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The pattern of sleep and circadian activity of the lesser mouse-deer (Tragulus kanchil) that is the smallest (body mass between 1.5 and 2.2 kg) representative of the basal group (Tragulidae) of even-toed ungulates which evolved 40-50 Ma were studied. In naturalistic conditions, a total of 30 days of full-day video of the animal behavior and 15 days of 24-h polysomnographic data were collected in 6 animals. The mouse-deer were active less than 20% of 24 h and were quiescent during 60-80% of the remaining time. Slow wave sleep (SWS) accounted for on average 49.7 ± 3.7% of 24 h and paradoxical (rapid eye movement, REM) sleep accounted for 1.7 ± 0.3% of 24 h. During the majority of SWS (87.0 ± 4.4%) the eyes were open. The most of SWS and REM sleep occurred during the daytime hours (9 a.m. to 4 p.m.) and in the first half of the night (8 p.m. to 2 a.m.); the animals were most active during twilight hours (4-6 a.m. and 6-7 p.m.). We suggest that the main features of sleep in the mouse-deer are largely determined by ecological factors, including environmental temperature and predation, as well as the size and physiology of the mouse-deer.

This is the first study estimating the ability of sea mammals to perceive and analyze information under the conditions of an almost complete sleep deprivation.

Female hypocretin knockout (Hcrt KO) mice have increased body weight despite decreased food intake compared to wild type (WT) mice. In order to understand the nature of the increased body weight, we carried out a detailed study of Hcrt KO and WT, male, and female mice. Female KO mice showed consistently higher body weight than WT mice, from 4 to 20 months (20-60%). Fat, muscle, and free fluid levels were all significantly higher in adult (7-9 months) as well as old (18-20 months) female KO mice compared to age-matched WT mice. Old male KO mice showed significantly higher fat content (150%) compared to age-matched WT mice, but no significant change in body weight. Respiratory quotient (-19%) and metabolic rates (-14%) were significantly lower in KO mice compared to WT mice, regardless of gender or age. Female KO mice had significantly higher serum leptin levels (191%) than WT mice at 18-20 months, but no difference between male mice were observed. Conversely, insulin resistance was significantly higher in both male (73%) and female (93%) KO mice compared to age- and sex-matched WT mice. We conclude that absence of the Hcrt peptide has gender-specific effects. In contrast, Hcrt-ataxin mice and human narcoleptics, with loss of the whole Hcrt cell, show weight gain in both sexes.

ObjectivesWe aimed to provide a consensus statement by the International Rapid Eye Movement Sleep Behavior Disorder Study Group (IRBD-SG) on devising controlled active treatment studies in rapid eye movement sleep behavior disorder (RBD) and devising studies of neuroprotection against Parkinson disease (PD) and related neurodegeneration in RBD.MethodsThe consensus statement was generated during the fourth IRBD-SG symposium in Marburg, Germany in 2011. The IRBD-SG identified essential methodologic components for a randomized trial in RBD, including potential screening and diagnostic criteria, inclusion and exclusion criteria, primary and secondary outcomes for symptomatic therapy trials (particularly for melatonin and clonazepam), and potential primary and secondary outcomes for eventual trials with disease-modifying and neuroprotective agents. The latter trials are considered urgent, given the high conversion rate from idiopathic RBD (iRBD) to Parkinsonian disorders (i.e., PD, dementia with Lewy bodies [DLB], multiple system atrophy [MSA]).ResultsSix inclusion criteria were identified for symptomatic therapy and neuroprotective trials: (1) diagnosis of RBD needs to satisfy the International Classification of Sleep Disorders, second edition, (ICSD-2) criteria; (2) minimum frequency of RBD episodes should preferably be ⩾2 times weekly to allow for assessment of change; (3) if the PD-RBD target population is included, it should be in the early stages of PD defined as Hoehn and Yahr stages 1-3 in Off (untreated); (4) iRBD patients with soft neurologic dysfunction and with operational criteria established by the consensus of study investigators; (5) patients with mild cognitive impairment (MCI); and (6) optimally treated comorbid OSA. Twenty-four exclusion criteria were identified. The primary outcome measure for RBD treatment trials was determined to be the Clinical Global Impression (CGI) efficacy index, consisting of a four-point scale with a four-point side-effect scale. Assessment of video-polysomnographic (vPSG) changes holds promise but is costly and needs further elaboration. Secondary outcome measures include sleep diaries; sleepiness scales; PD sleep scale 2 (PDSS-2); serial motor examinations; cognitive indices; mood and anxiety indices; assessment of frequency of falls, gait impairment, and apathy; fatigue severity scale; and actigraphy and customized bed alarm systems. Consensus also was established for evaluating the clinical and vPSG aspects of RBD. End points for neuroprotective trials in RBD, taking lessons from research in PD, should be focused on the ultimate goal of determining the performance of disease-modifying agents. To date no compound with convincing evidence of disease-modifying or neuroprotective efficacy has been identified in PD. Nevertheless, iRBD patients are considered ideal candidates for neuroprotective studies.ConclusionsThe IRBD-SG provides an important platform for developing multinational collaborative studies on RBD such as on environmental risk factors for iRBD, as recently reported in a peer-reviewed journal article, and on controlled active treatment studies for symptomatic and neuroprotective therapy that emerged during the 2011 consensus conference in Marburg, Germany, as described in our report.

