bluuebunny/crossref_metadata_2025_split huggingface dataset:
0895 Pharmacokinetics of pitolisant in breast milk and serum of healthy lactating women
Authors: Schmith Virginia , Bhise Neha , Dayno Jeffrey , Bauer Eric , Roy Michele , Budur Kumar , Brimhall Darin 
Published: May 2023

Abstract

Introduction
Pitolisant is a potent and highly selective histamine-3-receptor antagonist/inverse agonist approved for the treatment of excessive daytime sleepiness or cataplexy in adult patients with narcolepsy. A phase 4, open-label study was conducted to evaluate the pharmacokinetics (PK) of pitolisant and its major metabolite, BP1.3484, in breast milk and serum following a single dose of pitolisant administered to healthy lactating women.

Methods
In this study, eight healthy lactating women (aged 22-42 years) who met eligibility criteria were enrolled and received a single oral dose of pitolisant (35.6 mg). Serial breast milk samples were collected at pre-dose on Day 1 and at various intervals through 24 hours post-dose. Serial blood samples for PK analyses were collected at pre-dose and through 120 hours post-dose. Since the total infant dosage calculated from single dose data may be under-estimated, steady-state serum concentrations were predicted using noncompartmental methods and then multiplied by the 24-hour breast milk:serum ratio (AUCBM/S) to estimate a more appropriate total infant dose.

Results
Pitolisant was excreted in breast milk, with mean CmaxBM/S and AUCBM/S ratios of 85.2% and 123%, respectively. Concentrations of pitolisant in breast milk were only slightly lower than concentrations in serum. However, since the volume of breast milk was low, the percentage of the maternal dose expressed in breast milk was very low. Steady state calculations for a 6-month-old infant resulted in a mean total infant dosage of 0.005 mg/kg/day (SD 0.002), which is 1.15% of the maternal dose. For BP1.3484, maternal exposure and the calculated mean daily infant exposure were much lower than pitolisant. All subjects completed the study as planned. Five subjects (62.5%) reported a total of 8 treatment-emergent adverse events, which were mild in severity and resolved by end of the study.

Conclusion
Pitolisant is present in human milk, but the mean daily infant dosage in a 6-month-old infant after steady-state dosing of pitolisant in healthy lactating women was estimated to be very low. Overall, a single oral dose of pitolisant 35.6 mg was well-tolerated in healthy lactating women.

Support (if any)
The study was sponsored by Harmony Biosciences LLC.
0896 Predictors of Total Sleep Duration in Adults with Epilepsy
Authors: Smith Matthew , Araujo Matheus , Andrews Noah , Wang Lu , Foldvary-Schaefer Nancy 
Published: May 2023

Abstract

Introduction
Sleep deprivation is a common seizure trigger in adults with epilepsy (AWE). Yet, few prospective studies explore the relationship between seizure control and sleep duration. We studied factors associated with sleep duration in AWE participating in a prospective, cross sectional study investigating prevalence of sleep disorders. We hypothesized seizure frequency would be inversely associated with sleep duration.

Methods
Participants were AWE with quantifiable seizures who completed PSG, validated instruments and seizure/sleep diaries for at least 7 days in whom prior knowledge of sleep disorder symptoms was unknown. Linear regression models were fit for Total Sleep Duration (TSD; average sleep duration during the major sleep period) and 24-hour TSD (TSD24; average sleep duration during the major sleep period + daytime naps). Independent variables were monthly seizure frequency excluding auras(MSF), monthly generalized seizure frequency(GSF), epilepsy classification (focal vs. generalized), Beck Depression Inventory(BDI) and Insomnia Severity Index(ISI) scores, age, sex, body mass index(BMI), anti-seizure medication(ASM) number and standardized dose and apnea hypopnea index(AHI). Analyses were performed based on significance level 0.05, using SAS (version 9.4, Cary, NC).

Results
The sample included 126 participants (age 37.5(IQR:28,49), 67.5% female, BMI 28.0(IQR:24.0,32.3), 74.6% focal epilepsy). TSD was 7.5 + 1.9hr and TSD24 7.5 + 1.9hr. Median MSF was 0.5(IQR:0.0,4.0) with 75% having &gt;1 seizure/mo. Median GSF was 0.75 + 9.1 with 19% having &gt;1/mo. Median standardized ASM dose was 1.8(IQR:0.8,2.5) and 46.8% took monotherapy. After adjustment, female sex and ISI were inversely associated with TSD (female sex -1.01, 95%CI[-1.56,-0.17]; ISI -0.09, 95%CI[-0.15,-0.02]) and TSD24 (female sex -1.44, 95%CI[-2052,-0.37]; ISI -0.09, 95%CI[-0.17,-0.01]). GSF&gt;1 was associated with longer TSD24 than those with GSF &lt; 1(2.26, 95%CI[1.03,3.50] vs. 0.43, 95%CI[-0.49,1.35]). With every 1-unit increase in GSF, TSD24 increased 0.22hr(coefficient 0.22, 95%CI[0.07,0.36]). Other epilepsy-related variables were not associated with sleep duration.

