Temperature-Dependent Upregulation of Per2 Protein Expression Is Mediated by eIF2α Kinases PERK and PKR through PI3K Activation.

Temperature-dependent translational control of the core clock gene Per2 plays an important role in establishing entrainment of the circadian clock to physiological body temperature cycles. Previously, we found an involvement of the phosphatidylinositol 3-kinase (PI3K) in causing Per2 protein expression in response to a warm temperature shift (WTS) within a physiological range (from 35 to 38.5 °C). However, signaling pathway mediating the Per2 protein expression in response to WTS is only sparsely understood. Additional factor(s) other than PI3K remains unknown. Here we report the identification of eukaryotic initiation factor 2α (eIF2α) kinases, protein kinase R (PKR) and PKR-like endoplasmic reticulum kinase (PERK), as a novel mediator of WTS-dependent Per2 protein expression. Canonically, eIF2α has been regarded as a major downstream target of PERK and PKR. However, we found that PERK and PKR mediate WTS response of Per2 in a manner not involving eIF2α. We observed that PERK and PKR serve as an upstream regulator of PI3K rather than eIF2α in the context of WTS-dependent Per2 protein expression. There have been studies reporting PI3K activation occurring depending on PERK and PKR, while its physiological contribution has remained elusive. Our finding therefore not only helps to enrich the knowledge of how WTS affects Per2 protein expression but also extends the region of cellular biology involving the PERK/PKR-mediated PI3K activation to include entrainment-mechanism of the circadian clock.

Coexistence of periodic limb movements during sleep with restless legs syndrome and its association with hypertension in Japanese patients.

BACKGROUND: Caucasian patients with restless legs syndrome (RLS) frequently exhibit periodic limb movements during sleep (PLMS), which may increase the risk of hypertension. We evaluated the positivity rate of PLMS and factors associated with positivity in Japanese patients with RLS, and tested whether the complications of PLMS are associated with the presence of hypertension. METHODS: We retrospectively investigated polysomnographic data and the presence or absence of hypertension in patients with RLS. Patients with systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg or those taking antihypertensive medication were categorized as the group with hypertension. RESULTS: Among 468 patients, 200 (42.7%) had periodic limb movement index (PLMI) values ≥ 15/h and 108 (23.1%) met the criteria of positivity for hypertension. Multiple logistic regression analysis revealed that only higher age was significantly associated with PLMI values ≥ 15/h. Multiple linear regression analyses of factors associated with an increased PLMI also showed that increased PLMI was significantly correlated with higher age and male sex, but not with the international restless legs scale scores. Multiple logistic regression analysis also revealed that higher age and body mass index, not PLMI values ≥ 15/h, were significantly associated with the presence of hypertension. CONCLUSION: The PLMS-positivity rate may be lower in Japanese patients with RLS than in Caucasian patients, and it increases with age and male sex, but not with the severity of the disorder. Furthermore, PLMS complications were not associated with the risk of hypertension in Japanese patients with RLS.

Extracellular vesicles contain filamentous alpha-synuclein and facilitate the propagation of Parkinson's pathology.

Parkinson's disease (PD) is characterized by the pathological deposition of a-synuclein (a-syn) inclusions, known as Lewy bodies/neurites. Emerging evidence suggests that extracellular vesicles (EVs) play a role in facilitating the spreading of Lewy pathology between the peripheral nervous system and the central nervous system. We analyzed serum EVs obtained from patients with PD (n = 142), multiple system atrophy (MSA) (n = 18), progressive supranuclear palsy (PSP) (n = 28), rapid eye movement sleep behavior disorder (n = 31), and controls (n = 105). While we observed a significant reduction in the number of EVs in PD compared to controls (p = 0.006), we also noted a substantial increase in filamentous α-synuclein within EVs in PD compared to controls (p < 0.0001), MSA (0.012), and PSP (p = 0.03). Further analysis unveiled the role of EVs in facilitating the transmission of filamentous α-synuclein between neurons and from peripheral blood to the CNS. These findings highlight the potential utility of serum α-synuclein filaments within EVs as diagnostic markers for synucleinopathies and underscore the significance of EVs in promoting the dissemination of filamentous α-synuclein throughout the entire body.

