg for 76% (53/70) of patients and 75 mg for 24% (17/70). Most patients (67%) had 1 dose adjustment to reach their final dose; 4% had 2 adjustments, 4% had 3 adjustments, and 24% had none. Mean±SD time to reach a stable dose was 15.1±11.8 days overall, 19.4±9.3 days with de novo treatment, 15.0±13.7 days for transition, and 11.9±8.6 days for add-on. Physicians most frequently considered EDS severity (44% of patients) when titrating. Among patients transitioning, 14/22 (64%) taking a wake-promoting agent (WPA) discontinued it abruptly while 5/9 (56%) taking a stimulant were tapered off. Physicians were overall likely (n=33, 47%) or very likely (n=30, 43%) to recommend their approach for similar patients. Conclusion In a real-world study, the majority of physicians prescribing solriamfetol for patients with narcolepsy started at the 75-mg dose, tapered stimulants but abruptly discontinued WPAs, and made 1 adjustment to reach a stable dose across 15 days on average. Support (if any) Jazz Pharmaceuticals

481 Solriamfetol Titration &amp; AdministRaTion (START): Characteristics of patients with narcolepsy and solriamfetol prescriber rationale

Abstract Introduction Pharmacotherapy for excessive daytime sleepiness (EDS) associated with narcolepsy is diverse, with factors such as efficacy, side effects, and tolerance influencing treatment decisions. Solriamfetol (Sunosi®), a dopamine/norepinephrine reuptake inhibitor, is approved (US and EU) to treat EDS in adults with narcolepsy (75–150 mg/day) or obstructive sleep apnea (OSA) (37.5–150 mg/day). This study characterized real-world patients with narcolepsy starting solriamfetol and prescribers’ rationales for initiating treatment. Methods This virtual, descriptive study included a quantitative retrospective patient chart review among US-based physicians prescribing solriamfetol. Target enrollment was 25 physicians treating patients with EDS associated with OSA or narcolepsy. Treatment initiation was classified as de novo (no EDS medication prior to solriamfetol), transition (switched/switching from existing EDS medications onto solriamfetol), or add-on (adding solriamfetol to current EDS medication). Results Twenty-six physicians participated. Seventy patients with narcolepsy were analyzed (type 1, n=24; type 2, n=46; mean±SD age, 40±11 years; 57% female; 6 also had OSA); EDS was primarily moderate (59%) or severe (36%). Twenty-two patients (31%) were obese (BMI≥30); other common physician-reported comorbidities were migraine headaches (n=12, 17%), depression (n=10, 14%), and cardiovascular disorders (n=10, 14%). Solriamfetol initiation was de novo for 19 (27%) patients, transition for 31 (44%), and add-on for 20 (29%). Patients transitioning to solriamfetol were taking 1 (29/31, 94%) or 2 (2/31, 7%) prior EDS medications; patients adding solriamfetol were taking 1 (16/20, 80%), 2 (3/20, 15%) or 3 (1/20, 5%). Most patients transitioning to solriamfetol were taking wake-promoting agents (22/31, 71%); patients adding solriamfetol were most frequently taking sodium oxybate (11/20, 55%). Solriamfetol’s efficacy profile was the primary reason prompting the discussion to prescribe solriamfetol de novo (12/19, 63%); need for better efficacy/augmenting effects of other medications was the primary reason for transitioning (18/31, 58%) and add-on therapy (19/20, 95%). At data collection, 63 (90%) patients were still on a stable solriamfetol dose. The most common reasons for discontinuing solriamfetol were lack of efficacy (n=3) and side effects (n=3). Conclusion Efficacy and the need for improved efficacy over existing medication(s) were key considerations for physicians prescribing solriamfetol treatment to patients with narcolepsy in clinical practice. Support (if any) Jazz Pharmaceuticals