Narcolepsy type 1 (NT1) is associated with severe loss of orexin neurons and characterized by symptoms including excessive daytime sleepiness and cataplexy. Current medications indicated for NT1 often show limited efficacy, not addressing the full spectrum of symptoms, demonstrating a need for novel drugs. We discovered a parenteral orexin receptor 2 (OX2R) agonist, danavorexton, and an orally available OX2R agonist, TAK-994; both improving NT1 phenotypes in mouse models and individuals with NT1. However, danavorexton has limited oral availability and TAK-994 has a risk of off-target liver toxicity. To avoid off-target-based adverse events, a highly potent molecule with low effective dose is preferred. Here, we show that a novel OX2R-selective agonist, TAK-861 [N-{(2S,3R)-4,4-Difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3\',5\'-trifluoro[1,1\'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide], activates OX2R with a half-maximal effective concentration of 2.5 nM and promotes wakefulness at 1 mg/kg in mice and monkeys, suggesting ~ tenfold higher potency and lower effective dosage than TAK-994. Similar to TAK-994, TAK-861 substantially ameliorates wakefulness fragmentation and cataplexy-like episodes in orexin/ataxin-3 and orexin-tTA;TetO DTA mice (NT1 mouse models). Compared with modafinil, TAK-861 induces highly correlated brain-wide neuronal activation in orexin-tTA;TetO DTA mice, suggesting efficient wake-promoting effects. Thus, TAK-861 has potential as an effective treatment for individuals with hypersomnia disorders including narcolepsy, potentially with a favorable safety profile.

Background Narcolepsy is a chronic sleep disorder that is characterized by excessive daytime sleepiness and cataplexy. It has been increasingly diagnosed over the years, impacting productivity and employment rates. Awareness of healthcare providers is crucial for the early identification and management of this condition. Objectives This study assessed physicians\' knowledge of narcolepsy in the Makkah region of Saudi Arabia. Method This cross-sectional study was conducted from February to November 2023. An online self-administered questionnaire has been used to target physicians working in the Makkah region of Saudi Arabia. The utilized questionnaire assessed demographic and professional data as well as the participants\' knowledge of narcolepsy. Statistical analysis was performed using RStudio (R version 4.3.1.). Statistical differences in knowledge were assessed using Pearson\'s chi-squared and Fisher\'s exact tests. Factors associated with knowledge of narcolepsy were investigated through univariable and multivariable regression analyses expressed using beta coefficients and 95% confidence intervals (95% CIs). Statistical significance was considered at p < 0.05. Results A total of 226 physicians participated in this study. Male physicians (54.4%, n = 123), practicing in governmental hospitals (77.9%, n = 176) and residing in Makkah City (43.4%, n = 98) were predominant. Non-surgical specialties represented 73.5% (n = 166) of the sample. Around 81% (n = 184) of the participants were aware of narcolepsy, with a significant difference according to professional status (p = 0.045). The majority of physicians have correctly identified narcolepsy as a sleep disorder (78.3%, n = 177), but only 32.3% (n = 73) have identified its typical onset age group and recognized that there are two types of narcolepsy. Almost half of the respondents indicated a lack of knowledge about the diagnostic criteria for narcolepsy in the DSM-5 (52.2%, n = 118). Only 27.4% (n = 62) recognized the correct diagnostic criteria. Half of the sample (51.3%, n = 116) recognized the use of multiple sleep latency tests for the diagnosis. For factors associated with higher participants\' knowledge, non-surgical specialties showed significantly higher knowledge scores compared to surgical specialties (beta = 0.91, 95% CI, 0.13 to 1.7, p = 0.024). Conclusion This study has revealed a significant lack of knowledge about narcolepsy among physicians in Makkah region. This raises concerns about the timely identification, proper understanding, and accurate diagnosis of patients with narcolepsy. Adequate understanding of narcolepsy is crucial to avoid its misdiagnosis or delays in receiving appropriate treatment and support, ultimately impacting their quality of life.

My research has always focused on sleep, whether monitoring neural activity (microwires, c-Fos, calcium imaging), triggering it with optogenetics or pharmacologically (anandamide, cholinergic agonists), or measuring levels of endogenous sleep agents such as adenosine. A recurring theme of my research is to use new tools to find the sweet spot in the brain where the signal to sleep begins. My goal is to identify the circuit, determine whether it degrades with age or disease, and repair the circuit when it fails. I am deeply grateful to my mentors for introducing me to the science of sleep, to my students and colleagues for helping me in my quest, and to the NIH and VA Research for supporting the research. Because of the collective efforts of sleep researchers, the public is more aware of the importance of sleep to a healthy lifestyle.