Nightmare frequency is a risk factor for suicidal ideation during the COVID-19 pandemic.

The association between nightmare frequency (NMF) and suicidal ideation (SI) is well known, yet the impact of the COVID-19 pandemic on this relation is inconsistent. This study aimed to investigate changes in NMF, SI, and their association during the COVID-19 pandemic. Data were collected in 16 countries using a harmonised questionnaire. The sample included 9328 individuals (4848 women; age M[SD] = 46.85 [17.75] years), and 17.60% reported previous COVID-19. Overall, SI was significantly 2% lower during the pandemic vs. before, and this was consistent across genders and ages. Most countries/regions demonstrated decreases in SI during this pandemic, with Austria (-9.57%), Sweden (-6.18%), and Bulgaria (-5.14%) exhibiting significant declines in SI, but Italy (1.45%) and Portugal (2.45%) demonstrated non-significant increases. Suicidal ideation was more common in participants with long-COVID (21.10%) vs. short-COVID (12.40%), though SI did not vary by COVID-19 history. Nightmare frequency increased by 4.50% during the pandemic and was significantly higher in those with previous COVID-19 (14.50% vs. 10.70%), during infection (23.00% vs. 8.10%), and in those with long-COVID (18.00% vs. 8.50%). The relation between NMF and SI was not significantly stronger during the pandemic than prior (rs = 0.18 vs. 0.14; z = 2.80). Frequent nightmares during the pandemic increased the likelihood of reporting SI (OR = 1.57, 95% CI 1.20-2.05), while frequent dream recall during the pandemic served a protective effect (OR = 0.74, 95% CI 0.59-0.94). These findings have important implications for identifying those at risk of suicide and may offer a potential pathway for suicide prevention.

Efficacy and safety of lascufloxacin for nursing- and healthcare-associated pneumonia: A single-arm, open-label clinical trial.

BACKGROUND: Nursing- and healthcare-associated pneumonia (NHCAP) constitutes most of the pneumonia in elderly patients including aspiration pneumonia in Japan. Lascufloxacin (LSFX) possesses broad antibacterial activity against respiratory pathogens, such as Streptococcus spp. And anaerobes inside the oral cavity. However, the efficacy and safety of LSFX in NHCAP treatment remains unknown. We aimed to evaluate the efficacy and safety of LSFX tablets in the treatment of patients with NHCAP. METHODS: In this single-arm, open-label, uncontrolled study, LSFX was administered to patients with NHCAP at 24 facilities. The study participants were orally administered 75 mg LSFX once daily for 7 days. The primary endpoint was the clinical efficacy at the time of test of cure (TOC). The secondary endpoints included clinical efficacy at the time of end of treatment (EOT), early clinical efficacy, microbiological efficacy, and safety analysis. RESULT: During the study period, 75 patients provided written informed consent to participate and were included. Finally, 56 and 71 patients were eligible for clinical efficacy and safety analyses, respectively. The median age of the patients was significantly high at 86 years. All patients were classified as having moderate disease severity using the A-DROP scoring system. LSFX tablets demonstrated high efficacy rates of 78.6 % at TOC and 89.3 % at EOT. The risk factors for resistant bacteria or aspiration pneumonia did not affect clinical efficacy. No severe adverse events associated with the study drugs were observed. CONCLUSION: Oral LSFX is an acceptable treatment option for moderate NHCAP in elderly patients who can take oral medications.

Habitual short sleepers with pre-existing medical conditions are at higher risk of Long COVID.