Conclusion
In this first detailed analysis of TSD in AWE, female sex and higher insomnia severity were associated with shorter TSD and TSD24, and higher GSF was associated with longer TSD24. Neither TSD nor TSD24 were associated with MSF. These findings may inform future studies investigating sleep in AWE.

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0897 Sleep Architecture and Epileptiform Discharges in Rett Syndrome
Authors: Bricker Katelyn , Vaughn Bradley , Fan Zheng (Jane) 
Published: May 2023

Abstract

Introduction
Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder affecting females and is linked to mutations in the methyl-CpG-binding protein 2 (MeCP2) gene. Sleep issues and frequent epileptiform discharges are common in RTT. Typical comorbidities in RTT include poor growth, feeding difficulties, hyperventilation and breath-holding, seizures, scoliosis, and disrupted sleep. Although polysomnographic studies indicate sleep disruption in patients with RTT, few evaluate if the epileptiform activity is associated with significantly greater changes in sleep. We analyzed if epileptiform discharges were associated with greater sleep changes than those seen without epileptiform discharges.

Methods
This retrospective case control of 10 RTT subjects (mean age, 11.19 years; ranged from 1 to 33 years) underwent standard in-lab polysomnography (PSG) recording. Subjects were compared to 10 age and gender matched controls with an AHI &lt; 5 and no chronic medical problems. Rett children were divided into those with epileptiform discharges and those without. The two groups were compared using binomial cutoffs for each sleep parameter, and significance was determined by Fisher’s Exact Test. All studies were scored using the AASM criteria.

Results
Comparing our cohort of RTT patients to control subjects, the RTT patients have higher N3% of sleep, decreased N2%, and shorter sleep onset latency. 4 of the 10 PSGs are notable for frequent interictal epileptiform discharges. However, comparing those RTT patients with epileptiform discharges to those without, only REM latency trending shorter in those with epileptiform discharges (p= 0.057). No other significant differences were seen sleep staging, latency, total sleep time, efficiency, periodic limb movements nor respiratory parameters.

Conclusion
Our cohort did not find major differences in sleep features between those RTT patients with epileptiform discharges compared to those without. This may be related to a lack of influence of epileptiform discharges on these parameters or related to our small sample size. Although our cohort did not show major significant differences between those with epileptiform discharges, further study is required to delineate a more subtle relationship of these discharges to sleep.

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0899 Use of Artificial Intelligence for Early Characterization of Patients with RBD/RWA
Authors: Herdegen James , Cataline Joseph , Nygate Yoav , Gu Jiansan , Witek Natalie , Fernandez Chris , Watson Nathaniel 
Published: May 2023

Abstract

Introduction
The prevalence of polysomnography (PSG) confirmed REM sleep behavior disorder (RBD) has been estimated at 0.68% of the general population, and that of probable RBD at 5.65%. Isolated RBD is considered a pre-clinical marker of neurodegeneration with strong predictive value. Large longitudinal cohort studies demonstrate 81–91% of idiopathic RBD patients, followed for ≥14-years, will develop a definite neurodegenerative disease or mild cognitive impairment. Furthermore, high prevalence of sleep apnea (SA) exists in patients with RBD/REM without atonia (RWA), which can confound analysis of EMG tone and arousal activity. We demonstrate predictive AI models for RBD/RWA in subjects with and without SA.

Methods
Patients with known RBD/RWA who underwent PSG were divided into sub-groups with (n=86, RBDSA) and without SA (n=19, RBDNSA). Patient demographics, PSG characteristics, and co-morbid conditions were reviewed. Random forest (RF) models of PSG indices and Deep Learning (DL) methods identified predictive characteristics of RBD/RWA, sensitivity and specificity for RBD/RWA detection were estimated, and feature importance analysis was performed.