Several behavioral and physiological adaptations have been developed in evolution of Pinnipeds allowing them to sleep both on land and in water. To date sleep has been examined in detail in eared and true seals (the families of Otariidae and Phocidae). The aim of this study was to examine sleep in another semiaquatic mammal - the walrus, which is the only extant representative of the family Odobenidae. Slow wave and paradoxical sleep (SWS and PS) in the examined walrus (2 year old female, weight 130 kg) averaged 19.4 ± 2.0 and 6.9 ± 1.1% of 24-h when on land, and 20.5 ± 0.8% of 24-h and 1.1 ± 0.6% when in water, respectively. The average duration of PS episode was 6.4 ± 0.6 min (maximum 23 min) when on land and 1.8 ± 0.1 min (maximum 3.3 min) when in water. In water, sleep occurred predominantly while the walrus submerged and lay on the bottom of the pool (89% of total sleep time). The walrus usually woke up while emerging to the surface for breathing. Most often EEG slow waves developed synchronously in both cortical hemispheres (90% of SWS time when on land and 97% when in water). Short episodes of interhemispheric EEG asymmetry usually coincided with brief opening of one eye. The pattern of sleep in the walrus was similar to the pattern of sleep in the Otariidae seals while on land (predominantly bilateral SWS, accompanied by regular breathing) and to the pattern of sleep in the Phocidae while in water (sleep during apneas both in depth and at the surface, interrupted by brief arousal when emerging for breathing).

Hypocretin (Hcrt) has been implicated in the control of motor activity and in respiration and cardiovascular changes. Loss of Hcrt in narcolepsy is linked to sleepiness and to cataplexy, a sudden loss of muscle tone which is triggered by sudden strong emotions. In the current study, we have compared the effects of treadmill running to yard play on cerebrospinal fluid (CSF) Hcrt level in normal dogs. We find that treadmill locomotion, at a wide range of speeds, does not increase Hcrt level beyond baseline, whereas yard play produces a substantial increase in Hcrt, even though both activities produce comparable increases in heart rate, respiration and body temperature. We conclude that motor and cardiovascular changes are not sufficient to elevate CSF levels of Hcrt and we hypothesize that the emotional aspects of yard play account for the observed increase in Hcrt.

Up to 30% of patients in primary care have occasional difficulty sleeping, and 10% of those may have a chronic sleep disorder.Causes of excessive daytime sleepiness (EDS) include poor sleep hygiene, sleep apnea, and narcolepsy.Long-term EDS is associated with lower quality of life, psychological disturbances, and increased cardiovascular disease.Structured behavioral and cognitive interventions can correct many cases of EDS.Pharmacotherapy includes the shortterm use of hypnotics or stimulants for EDS and modafinil for narcolepsy.An investigational hypocretin analog for narcolepsy shows potential for greater efficacy. [ABSTRACT FROM AUTHOR]

Jerome M. Siegel. PhD. is professor of psychiatry at the University of California. Los Angeles, former president of the Sleep Research Society and the recipient of Merit and Javits awards from the National Institutes of Health and the Distinguished Scientist award from the Sleep Research Society. His laboratory has made discoveries concerning the role of hypocretin in human narcolepsy and Parkinson's disease. He has studied the phytogeny of sleep as a clue to sleep function, discoveritjg that the primitive mammal platypus has rapid eye movement sleep and that marine mammals can go without extended periods of sleep for long periods without ill effects. [ABSTRACT FROM AUTHOR]