STUDY OBJECTIVES: Preliminary evidence suggests that the risk of Long COVID is higher among people with pre-existing medical conditions. Based on its proven adjuvant role in immunity, habitual sleep duration may alter the risk of developing Long COVID. The objective of this study was to determine whether the odds of Long COVID are higher among those with pre-existing medical conditions, and whether the strength of this association varies by habitual sleep duration. METHODS: Using data from 13,461 respondents from 16 countries who participated in the 2021 survey-based International COVID Sleep Study II (ICOSS II), we studied the associations between habitual sleep duration, pre-existing medical conditions, and Long COVID. RESULTS: Of 2,508 individuals who had COVID-19, 61% reported at least 1 Long COVID symptom. Multivariable logistic regression analysis showed that the risk of having Long COVID was 1.8-fold higher for average-length sleepers (6-9 h/night) with pre-existing medical conditions compared with those without pre-existing medical conditions (adjusted odds ratio [aOR] 1.84 [1.18-2.90]; P = .008). The risk of Long COVID was 3-fold higher for short sleepers with pre-existing medical conditions (aOR 2.95 [1.04-8.4]; P = .043) and not significantly higher for long sleepers with pre-existing conditions (aOR 2.11 [0.93-4.77]; P = .073) compared with average-length sleepers without pre-existing conditions. CONCLUSIONS: Habitual short nighttime sleep duration exacerbated the risk of Long COVID in individuals with pre-existing conditions. Restoring nighttime sleep to average duration represents a potentially modifiable behavioral factor to lower the odds of Long COVID for at-risk patients. CITATION: Berezin L, Waseem R, Merikanto I, et al. Habitual short sleepers with pre-existing medical conditions are at higher risk of long COVID. J Clin Sleep Med. 2024;20(1):111-119.

The association of insomnia with long COVID: An international collaborative study (ICOSS-II).

OBJECTIVE: There is evidence of a strong association between insomnia and COVID-19, yet few studies have examined the relationship between insomnia and long COVID. This study aimed to investigate whether COVID-19 patients with pre-pandemic insomnia have a greater risk of developing long COVID and whether long COVID is in turn associated with higher incident rates of insomnia symptoms after infection. METHODS: Data were collected cross-sectionally (May-Dec 2021) as part of an international collaborative study involving participants from 16 countries. A total of 2311 participants (18-99 years old) with COVID-19 provided valid responses to a web-based survey about sleep, insomnia, and health-related variables. Log-binomial regression was used to assess bidirectional associations between insomnia and long COVID. Analyses were adjusted for age, sex, and health conditions, including sleep apnea, attention and memory problems, chronic fatigue, depression, and anxiety. RESULTS: COVID-19 patients with pre-pandemic insomnia showed a higher risk of developing long COVID than those without pre-pandemic insomnia (70.8% vs 51.4%; adjusted relative risk [RR]: 1.33, 95% confidence interval [CI]: 1.07-1.65). Among COVID-19 cases without pre-pandemic insomnia, the rates of incident insomnia symptoms after infection were 24.1% for short COVID cases and 60.6% for long COVID cases (p < .001). Compared with short COVID cases, long COVID cases were associated with an increased risk of developing insomnia symptoms (adjusted RR: 2.00; 95% CI: 1.50-2.66). CONCLUSIONS: The findings support a bidirectional relationship between insomnia and long COVID. These findings highlight the importance of addressing sleep and insomnia in the prevention and management of long COVID.

Associations between changes in habitual sleep duration and lower self-rated health among COVID-19 survivors: findings from a survey across 16 countries/regions.

