Transmission of COVID-19 in Nightlife, Household, and Health Care Settings in Tokyo, Japan, in 2020.

Importance: There have been few studies on the heterogeneous interconnection of COVID-19 outbreaks occurring in different social settings using robust, surveillance epidemiological data. Objectives: To describe the characteristics of COVID-19 transmission within different social settings and to evaluate settings associated with onward transmission to other settings. Design, Setting, and Participants: This is a case series study of laboratory-confirmed COVID-19 cases in Tokyo between January 23 and December 5, 2020, when vaccination was not yet implemented. Using epidemiological investigation data collected by public health centers, epidemiological links were identified and classified into 7 transmission settings: imported, nightlife, dining, workplace, household, health care, and other. Main Outcomes and Measures: The number of cases per setting and the likelihood of generating onward transmissions were compared between different transmission settings. Results: Of the 44 054 confirmed COVID-19 cases in this study, 25 241 (57.3%) were among male patients, and the median (IQR) age of patients was 36 (26-52) years. Transmission settings were identified in 13 122 cases, including 6768 household, 2733 health care, and 1174 nightlife cases. More than 6600 transmission settings were detected, and nightlife (72 of 380 [18.9%]; P < .001) and health care (119 [36.2%]; P < .001) settings were more likely to involve 5 or more cases than dining, workplace, household, and other settings. Nightlife cases appeared in the earlier phase of the epidemic, while household and health care cases appeared later. After adjustment for transmission setting, sex, age group, presence of symptoms, and wave, household and health care cases were less likely to generate onward transmission compared with nightlife cases (household: adjusted odds ratio, 0.03; 95% CI, 0.02-0.05; health care: adjusted odds ratio, 0.57; 95% CI, 0.41-0.79). Household settings were associated with intergenerational transmission, while nonhousehold settings mainly comprised transmission between the same age group. Among 30 932 cases without identified transmission settings, cases with a history of visiting nightlife establishments were more likely to generate onward transmission to nonhousehold settings (adjusted odds ratio, 5.30 [95% CI, 4.64-6.05]; P < .001) than those without such history. Conclusions and Relevance: In this case series study, COVID-19 cases identified in nightlife settings were associated with a higher likelihood of spreading COVID-19 than household and health care cases. Surveillance and interventions targeting nightlife settings should be prioritized to disrupt COVID-19 transmission, especially in the early stage of an epidemic.

Effects of paraxanthine and caffeine on sleep, locomotor activity, and body temperature in orexin/ataxin-3 transgenic narcoleptic mice.

STUDY OBJECTIVE: Caffeine, an adenosine A1 and A2a receptor antagonist, is a widely consumed stimulant and also used for the treatment of hypersomnia; however, the wake-promoting potency of caffeine is often not strong enough, and high doses may induce side effects. Caffeine is metabolized to paraxanthine, theobromine, and theophylline. Paraxanthine is a central nervous stimulant and exhibits higher potency at A1 and A2 receptors, but has lower toxicity and lesser anxiogenic effects than caffeine. DESIGN: We evaluated the wake-promoting efficacy of paraxanthine, caffeine, and a reference wake-promoting compound, modafinil, in a mice model of narcolepsy, a prototypical disease model of hypersomnia. Orexin/ataxin-3 transgenic (TG) and wild-type (WT) mice were subjected to oral administration (at ZT 2 and ZT14) of 3 doses of paraxanthine, caffeine, modafinil, or vehicle. RESULTS: Paraxanthine, caffeine, and modafinil significantly promoted wakefulness in both WT and narcoleptic TG mice and proportionally reduced NREM and REM sleep in both genotypes. The wake-promoting potency of 100 mg/kg p.o. of paraxanthine during the light period administration roughly corresponds to that of 200 mg/kg p.o. of modafinil. The wake-promoting potency of paraxanthine is greater and longer lasting than that of the equimolar concentration of caffeine, when the drugs were administered during the light period. The wake-promotion by paraxanthine, caffeine, and modafinil are associated with an increase in locomotor activity and body temperature. However, the higher doses of caffeine and modafinil, but not paraxanthine, induced hypothermia and reduced locomotor activity, thereby confirming the lower toxicity of paraxanthine. Behavioral evaluations of anxiety levels in WT mice revealed that paraxanthine induced less anxiety than caffeine did. CONCLUSIONS: Because it is also reported to provide neuroprotection, paraxanthine may be a better wake-promoting agent for hypersomnia associated with neurodegenerative diseases.

Biperiden-induced delirium model in rats: a behavioral and electroencephalographic study.

AIMS AND METHODS: In order to elucidate the neural mechanisms of delirium, we administered the anticholinergic drug, biperiden (40 mg/kg i.p.), to 10 adult male Wistar rats and examined the resulting polygraphic recordings, including electroencephalography (EEG), electrooculography (EOG), and electromyography (EMG), for 60 min following injection. EEG data were investigated quantitatively by power spectrum analyses using fast Fourier transformation. Ten male Wistar rats receiving saline (i.p.) were used as the control group. RESULTS: Treated rats demonstrated two types of alternating behavioral change: a hyperactive and hypoactive state. In the hyperactive state, rapid walking, excessive random sniffing, and retropulsion were observed, with EEG desynchronization (significantly increased alpha1 (8.0-10.0 Hz), alpha2 (10.0-13.0 Hz), and beta (13.0-30.0 Hz) power values), as well as EEG slowing (significantly increased delta (0.5-4.0 Hz) and theta1 (4.0-6.0 Hz) power values): significantly marked rapid eye movement, and increased EMG activity. In the hypoactive state, motor arrest and drowsiness were observed, with prominent EEG slowing (significantly increased delta and theta1 power values): significantly decreased rapid eye movement and moderately decreased EMG activity. On the other hand, the control group did not show any behavioral or polygraphic changes. CONCLUSIONS: The behavioral and polygraphic changes induced by biperiden administration in rats are similar to those of delirium in humans. Therefore, it is proposed that biperiden-treated rats are a good delirium model and the anticholinergic mechanism is one of the potent factors in the development of delirium in humans.