Objectives: This study tested the efficacy of an 8-week, culturally targeted community-based nutrition and physical activity promotion intervention, Fight Cancer with Fitness! (FCF).Methods: A randomized, controlled trial was conducted in a black-owned commercial gym in a sample of 366 predominantly overweight or obese, healthy African-American women.Results: Dietary quality as indexed by fruit and vegetable intake improved significantly in the intervention group compared to the control group at 12-month follow-up, and proportion of calories consumed as fat decreased in both groups.Conclusions: This individually targeted cancer prevention intervention produced beneficial effects on dietary quality that were sustained for at least 12 months. [ABSTRACT FROM AUTHOR]

Narcolepsy is mainly associated with excessive daytime sleepiness, but the characteristic feature is abnormal rapid eye movement (REM) sleep phenomena. REM sleep disturbances can manifest as cataplexy (in narcolepsy type 1), sleep paralysis, sleep-related hallucinations, REM sleep behavior disorder, abnormal dreams, polysomnographic evidence of REM sleep disruption with sleep-onset REM periods, and fragmented REM sleep. Characterization of REM sleep and related symptoms facilitates the differentiation of narcolepsy from other central hypersomnolence disorders and aids in distinguishing between narcolepsy types 1 and 2. A circuit comprising regions within the brainstem, forebrain, and hypothalamus is involved in generating and regulating REM sleep, which is influenced by changes in monoamines, acetylcholine, and neuropeptides. REM sleep is associated with brainstem functions, including autonomic control, and REM sleep disturbances may be associated with increased cardiovascular risk. Medications used to treat narcolepsy (and REM-related symptoms of narcolepsy) include stimulants/wake-promoting agents, pitolisant, oxybates, and antidepressants; hypocretin agonists are a potential new class of therapeutics. The role of REM sleep disturbances in narcolepsy remains an area of active research in pathophysiology, symptom management, and treatment. This review summarizes the current understanding of the role of REM sleep and its dysfunction in narcolepsy., Competing Interests: Declaration of competing interest MJ Thorpy has received research/grant support and consultancy fees from Axsome, Balance Therapeutics, Flamel/Avadel, Harmony Biosciences, LLC, Jazz Pharmaceuticals, Suven Life Sciences Ltd., Takeda Pharmaceutical Co., Ltd, NLS Pharmaceuticals, XW Pharma, Idorsia Pharmaceuticals, and Eisai Pharmaceuticals. JMSiegel receives research support from the National Institutes of HealthDA034748, HLB148574, Jazz Pharmaceuticals, and the US Department of Veterans Affairs. Y Dauvilliers is a consultant for and has participated in advisory boards for Jazz Pharmaceuticals, Centessa, Avadel, Idorsia, Takeda, Harmony Biosciences, and Bioprojet., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Time-to-event estimands are central to many oncology clinical trials. The estimands framework (addendum to the ICH E9 guideline) calls for precisely defining the treatment effect of interest to align with the clinical question of interest and requires predefining the handling of intercurrent events (ICEs) that occur after treatment initiation and "affect either the interpretation or the existence of the measurements associated with the clinical question of interest." We discuss a practical problem in clinical trial design and execution, that is, in some clinical contexts it is not feasible to systematically follow patients to an event of interest. Loss to follow-up in the presence of intercurrent events can affect the meaning and interpretation of the study results. We provide recommendations for trial design, stressing the need for close alignment of the clinical question of interest and study design, impact on data collection, and other practical implications. When patients cannot be systematically followed, compromise may be necessary to select the best available estimand that can be feasibly estimated under the circumstances. We discuss the use of sensitivity and supplementary analyses to examine assumptions of interest., (© 2024 The Authors. Pharmaceutical Statistics published by John Wiley & Sons Ltd.)

We developed a composite symptom score (CSS) representing disease-related symptom burden over time in patients with malignant pleural mesothelioma (MPM). Longitudinal data were collected from an open-label Phase IIB study in which 239 patients completed the validated MD Anderson Symptom Inventory for MPM (MDASI-MPM). A blinded, independent review committee of external patient-reported outcomes experts advised on MDASI-MPM symptoms to include in the CSS. Through iterative analyses of potential symptom-item combinations, 5 MPM symptoms (pain, fatigue, shortness of breath, muscle weakness, coughing) were selected. The CSS correlated strongly with the full MDASI-MPM symptom set (0.92-0.94) and the Lung Cancer Symptom Scale-Mesothelioma (0.79-0.87) at each co-administration of the scales. The CSS also had good sensitivity to worsening disease and global quality-of-life ratings. The MDASI-MPM CSS can be used as an outcome in MPM clinical trials, including in responder analyses and at the individual patient level. It is brief enough to administer frequently, including electronically, to better capture symptom trajectories during and after a trial and in clinical practice. As a single score, the CSS addresses multiplicity issues that can arise when several symptoms increase due to worsening disease. Our process can be adapted to produce a CSS for other advanced-cancer trials., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