BACKGROUND: Self-rated health (SRH) is widely recognized as a clinically significant predictor of subsequent mortality risk. Although COVID-19 may impair SRH, this relationship has not been extensively examined. The present study aimed to examine the correlation between habitual sleep duration, changes in sleep duration after infection, and SRH in subjects who have experienced SARS-CoV-2 infection. METHODS: Participants from 16 countries participated in the International COVID Sleep Study-II (ICOSS-II) online survey in 2021. A total of 10,794 of these participants were included in the analysis, including 1,509 COVID-19 individuals (who reported that they had tested positive for COVID-19). SRH was evaluated using a 0-100 linear visual analog scale. Habitual sleep durations of < 6 h and > 9 h were defined as short and long habitual sleep duration, respectively. Changes in habitual sleep duration after infection of ≤ -2 h and ≥ 1 h were defined as decreased or increased, respectively. RESULTS: Participants with COVID-19 had lower SRH scores than non-infected participants, and those with more severe COVID-19 had a tendency towards even lower SRH scores. In a multivariate regression analysis of participants who had experienced COVID-19, both decreased and increased habitual sleep duration after infection were significantly associated with lower SRH after controlling for sleep quality (ß = -0.056 and -0.058, respectively, both p < 0.05); however, associations between current short or long habitual sleep duration and SRH were negligible. Multinomial logistic regression analysis showed that decreased habitual sleep duration was significantly related to increased fatigue (odds ratio [OR] = 1.824, p < 0.01), shortness of breath (OR = 1.725, p < 0.05), diarrhea/nausea/vomiting (OR = 2.636, p < 0.01), and hallucinations (OR = 5.091, p < 0.05), while increased habitual sleep duration was significantly related to increased fatigue (OR = 1.900, p < 0.01). CONCLUSIONS: Changes in habitual sleep duration following SARS-CoV-2 infection were associated with lower SRH. Decreased or increased habitual sleep duration might have a bidirectional relation with post-COVID-19 symptoms. Further research is needed to better understand the mechanisms underlying these relationships for in order to improve SRH in individuals with COVID-19.

The optimal dose of Ramelteon for the better treatment adherence of delayed sleep-wake phase disorder: a dropout rate study.

Background: Evidence regarding the effectiveness of melatonin receptor agonists in treating delayed sleep-wake phase disorder (DSWPD) remains limited. This study aimed to determine the optimal dose of ramelteon, a melatonin receptor agonist, for the better treatment adherence of DSWPD. Methods: The patients who were diagnosed definitely as having DSWPD by board-certified physicians specialized in sleep medicine and started to receive strategically timed ramelteon medications after the diagnosis were included. Data on the initial ramelteon dose and follow-up duration (up to 24 months) were collected retrospectively. Patients with treatment discontinuation, changes in ramelteon dose, or the addition of other sleep-related medications were considered dropouts. Kaplan-Meier estimates, log-rank tests, and Cox regression analyses were performed. Results: Overall, 373 patients were analyzed. The findings revealed that the 2 mg dose of ramelteon was associated with a lower dropout rate compared to the other doses (8 mg, 4 mg, and 1 mg). The dropout rate for the 2 mg group was estimated to have a hazard ratio (HR) of 0.5762 when compared with the 8 mg dose group. Sex did not reveal a significant HR, whereas older age exhibited a small but significant HR (0.9858). Conclusion: For achieving better adherence, a dosing regimen of strategically timed 2 mg ramelteon may be the best for the treatment of DSWPD. The therapeutic dose window for better adherence seems to center approximately 2 mg of ramelteon. Furthermore, caution should be exercised when treating younger patients to prevent dropouts.

Efficacy and safety of lemborexant in subjects previously treated with placebo for 6 months in a randomized phase 3 study.

OBJECTIVE/BACKGROUND: To examine the effects of lemborexant (LEM) 5 mg (LEM5) or LEM 10 mg (LEM10) following extended placebo treatment. This post-hoc analysis used subject-reported sleep outcomes data from a phase 3 trial. PATIENTS/METHODS: The subjects in these post-hoc analyses were randomized to placebo for 6 months (Time Period [TP]1) in Study E2006-G000-303 (SUNRISE-2; NCT02952820). Following placebo exposure, subjects were re-randomized to LEM5 or LEM10 for another 6 months (TP2). Subject-reported sleep outcomes derived from sleep diaries included sleep onset latency (sSOL), wake after sleep onset (sWASO), sleep efficiency (sSE), and total sleep time (sTST). Magnitude and change rate in parameters were assessed for 7 days before/after initial randomization to placebo and 7 days before/after re-randomization to LEM (6 months later). Month 6 placebo non-responders were assessed for LEM response in TP2 using predetermined responder definitions. Safety was monitored throughout the study. RESULTS: Overall, 321 subjects received placebo; 258 re-randomized subjects received LEM5 (n = 133) and LEM10 (n = 125). Subjective sleep outcomes improved during TP1 with approximately 62 subjects (∼20%) exhibiting a sustained placebo response. Upon re-randomization to LEM, all measures showed an additional incremental benefit, most prominently in sSOL and sTST. Among Month 6 placebo non-responders, 11%-15% subsequently responded to LEM as assessed at Month 12. The safety profile was similar between treatment periods and treatment groups. CONCLUSIONS: These data suggest that even when insomnia symptoms have improved over time with placebo treatment, additional and sustained clinical gains in sleep outcomes are possible with active treatment using lemborexant.