Chronic Powder Diet After Weaning Induces Sleep, Behavioral, Neuroanatomical, and Neurophysiological Changes in Mice.

The purpose of this study is to clarify the effects of chronic powder diet feeding on sleep patterns and other physiological/anatomical changes in mice. C57BL/6 male mice were divided into two groups from weaning: a group fed with solid food (SD) and a group fed with powder food (PD), and sleep and physiological and anatomical changes were compared between the groups. PD exhibited less cranial bone structure development and a significant weight gain. Furthermore, these PD mice showed reduced number of neurogenesis in the hippocampus. Sleep analysis showed that PD induced attenuated diurnal sleep/wake rhythm, characterized by increased sleep during active period and decreased sleep during rest period. With food deprivation (FD), PD showed less enhancement of wake/locomotor activity compared to SD, indicating reduced food-seeking behavior during FD. These results suggest that powder feeding in mice results in a cluster of detrimental symptoms caused by abnormal energy metabolism and anatomical/neurological changes.

Histamine from brain resident MAST cells promotes wakefulness and modulates behavioral states.

Mast cell activation and degranulation can result in the release of various chemical mediators, such as histamine and cytokines, which significantly affect sleep. Mast cells also exist in the central nervous system (CNS). Since up to 50% of histamine contents in the brain are from brain mast cells, mediators from brain mast cells may significantly influence sleep and other behaviors. In this study, we examined potential involvement of brain mast cells in sleep/wake regulations, focusing especially on the histaminergic system, using mast cell deficient (W/W(v)) mice. No significant difference was found in the basal amount of sleep/wake between W/W(v) mice and their wild-type littermates (WT), although W/W(v) mice showed increased EEG delta power and attenuated rebound response after sleep deprivation. Intracerebroventricular injection of compound 48/80, a histamine releaser from mast cells, significantly increased histamine levels in the ventricular region and enhanced wakefulness in WT mice, while it had no effect in W/W(v) mice. Injection of H1 antagonists (triprolidine and mepyramine) significantly increased the amounts of slow-wave sleep in WT mice, but not in W/W(v) mice. Most strikingly, the food-seeking behavior observed in WT mice during food deprivation was completely abolished in W/W(v) mice. W/W(v) mice also exhibited higher anxiety and depression levels compared to WT mice. Our findings suggest that histamine released from brain mast cells is wake-promoting, and emphasizes the physiological and pharmacological importance of brain mast cells in the regulation of sleep and fundamental neurobehavior.

Identification of QTLs involved in the development of amygdala kindling in the rat.

Amygdala kindling is useful for modeling human epilepsy development. It has been known that genetic factors are involved in the development of amygdala kindling. The purpose of this study was to identify the loci that are responsible for the development of amygdala kindling. To achieve this, rat strains from a LEXF/FXLE recombinant inbred (RI) strain panel were used. The phenotypes of amygdala kindling-related parameters for seven RI strains and parental LE/Stm and F344/Stm strains were determined. They included the afterdischarge threshold (ADT), the afterdischarge duration (ADD), and the kindling rate, an incidence of development of kindling. Quantitative trait loci (QTL) analysis was performed to identify linkage relationships between these phenotypes and 1,033 SNP markers. Although no significant differences in pre-kindling ADT and ADD were observed, a significant difference in the kindling rate was found for the LEXF/FXLE RI strain. Two QTLs for the amygdala kindling rate (Agkr1 and Agkr2) were identified on rat chromosome 2. These findings clearly prove the existence of genetic influences that are involved in kindling development and suggest that substantial genetic components contribute to the progression of partial seizures into generalized seizures.

Effects of levetiracetam on hippocampal kindling in Noda epileptic rats.

In order to clarify the seizure susceptibility of Noda epileptic rat (NER) and the antiepileptic effects of levetiracetam (LEV), we performed electrical hippocampal kindling in NERs compared with Wistar rats (experiment 1), and hippocampal kindling in NERs with LEV administration (experiment 2). In experiment 1, electrical stimulation was administered to the right dorsal hippocampus of NERs and Wistar rats once per day. In experiment 2, NERs were randomly assigned to group L (LEV administration) and C (saline administration). Following daily administration of LEV (240 mg/kg, i.p.) to group L and saline to group C, hippocampal kindling was performed from the 5th day of consecutive LEV or saline administration. As a result of experiment 1, all NERs exhibited stage 5 (falling) or stage 6 seizure (running/jumping, subsequent seizure) from the first electrical stimulation. In experiment 2, LEV suppressed development of hippocampal kindling, increased the afterdischarge threshold of the hippocampus and inhibited stage 6 seizures in NER. Although LEV prolonged the afterdischarge duration at the first stage 5 seizure significantly, there was a tendency to prolong the latency to generalization by LEV. These findings indicate that NER is susceptible not only to limbic seizures but also to brainstem seizures. Furthermore, LEV may have inhibitory effects not only on the hippocampus but also on other neuronal pathways to secondary generalization in this rat model.