While the majority of studies have concluded that sleep deprivation causes detrimental effects on various cognitive processes, some studies reported conflicting results. We examined the effects of a 108-h total sleep deprivation (TSD) on working memory in the northern fur seal, an animal with unusual sleep phenomenology and long-range annual migrations. The performance of fur seals was evaluated in a two-choice visual delayed matching to sample (DMTS) task, which is commonly used to evaluate working memory. In baseline conditions, the performance of fur seals in a DMTS task based on the percentage of errors was somewhat comparable with that in nonhuman primates at similar delays. We have determined that a 108-h TSD did not affect fur seals' performance in a visual DMTS task as measured by overall percentage of errors and response latencies. On the contrary, all fur seals improved task performance over the study, including the baseline, TSD and recovery conditions. In addition, TSD did not change the direction and strength of the pattern of behavioral lateralization in fur seals. We conclude that a 108-h TSD did not interfere with working memory in a DMTS test in northern fur seals., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Most women with advanced breast cancer have skeletal metastases. Radium-223 is an alpha-emitting radionuclide that selectively targets areas of bone metastases., Methods: Two double-blind, placebo-controlled studies of radium-223 were conducted in women with hormone receptor-positive (HR+), bone-predominant metastatic breast cancer. All patients received endocrine therapy (ET), as a single agent of the investigator's choice (Study A) or exemestane + everolimus (Study B). Patients were randomized to receive radium-223 (55 kBq/kg) or placebo intravenously every 4 weeks for six doses. Accrual was halted following unblinded interim analyses per protocol amendments, and both studies were terminated. We report pooled analyses of symptomatic skeletal event-free survival (SSE-FS; primary endpoint), radiologic progression-free survival (rPFS) and overall survival (OS; secondary), and time to bone alkaline phosphatase (ALP) progression (exploratory)., Results: In total, 382 patients were enrolled, and 196 SSE-FS events (70% planned total) were recorded. Hazard ratios (95% confidence intervals) and nominal p values for radium-223 + ET versus placebo + ET were: SSE-FS 0.809 (0.610-1.072), p = 0.1389; rPFS 0.956 (0.759-1.205), p = 0.7039; OS 0.889 (0.660-1.199), p = 0.4410; and time to bone ALP progression 0.593 (0.379-0.926), p = 0.0195. Radium-223- or placebo-related treatment-emergent adverse events were reported in 50.3% versus 35.1% of patients (grade 3/4: 25.7% vs. 8.5%), with fractures/bone-associated events in 23.5% versus 23.9%., Conclusions: In patients with HR+ bone-metastatic breast cancer, numeric differences favoring radium-223 + ET over placebo + ET for the primary SSE-FS endpoint were suggestive of efficacy, in line with the primary outcome measure used in the underlying phase 2 studies. No similar evidence of efficacy was observed for secondary progression or survival endpoints. Adverse events were more frequent with radium-223 + ET versus placebo + ET, but the safety profile of the combination was consistent with the safety profiles of the component drugs. Clinical trial registration numbers Study A: NCT02258464, registered October 7, 2014. Study B: NCT02258451, registered October 7, 2014., (© 2023. The Author(s).)

A new study presents evidence of sex-related sleep reduction in males of two marsupial mice species but not in females. The growing experimental data suggest that seasonal sleep reduction, linked to migrations and reproductive periods, is common among animals., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The relationship between postures, sleep stages and eye state was established in two species of deer, the Indian sambar (Rusa unicolor) and sika deer (Cervus nippon), based on video recording. In both species, the state of rest or behavioral sleep was recorded in the sternal position, holding the head above the ground, and in the lateral position, with the head resting on the croup or on the ground. Rest accounted for at least 80% of the time in these positions. Based on behavior criteria a substantial portion of rest represented slow-wave sleep. Episodes of rapid eye movements (REM sleep) were recorded in the lateral position. They did not exceed 2 min. When the deer were in the sternal posture, they kept their eyes open most of the time: in average 96% of the time in sambars and 82% in sika deer. Episodes of the open eye in this posture lasted up to 8.4 min in sambars and up to 3.3 min in sika deer. In the lateral position, such episodes were 4 and 1.5 times shorter. Sleeping with open eyes in ungulates may be an important mechanism of maintaining vigilance., (© 2023. Pleiades Publishing, Ltd.)