Oral Orexin Receptor 2 Agonist in Narcolepsy Type 1.

BACKGROUND: Narcolepsy type 1 is caused by severe loss or lack of brain orexin neuropeptides. METHODS: We conducted a phase 2, randomized, placebo-controlled trial of TAK-994, an oral orexin receptor 2-selective agonist, in patients with narcolepsy type 1. Patients with confirmed narcolepsy type 1 according to clinical criteria were randomly assigned to receive twice-daily oral TAK-994 (30 mg, 90 mg, or 180 mg) or placebo. The primary end point was the mean change from baseline to week 8 in average sleep latency (the time it takes to fall asleep) on the Maintenance of Wakefulness Test (range, 0 to 40 minutes; normal ability to stay awake, ≥20 minutes). Secondary end points included the change in the Epworth Sleepiness Scale (ESS) score (range, 0 to 24, with higher scores indicating greater daytime sleepiness; normal, <10) and the weekly cataplexy rate. RESULTS: Of the 73 patients, 17 received TAK-994 at a dose of 30 mg twice daily, 20 received 90 mg twice daily, 19 received 180 mg twice daily, and 17 received placebo. The phase 2 trial and an extension trial were terminated early owing to hepatic adverse events. Primary end-point data were available for 41 patients (56%); the main reason for missing data was early trial termination. Least-squares mean changes to week 8 in average sleep latency on the MWT were 23.9 minutes in the 30-mg group, 27.4 minutes in the 90-mg group, 32.6 minutes in the 180-mg group, and -2.5 minutes in the placebo group (difference vs. placebo, 26.4 minutes in the 30-mg group, 29.9 minutes in the 90-mg group, and 35.0 minutes the 180-mg group; P<0.001 for all comparisons). Least-squares mean changes to week 8 in the ESS score were -12.2 in the 30-mg group, -13.5 in the 90-mg group, -15.1 in the 180-mg group, and -2.1 in the placebo group (difference vs. placebo, -10.1 in the 30-mg group, -11.4 in the 90-mg group, and -13.0 in the 180-mg group). Weekly incidences of cataplexy at week 8 were 0.27 in the 30-mg group, 1.14 in the 90-mg group, 0.88 in the 180-mg group, and 5.83 in the placebo group (rate ratio vs. placebo, 0.05 in the 30-mg group, 0.20 in the 90-mg group, and 0.15 in the 180-mg group). A total of 44 of 56 patients (79%) receiving TAK-994 had adverse events, most commonly urinary urgency or frequency. Clinically important elevations in liver-enzyme levels occurred in 5 patients, and drug-induced liver injury meeting Hy's law criteria occurred in 3 patients. CONCLUSIONS: In a phase 2 trial involving patients with narcolepsy type 1, an orexin receptor 2 agonist resulted in greater improvements on measures of sleepiness and cataplexy than placebo over a period of 8 weeks but was associated with hepatotoxic effects. (Funded by Takeda Development Center Americas; TAK-994-1501 and TAK-994-1504 ClinicalTrials.gov numbers, NCT04096560 and NCT04820842.).

Reliability and validity of the Japanese version of the Ullanlinna Narcolepsy Scale and Swiss Narcolepsy Scale for screening Japanese individuals with narcolepsy type 1.