UNASSIGNED: Excessive daytime sleepiness (EDS) can have a significant impact on health and quality of life but may remain undiagnosed due to low awareness and underestimation of the clinical impact of the symptoms. An online screening tool supported by media campaigns might increase awareness and help detect undiagnosed cases of EDS and narcolepsy. The aim of this study was to develop an online screening method, along with a media campaign focusing on EDS, and evaluate its feasibility.
UNASSIGNED: Online screening supported by a media campaign targeting young and middle-aged adults (18-45 years old) were developed and implemented over a period of 1 year starting from November 2022. The Epworth Sleepiness Scale was used to identify EDS, and the Swiss Narcolepsy Scale was used to identify narcolepsy. In addition, the data on sociodemographic characteristics, selected sleep and health indicators and lifestyle behaviors were collected to indicate the etiology of the EDS. Feasibility, e.g., implementation and practicality, was assessed by the response rate, response to the promotion strategy, time spent on the tool, sample characteristics, and the prevalence of identified EDS and narcolepsy cases.
UNASSIGNED: A total of 2,390 people opened the screening link; 568 of them completed the online screening (23.8%), and most of them (n = 437, 76.9%) left their contact data to receive feedback. We identified 171 (30.1%) respondents at risk of EDS and 61 (10.7%) at risk of narcolepsy. The mean time of the screening was 15 min.
UNASSIGNED: An online screening tool supported with a campaign seems to be a feasible way to increase awareness about EDS and prevent delayed detection of EDS cases.

Narcolepsy type 1 (NT1) is a unique central sleepiness disorder that affects individuals with excessive daytime sleepiness (EDS), cataplexy, sleep paralysis, and hypnagogic hallucinations. The etiology and pathogenesis of NT1 remains unclear, although some viral infections are thought to be related to NT1. This paper reports an unusual case of late-onset NT1 with human immunodeficiency virus (HIV) infection and antiretroviral therapy for five years. The relationship between HIV infection, immune, Immune reconstitution inflammatory syndrome (IRIS) and NT1 should be further investigated, as excessive daytime sleepiness is more common in HIV-infected patients than in the general population.

UNASSIGNED: Sleeping disorders were reported in many patients who took vaccines during previous pandemics. We aim to investigate the relationship between coronavirus disease 2019 (COVID-19) vaccines and the incidence of narcolepsy symptoms in the Jordanian population.
UNASSIGNED: We used a descriptive, cross-sectional, online self-administered survey conducted between December 2022 and May 2023. The survey targeted males and females above the age of 18 years who took any type of COVID-19 vaccine, had no chronic diseases, and had no sleep disorders prior to taking the vaccine. The survey was distributed via social media platforms.
UNASSIGNED: A total of 873 participants were included in this study, consisting of 44.4% males and 55.6% females, with the majority being in the 18-29 age group. Most participants (79.8%) received two vaccine doses, with the Pfizer vaccine being the most common. Nearly half of the participants reported excessive daytime sleepiness. Sleep paralysis and hypnagogic hallucinations were reported by a notable proportion of participants, but no significant differences were found among the vaccine types. Sleep attacks and fragmented nighttime sleep were associated with the number of vaccine doses received, suggesting a possible influence of the dose count on these symptoms. The presence of excessive daytime sleepiness, sudden loss of muscle tone, sleep paralysis, and hypnagogic hallucinations showed no significant association with the number of doses taken.
UNASSIGNED: We hypothesize a possible link between COVID-19 vaccination and the emergence of narcolepsy symptoms in Jordanian individuals. Additional investigations and continuous monitoring to determine the extent of the risk and uncover potential mechanisms behind this connection should be performed.

UNASSIGNED: This is a plain language summary of a published article in the journal Sleep. Narcolepsy is a sleep condition that has 2 different subtypes: narcolepsy type 1 and narcolepsy type 2. These are called NT1 and NT2 for short. Sodium oxybate (SXB) is approved to treat excessive daytime sleepiness (EDS) and cataplexy. People with NT1 and NT2 both have EDS, but cataplexy is only present in people with NT1. Limited information is available about how SXB works in people with NT2. This is because previous trials have included only people with NT1 or people with unspecified narcolepsy. For more than 20 years, the only available formulation of this medicine had to be given twice during the night. Many people with narcolepsy find that chronically waking up in the middle of the night for a second dose of SXB is disruptive to themselves or others in their household. People have also reported sleeping through alarm clocks, missing their second dose, and feeling worse the next day. Some people have accidentally taken the second dose too early, putting them at risk for serious adverse effects. These adverse effects may include slow breathing, low blood pressure, or sedation. The US Food and Drug Administration (FDA) approved a medicine called LUMRYZ™ (sodium oxybate) for extended-release oral suspension in May 2023. LUMRYZ is a once-nightly formulation of SXB (ON-SXB for short) and is taken as a single dose before bedtime. This medicine treats EDS and muscle weakness (also known as cataplexy) in people with narcolepsy. A clinical trial called REST-ON studied ON-SXB to find out if it was better at treating narcolepsy symptoms than a medicine with no active ingredients (placebo). This summary describes a study that tested whether ON-SXB was better than placebo at treating narcolepsy symptoms in people with NT1 or NT2.
UNASSIGNED: This study showed that compared to people who took placebo, people who took ON-SXB were able to stay awake longer during the day, felt less sleepy during the daytime, had less cataplexy, and had more improvements in their symptoms overall than people who took placebo.
UNASSIGNED: ON-SXB has been proven effective for people with NT1 or NT2. Unlike prior formulations of SXB, ON-SXB is taken once at bedtime, without requiring waking up in the middle of the night for a second dose.