Results
Subjects with RBDSA compared to RBDNSA demonstrated greater BMI, AHI, Arousals (ArI), and Periodic Limb Movements (PLMs). In a Parkinson’s disease subgroup (n=12, RBDPD) compared to non-Parkinson’s sub-group, sleep was more fragmented, showing higher WASO, ArI, and PLMs. RF modeling demonstrated sensitivity/specificity of 67%/96% for RBDNSA subjects, and 79%/52% for RBDSA. Feature importance analysis resulted in several top-features for RBDNSA: N3 time, TST, AHI, REM duration, and sleep latency, while different top-features were observed for RBDSA: ratio of leg events in REM vs. non-REM, TST, ratio of arousals in REM vs. non-REM, REM duration, and REM time.

Conclusion
AI approaches including RF models produced high specificity and moderate sensitivity for RBDNSA subjects. Observed specificity was lower for RBDSA patients. We hypothesize the performance difference attributable to similarity and additional complexity in sleep disturbance characteristics between RBD and SA. Broad implementation of AI methods show potential to expand early detection and diagnosis of RBD and associated neurodegenerative conditions through expanded analysis, and follow-up, including RWA spectrum patients that don’t meet clinical thresholds for diagnosable RBD.

Support (if any)
None
0906 Feasibility of measures of sleep, circadian timing and lipid profiles for identifying mild cognitive impairment
Authors: Kim Seong Jae , Jang Jae-Won , Choi Min Seo , Suh In Bum , Lee Jung Hie 
Published: May 2023

Abstract

Introduction
Sleep disruption and circadian misalignment has been evident in patients with mild cognitive impairment (MCI). Together, sleep and circadian rhythm dysregulation can contribute to dyslipidemia, which has been proposed to play crucial roles in neurodegenerative process according to its known neurotoxicity. We aimed to compare parameters regarding lipid, nocturnal sleep and circadian timing between amnestic MCI (aMCI) and normal controls (NC), and to determine whether those parameters can be associated with the presence of aMCI in the elderly.

Methods
Participants above 50 years old were recruited from the Dementia Clinic at Kangwon National University Hospital, and two Public Care Centers for dementia patients. Neurocognitive tests were administered to each participant. The diagnosis of aMCI was made according to Petersen’s criteria. Eighteen aMCI patients (76.6 ±6.1 years) and 21 NC (70.4±6.7years) were finally selected. Actigraphy monitoring (Actiwatch 2; Respironics, USA) was conducted for 5 days. The dim light melatonin onset (DLMO) as an indicator of circadian timing was determined from five hourly saliva samples obtained before sleep onset. Fasting plasma total cholesterol, triglycerides, high density lipoprotein cholesterol, and low density lipoprotein cholesterol were assayed. The sleep parameters, DLMO and lipid profiles were compared between the two groups. For these measures, receiver operating characteristic (ROC) analysis was performed to assess the usefulness of discriminating between the aMCI and NC.

Results
There were no significant differences in sleep parameters, DLMO and lipid profiles between the aMCI and NC groups. The bedtime and sleep onset were derived as indicators for discriminating aMCI (p=0.003 and p=0.054, respectively). The area under the ROC for bedtime was 0.861(cut-off scores ≥ 22:02, sensitivity= 0.76, specificity=0.75).

Conclusion
We did not reveal the usefulness of the DLMO and lipid profiles for identifying aMCI. However, we found that the bedtime had good discrimination power between aMCI and cognitively normal elderly, suggesting later sleep habits would be associated with the presence of aMCI in the elderly.

Support (if any)
Basic Science Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Science and ICT (2020R1F1A1050416); Research Funds from the Institute of Medical Science, Chosun University, Republic of Korea, 2022.
0907 Macro and microarchitectural sleep features in Alzheimer’s dementia and mild cognitive impairment in a large clinical cohort
Authors: Zheng Kevin , Little David , Laberinto Kim , Jaiyeola A J , Sadeghi Kolia , Tjiptarto Nurkurniati , Arslan Alex , Martin Ciara , Patino Angelica , Kleinschmidt Dave , Alday Phillip , Puryear Corey , Westover M Brandon , Donoghue Jacob , Pathmanathan Jay 
Published: May 2023

Abstract

Introduction
Recent work has characterized polysomnographic (PSG) changes in Alzheimer’s Dementia (AD) that correlate with disease severity and precede clinical diagnosis, although these findings are limited by relatively small sample sizes and a lack of studies examining sleep microarchitecture. In this study we examined sleep macro- and microarchitectural features in large cohorts of patients with AD and mild cognitive impairment (MCI).

Methods
Using a database of over 15,000 clinical PSGs with associated clinical metadata, 125 and 173 subjects were identified with mild AD and MCI, respectively. 260 age and sex matched subjects without neurological disease were identified as healthy controls (HC). Sleep staging results were based on AASM criteria, and micro-architectural features were assessed using an algorithm (Wake EEG Similarity Index, WESI) trained to predict state using spectral data from a unique healthy adult cohort.