OBJECTIVE: To validate the Japanese versions of the Ullanlinna Narcolepsy Scale (J-UNS) and Swiss Narcolepsy Scale (J-SNS) for screening narcolepsy in the Japanese population and to discuss strategies for their use in hypersomniac individuals. METHODS: We selected 451 outpatients with excessive daytime sleepiness (EDS) already diagnosed according to the International Classification of Sleep Disorders third edition. They responded to both scales twice at 1-month intervals. After eliminating individuals who met the exclusion criteria, validity and reliability analyses were performed on 408 and 381 participants, respectively. RESULTS: Patients with narcolepsy type 1 (NT1) displayed higher J-UNS and lower J-SNS scores than those with NT2 and other sleep disorders. The intraclass correlation coefficients and weighted κ coefficient for scale scores in the total participants and patients with NT1 were ≥0.70 and ≥ 0.40, respectively, indicating high reliability. Furthermore, both the sensitivity and specificity of these scales upon using the original cut-off scores (14 for UNS and 0 for SNS) for detecting NT1 were 0.70 or ≥0.70, suggesting high validity. Additionally, the receiver operating characteristic curve analysis revealed that the best cut-off score did not change for the J-SNS but that for the J-UNS, it increased to 18. In our study, the scale's sensitivity and specificity changed from 96% to 82% and 58%-78%, respectively. CONCLUSIONS: Both scales revealed satisfactory screening abilities for NT1 in the Japanese population. However, it may be better to use J-UNS cut-off scores of 18 for a population with EDS.

Delayed sleep-wake phase disorder and its related sleep behaviors in the young generation.

Delayed sleep-wake phase disorder (DSWPD) is a sleep disorder in which the habitual sleep-wake timing is delayed, resulting in difficulty in falling asleep and waking up at the desired time. Patients with DSWPD frequently experience fatigue, impaired concentration, sleep deprivation during weekdays, and problems of absenteeism, which may be further complicated by depressive symptoms. DSWPD is typically prevalent during adolescence and young adulthood. Although there are no studies comparing internationally, the prevalence of DSWPD is estimated to be approximately 3% with little racial differences between Caucasians and Asians. The presence of this disorder is associated with various physiological, genetic and psychological as well as behavioral factors. Furthermore, social factors are also involved in the mechanism of DSWPD. Recently, delayed sleep phase and prolonged sleep duration in the young generation have been reported during the period of COVID-19 pandemic-related behavioral restrictions. This phenomenon raises a concern about the risk of a mismatch between their sleep-wake phase and social life that may lead to the development of DSWPD after the removal of these restrictions. Although the typical feature of DSWPD is a delay in circadian rhythms, individuals with DSWPD without having misalignment of objectively measured circadian rhythm markers account for approximately 40% of the cases, wherein the psychological and behavioral characteristics of young people, such as truancy and academic or social troubles, are largely involved in the mechanism of this disorder. Recent studies have shown that DSWPD is frequently comorbid with psychiatric disorders, particularly mood and neurodevelopmental disorders, both of which have a bidirectional association with the pathophysiology of DSWPD. Additionally, patients with DSWPD have a strong tendency toward neuroticism and anxiety, which may result in the aggravation of insomnia symptoms. Therefore, future studies should address the effectiveness of cognitive-behavioral approaches in addition to chronobiological approaches in the treatment of DSWPD.

Association between hypersomnolence and the COVID-19 pandemic: The International COVID-19 Sleep Study (ICOSS).