BACKGROUND: Optimal measurement tools for problematic sleep inertia, common in some central disorders of hypersomnolence (CDH), have not yet been determined. We evaluated the performance of the Sleep Inertia Questionnaire (SIQ) in CDH, and how well it distinguished hypersomnolent groups from controls, and IH (idiopathic hypersomnia) from narcolepsy type 1 (NT1).
METHODS: This prospective, bi-centric study included 63 control, 84 IH, 16 NT1, 18 narcolepsy type 2 (NT2), and 88 subjective excessive daytime sleepiness (sEDS) participants, using ICSD-3 criteria. 126 (47.2 %) participants were on any medication at the time of SIQ completion. We assessed construct validity of SIQ scores, and sleep inertia duration (SID), and compared them across diagnoses, controlling for age and center. We derived cutpoints to distinguish hypersomnolent patients from controls and IH from NT1. Sensitivity analyses for depression, chronotype, and medication were performed.
RESULTS: The SIQ sum and composite score were significantly lower in controls than in other groups (p < 0.0001), demonstrating outstanding ability to distinguish patients from controls (AUCs 0.92), without differences among hypersomnolent groups. SID (AUC 0.76) was significantly shorter in controls than in all hypersomnolent groups except NT1, and was shorter in NT1 than in IH or sEDS. Optimal SIQ sum cutpoint was 42 (J = 0.71) for patients versus controls. Optimal SID cutpoint in distinguishing IH from NT1 was 25 min (J = 0.39).
CONCLUSIONS: The SIQ has excellent ability to distinguish hypersomnolent patients from healthy controls, after controlling for depression, eveningness, and medication. SID is best at distinguishing IH from NT1.

Tongkat Ali (TA), also known as Eurycoma longifolia, has been used as a traditional herbal medicine for anti-aging, evidenced by clinical trials presenting the beneficial effects on energy, fatigue, and mood disturbance. We have recently shown that TA supplementation dose-dependently enhances the rest-activity pattern in C57BL/6 mice. Since destabilization of wakefulness and sleep is one of the typical symptoms of not only the elderly but also narcolepsy, we performed sleep analysis with and without dietary TA extract supplementation in middle-aged (10-12 months old) wild-type (WT) and narcoleptic DTA mice. We found that TA supplementation enhanced diurnal rhythms of locomotion and temperature in a time-of-day-dependent manner in WT mice but attenuated in DTA mice. In WT mice, TA supplementation consolidated wakefulness with a long bout duration and led to less entries into the sleep state during the active period, while it consolidated NREM sleep with long bout duration during the resting period. Neither disturbed sleep and wake cycles nor cataplexy was sufficiently improved in DTA mice. EEG spectral analysis revealed that TA supplementation enhanced slow wave activity (SWA) at both delta and low delta frequencies (0.5-4.0 and 0.5-2.0 Hz) during the light period, suggesting TA extract may induce vigilance during the active period, which then elicits a rebound effect during the resting period. Interestingly, DTA mice also slightly, but significantly, increased SWA at low frequencies during the light period. Taken together, our results suggest that TA supplementation enhances the Yin-Yang balance of sleep, temperature, and locomotion in WT mice, while its efficacy is limited in narcoleptic mice.

Several pivotal differences in sleep and sleep disorders are recognized between women and men. This is not only due to changes in hormonal balance during women\'s reproductive life, such as in pregnancy and menopause. Women are more likely to report insomnia and non-specific symptoms of apneas, such as fatigue or mood disturbance, compared to men. Thus, it is important for clinicians and researchers to take sex and gender differences into account when addressing sleep disorders in order to acknowledge the biology unique to women. We present a narrative review that delves into the primary sleep disorders, starting from basic science, to explore the impact of gender differences on sleep and the current status of research on women\'s sleep health.