Results
Sleep fragmentation was apparent in both the MCI and AD cohorts (relative to healthy controls), with AD subjects demonstrating substantially more severe PSG disturbances. Healthy controls demonstrated 400 minutes of total sleep time, in contrast to 374 minutes for MCI subjects and 362 minutes for AD subjects. Healthy subjects demonstrated 33 minutes of wake after sleep onset (WASO), compared to 60 and 67 minutes for MCI and AD subjects, respectively. As has been previously reported in smaller cohorts, wakeful bouts and N1 durations were substantially prolonged for AD and (to a lesser extent) MCI subjects, while N2, N3, and REM durations were reduced (with a pronounced reduction in AD N3 percentage). Sleep microarchitectural features assessed using WESI demonstrated that AD and MCI subjects had markedly higher relative wakefulness in all sleep stages except for N3, which showed the same sleep depth as HC.

Conclusion
We confirm increased sleep fragmentation and loss of deeper sleep stages that correlate to disease severity. Spectral features of all sleep stages except N3 appear more wakeful in AD and MCI subjects, suggesting microarousals or impaired sleep maintenance contribute to sleep pathology. While N3 duration was markedly reduced, depth of sleep as measured by the WESI algorithm was comparable between populations. PSG findings offer promise as early diagnostic and therapeutic targets.

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0911 Sleep Duration Is Associated with Subclinical Carotid Plaque Burden
Authors: Agudelo Christian , Ramos Alberto , Gardener Hannah , Cheung Ken , Elkind Mitchell , Sacco Ralph , Rundek Tatjana 
Published: May 2023

Abstract

Introduction
Sleep duration is associated with stroke risk and is one of eight essential components of cardiovascular health according to the American Heart Association. As stroke disproportionately burdens Black and Hispanic populations in the United States, we hypothesized that long and short sleep duration would be associated with greater subclinical carotid atherosclerosis, a precursor of stroke, in the racially and ethnically diverse Northern Manhattan Study (NOMAS).

Methods
NOMAS is a study of community-dwelling adults that recorded self-reported nightly sleep duration and daytime sleepiness. Carotid plaque presence, total plaque area, and intima media thickness were measured by ultrasound. Linear and logistic regression models examined the cross-sectional associations of sleep duration groups (primary exposure) or daytime sleepiness (secondary exposure) with measures of carotid atherosclerosis. Models adjusted for age, sex, race/ethnicity, education, health insurance, smoking, alcohol use, physical activity, body mass index, hypertension, diabetes, hypercholesterolemia, and cardiac disease.

Results
The sample (n=1,553) had a mean age of 64.7±8.5 years and was 61.9% female, 64.8% Hispanic and 18.2% non-Hispanic Black. Of the sample, 55.6% had carotid plaque, 22.3% reported nightly short sleep (&lt; 6 hours), 66.6% intermediate sleep (≥6 and &lt; 9 hours), and 11.1% long sleep (≥9 hours). Compared to intermediate sleep, long sleep was associated with greater odds of carotid plaque presence (OR 1.5, 95% CI 1.1-2.2) and greater odds of plaque within the tertile of largest plaque area (OR 1.7, 95% CI 1.0-2.7), each relative to plaque absence after full covariate adjustment. Short sleep was associated with lower odds of plaque within the tertile of largest carotid plaque area but was not associated with plaque presence. Daytime sleepiness was not associated with carotid measures.

Conclusion
Subclinical carotid atherosclerosis may mediate previously observed relationships between long sleep and increased stroke risk.

Support (if any)
This work was supported by the National Institutes of Health through grants from the National Institute of Neurological Disorders and Stroke (R37 NS029993, PI: Sacco/Elkind) and the National Institute on Aging (R01 AG067568, PI: Ramos), and by The Evelyn F. McKnight Brain Institute.
0912 Striatal atrophy and clinical correlates in REM sleep behavior disorder
Authors: Tang Shi , Huang Bei , Wang Jing , Zhou Li , Chau Steven Wai Ho , Chan Joey , Liu Yaping , Wing Yun Kwok 
Published: May 2023

Abstract

Introduction
Idiopathic/isolated REM sleep behavior disorder (iRBD) is regarded as the most specific prodromal stage of ⍺-synucleinopathies including Parkinson’s disease (PD). Striatal dopamine dysfunction is a pathological hallmark in PD, which has been similarly reported in iRBD as a sensitive marker for detecting early ⍺-synucleinopathies. In contrary, although there is a broad consensus that patients with PD have striatal volumes reduction, studies in iRBD are relatively scarce and inconsistent. In this study, we aim to investigate the difference of striatal nuclei volumes between iRBD and controls and their correlation with clinical presentations.