BACKGROUND: The COVID-19 pandemic and related restriction measures have affected our daily life, sleep, and circadian rhythms worldwide. Their effects on hypersomnolence and fatigue remain unclear. METHODS: The International COVID-19 Sleep Study questionnaire which included items on hypersomnolence such as excessive daytime sleepiness (EDS), and excessive quantity of sleep (EQS), as well as sociodemographic factors, sleep patterns, psychological symptoms, and quality of life was distributed in 15 countries across the world from May to September in 2020. RESULTS: Altogether responses from 18,785 survey participants (65% women, median age 39 years) were available for analysis. Only 2.8% reported having had COVID-19. Compared to before the pandemic, the prevalence of EDS, EQS, and fatigue increased from 17.9% to 25.5%, 1.6%-4.9%, and 19.4%-28.3% amid the pandemic, respectively. In univariate logistic regression models, reports of having a COVID-19 were associated with EQS (OR 5.3; 95%-CI 3.6-8.0), EDS (2.6; 2.0-3.4), and fatigue (2.8; 2.1-3.6). In adjusted multivariate logistic regression, sleep duration shorter than desired (3.9; 3.2-4.7), depressive symptoms (3.1; 2.7-3.5), use of hypnotics (2.3; 1.9-2.8), and having reported COVID-19 (1.9; 1.3-2.6) remained strong predictors of EDS. Similar associations emerged for fatigue. In the multivariate model, depressive symptoms (4.1; 3.6-4.6) and reports of having COVID-19 (2.0; 1.4-2.8) remained associated with EQS. CONCLUSIONS: A large increase in EDS, EQS, and fatigue occurred due to the COVID-19 pandemic, and especially in self-reported cases of COVID-19. These findings warrant a thorough understanding of their pathophysiology to target prevention and treatment strategies for long COVID condition.

Minimal upstream open reading frame of Per2 mediates phase fitness of the circadian clock to day/night physiological body temperature rhythm.

Body temperature in homeothermic animals does not remain constant but displays a regular circadian fluctuation within a physiological range (e.g., 35°C-38.5°C in mice), constituting a fundamental systemic signal to harmonize circadian clock-regulated physiology. Here, we find the minimal upstream open reading frame (uORF) encoded by the 5' UTR of the mammalian core clock gene Per2 and reveal its role as a regulatory module for temperature-dependent circadian clock entrainment. A temperature shift within the physiological range does not affect transcription but instead increases translation of Per2 through its minimal uORF. Genetic ablation of the Per2 minimal uORF and inhibition of phosphoinositide-3-kinase, lying upstream of temperature-dependent Per2 protein synthesis, perturb the entrainment of cells to simulated body temperature cycles. At the organismal level, Per2 minimal uORF mutant skin shows delayed wound healing, indicating that uORF-mediated Per2 modulation is crucial for optimal tissue homeostasis. Combined with transcriptional regulation, Per2 minimal uORF-mediated translation may enhance the fitness of circadian physiology.

Persistent short nighttime sleep duration is associated with a greater post-COVID risk in fully mRNA-vaccinated individuals.

Short nighttime sleep duration impairs the immune response to virus vaccination, and long nighttime sleep duration is associated with poor health status. Thus, we hypothesized that short (<6 h) and long (>9 h) nighttime sleepers have a higher post-COVID risk than normal nighttime sleepers, despite two doses of mRNA vaccine (which has previously been linked to lower odds of long-lasting COVID-19 symptoms). Post-COVID was defined as experiencing at least one core COVID-19 symptom for at least three months (e.g., shortness of breath). Multivariate logistic regression adjusting for age, sex, BMI, and other factors showed in 9717 respondents (age span 18-99) that two mRNA vaccinations lowered the risk of suffering from post-COVID by about 21% (p < 0.001). When restricting the analysis to double-vaccinated respondents (n = 5918), short and long sleepers exhibited a greater post-COVID risk than normal sleepers (adjusted OR [95%-CI], 1.56 [1.29, 1.88] and 1.87 [1.32, 2.66], respectively). Among respondents with persistent sleep duration patterns during the pandemic compared to before the pandemic, short but not long sleep duration was significantly associated with the post-COVID risk (adjusted OR [95%-CI], 1.59 [1.24, 2.03] and 1.18 [0.70, 1.97], respectively). No significant association between sleep duration and post-COVID symptoms was observed in those reporting positive SARS-CoV-2 test results (n = 538). Our findings suggest that two mRNA vaccinations against SARS-CoV-2 are associated with a lower post-COVID risk. However, this protection may be less pronounced among those sleeping less than 6 h per night. Our findings warrant replication in cohorts with individuals with confirmed SARS-CoV-2 infection.

The prevalence and associated factors of seasonal exacerbation of subjective symptoms in Japanese patients with restless legs syndrome.

OBJECTIVES: To elucidate the prevalence of seasonal exacerbation in patients with restless legs syndrome (RLS) and identify its associated factors. METHODS: We investigated the presence/absence of seasonal exacerbation of RLS by distributing self-administered questionnaires with an interval of three years. Patients who reported having seasonal exacerbation in both surveys were defined as having seasonal exacerbation. RLS severity was determined using the International Restless Legs Syndrome Rating Scale (IRLS). RESULTS: Among 180 patients, 89 reported having seasonal exacerbation in the first survey. Among them, only two reported not having seasonal exacerbation in the second survey; thus, 87 (48.3%) patients were considered to have a seasonal exacerbation. Although many of them (68 out of 87, 78.2%) experienced exacerbation in spring or summer, 19 out of 87 (21.8%) reported that their symptoms worsened in fall or winter. All the patients in this study had mild to moderate degrees of RLS severity according to the IRLS score. Multiple logistic regression analyses revealed that having a family history of RLS (p < 0.05) and moderate RLS (p < 0.001) were significantly associated with the presence of seasonal exacerbation. CONCLUSIONS: This study revealed that approximately half of all RLS patients had seasonal exacerbation of the symptoms and that about 80% of the exacerbation was observed during the spring/summer season. Moreover, seasonal exacerbation is likely to be present even in patients whose symptoms had been improved to moderate severity with pharmacological treatment.

Comparison of the treatment effectiveness between lemborexant and zolpidem tartrate extended-release for insomnia disorder subtypes defined based on polysomnographic findings.

STUDY OBJECTIVES: Patients with chronic insomnia may respond differently to therapeutic modalities. This study examined differences in response of individuals with 2 insomnia phenotypes-short sleep duration (I-SSD; < 6 hours) and normal sleep duration (I-NSD; ≥ 6 hours) determined by polysomnography-to treatment with lemborexant and zolpidem tartrate extended-release 6.25 mg (zolpidem ER), compared with placebo. METHODS: Study E2006-G000-304 (Study 304; SUNRISE-1; NCT02783729) was a global, randomized, double-blind, placebo, and active comparator-controlled, parallel-group study comparing lemborexant 5 and 10 mg in individuals aged ≥ 55 years with insomnia disorder. In this analysis, changes in subjective (self-reported) variables based on sleep diaries and objective variables based on polysomnographs were assessed after 1-month administration of study drugs. Data from participants with I-SSD and I-NSD were compared. RESULTS: In the I-SSD subgroup, both lemborexant doses provided significant benefit for sleep-onset latency (SOL), total sleep time (TST), and wake after sleep onset (WASO) vs placebo; zolpidem ER also provided significant benefit for TST and WASO, but not SOL, on both measures vs placebo. In the I-NSD subgroup, lemborexant and zolpidem ER provided significant benefit for TST and WASO vs placebo objectively but not subjectively; both doses of lemborexant provided significant benefit for SOL vs placebo subjectively, but not objectively. CONCLUSIONS: Both drugs, but lemborexant more consistently, showed subjective and objective benefits compared with placebo in participants with insomnia with objective short sleep duration. However, neither lemborexant nor zolpidem provided consistent benefits for participants with normal sleep duration on sleep-onset and sleep maintenance variables. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Study of the Efficacy and Safety of Lemborexant in Subjects 55 Years and Older With Insomnia Disorder (SUNRISE 1); URL: https://clinicaltrials.gov/ct2/show/record/NCT02783729; Identifier: NCT02783729. CITATION: Inoue Y, Nishida M, Kubota N, et al. Comparison of the treatment effectiveness between lemborexant and zolpidem tartrate extended-release for insomnia disorder subtypes defined based on polysomnographic findings. J Clin Sleep Med. 2023;19(3):519-528.