Methods
Altogether 105 patients (mean age=68.19, male 76.2%) with polysomnography-confirmed iRBD and 85 age and sex comparable controls (mean age=66.74, male 64.7%) underwent 3-tesla MRI and clinical assessments. FreeSurfer automatic segmentation pipelines measured the size of bilateral striatal nuclei including caudate, putamen, pallidum and accumbens area. The comparisons of the volume of individual striatal nucleus were made between iRBD and controls with age, sex, handness, and total intracranial volume as covariates. Correlations were performed to investigate the association between striatal nuclei volume and clinical domains in motor (Unified Parkinson’s Disease Rating Scale, Part III), cognitive (Montreal Cognitive Assessment, MoCA), visual (pareidolia), autonomic function (Scales for Outcomes in Parkinson’s Disease - Autonomic Dysfunction, SCOPA-AUT) and mood symptoms (Hospital Anxiety and Depression Scale).

Results
There were smaller volumes in the bilateral putamen (t=-2.13/-2.32, p=0.03/0.02, left/right side respectively) and accumbens area (t=-2.58/-2.07, p=0.01/0.04, left/right side respectively) in iRBD comparing to controls. In addition, MoCA score was significantly positively correlated with the volumes of bilateral putamen (r=0.212/0.213, p=0.032/0.033), while pareidolia score was significantly negatively correlated with volumes of bilateral putamen (r=-0.205/-0.233, p=0.039/0.018,) and accumbens area (r=-0.249/-0.279, p=0.012/0.004, left/right respectively). The SCOPA-AUT score was significantly negatively correlated with volumes of the left putamen (r=-0.286, p=0.014) and the left accumbens area (r=-0.245, p=0.037). No other correlations with mood and motor features were found.

Conclusion
In this large case-control study, PD-like striatal atrophy was already present in patients with iRBD, which were significantly associated with worse cognitive performance, visual and autonomic dysfunction.

Support (if any)
This study was supported by Hong Kong Health and Medical Research Fund, 08191416.
0913 Evaluation of a Single-Session Sleep Intervention for Air Force Trainees
Authors: Ellis Jordan , Burns Rosemary Estevez , Mallawaarachchi Indika , Qun Xin Wang , Cassidy Daniel , Aycock Chase , Krunnfusz Andrea , Jones John , Klesges Robert , Talcott Wayne 
Published: May 2023

Abstract

Introduction
Sleep insufficiency is highly prevalent in military personnel and has detrimental impacts on operational readiness and health. Sleep health across this population does not appear to have improved despite targeted health promotion programs and efforts to bolster evidence-based tertiary care for sleep disorders. There is some evidence that problematic sleep may emerge in early military training environments and persist throughout a service member’s career. Approximately 37,000 personnel complete Air Force (USAF) technical training each year to learn job-specific skills. The purpose of the present study was to assess the effectiveness of a single-session, group-based sleep intervention in USAF Technical Training.

Methods
A brief (40-min) intervention incorporating behavioral sleep medicine interventions and motivational interviewing was developed and tailored for the target population. Three military units were assigned to receive either the brief sleep intervention (n = 203) or an active control group receiving a brief tobacco intervention (n = 118). Students were queried at two weeks post-intervention to assess their sleep time and quality using the Self-Assessment of Sleep Survey-Split (SASS-Y). Participants included 321 USAF technical school students (Mean age = 21), and the majority identified as male (82%), White (67%), and non-Hispanic (75%). Propensity-score-weighted multivariable logistic regression was utilized to compare the sleep outcomes between intervention and control groups at follow-up.

Results
At follow-up, students in the sleep intervention were significantly more likely to report sleeping &gt; 6 hours per night on weekdays (OR = 1.49, p &lt; .001) and more likely to endorse “Good” or “Very Good” sleep quality (OR = 1.50, p = .032) as compared to the control group. Follow-up results also showed that 69.2% of students in the sleep intervention group reported having engaged in the self-selected positive sleep ‘Action Step’ they chose and wrote down during the intervention.

Conclusion
This is, to our knowledge, the first study to design and test a brief motivational interviewing and behavioral sleep intervention in USAF technical training. Results suggest that a single-session, group-level intervention can promote behavioral changes and improve sleep health. Future efforts should consider low-touch additions (e.g., text messaging) to support the durability of intervention effects.

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