Since the discovery of REM (Rapid Eye Movement) sleep in 1953, misconceptions have arisen as to the evidence for its adaptive function and its relation to dreams. Eye movements recorded during REM sleep have not been consistently reported to mirror the eye movements predicted by dream reports. But evidence on eye movement and somatic motor expression from patients with REM sleep behavior disorder (RBD) is consistent with dream enacting behavior. The assumption that dreaming occurs only in REM sleep is incorrect, with numerous reports of nonREM dreaming. However, there may be qualitative differences between REM and nonREM dreams. Early studies that suggested a vital role for REM sleep in psychological well-being are refuted by studies of pharmacologically induced partial or complete REM sleep suppression. Studies of sleep across species show that the primitive monotreme mammals, platypus and echidna, have far more REM sleep than any other homeotherm group, whereas birds have far less REM sleep than any other homeotherm group. Human REM sleep amounts are not unusual, are correlated with nonREM sleep durations but are not correlated with intelligence. Across groups of homeotherms, REM sleep time is highly and inversely correlated (r=-0.975, P=0.02) with average core body temperature, suggesting that REM sleep cycles with nonREM sleep to regulate brain temperature during sleep. Cetacean mammals (dolphins and whales) do not have REM sleep despite their very large brain sizes and impressive cognitive abilities. Reports of "REM sleep-like states" in arachnids, cephalopods and in zebrafish larvae are lacking critical evidence that the observed behaviors are occurring during sleep and that the behaviors are homologous to mammalian REM sleep., (Copyright © 2023. Published by Elsevier Masson SAS.)

Long-term use of sodium oxybate (SXB), (also called gamma-hydroxybutyrate [GHB]) attenuates the cataplexy and sleepiness of human narcolepsy. We had previously found that chronic opiate usage in humans and long-term opiate administration to mice significantly increased the number of detected hypocretin/orexin (Hcrt) neurons, decreased their size, and increased Hcrt level in the hypothalamus. We also found that opiates significantly decreased cataplexy in human narcoleptics as well as in narcoleptic mice and that cessation of locus coeruleus neuronal activity preceded and was tightly linked to cataplectic attacks in narcoleptic dogs. We tested the hypothesis that SXB produces changes similar to opiates and now report that chronic SXB administration significantly increased the size of Hcrt neurons, the reverse of what we had seen with opiates in humans and mice. Levels of Hcrt in the hypothalamus were nonsignificantly lower, in contrast to the significant increase in hypothalamic Hcrt level after opiates. SXB decreased tyrosine hydroxylase levels in the locus coeruleus, the major descending projection of the hypocretin system, also the reverse of what we saw with opioids. Therefore despite some similar effects on narcoleptic symptomatology, SXB does not produce anatomical changes similar to those elicited by opiates. Analysis of changes in other links in the cataplexy pathway might further illuminate SXB's mechanism of action on narcolepsy., (Published by Oxford University Press on behalf of Sleep Research Society (SRS) 2023.)

Human heroin addicts and mice administered morphine for a 2 week period show a greatly increased number of hypothalamic hypocretin (Hcrt or orexin) producing neurons with a concomitant reduction in Hcrt cell size. Male rats addicted to cocaine similarly show an increased number of detectable Hcrt neurons. These findings led us to hypothesize that humans with alcohol use disorder (AUD) would show similar changes. We now report that humans with AUD have a decreased number and size of detectable Hcrt neurons. In addition, the intermingled melanin concentrating hormone (MCH) neurons are reduced in size. We saw no change in the size and number of tuberomammillary histamine neurons in AUD. Within the Hcrt/MCH neuronal field we found that microglia cell size was increased in AUD brains. In contrast, male rats with 2 week alcohol exposure, sufficient to elicit withdrawal symptoms, show no change in the number or size of Hcrt, MCH and histamine neurons, and no change in the size of microglia. The present study indicates major differences between the response of Hcrt neurons to opioids and that to alcohol in human subjects with a history of substance abuse., (Published by Elsevier Ltd.)

Prospective epidemiological studies in industrial societies indicate that 7 h of sleep per night in people aged 18 years or older is optimum, with higher and lower amounts of sleep predicting a shorter lifespan. Humans living a hunter-gatherer lifestyle (eg, tribal groups) sleep for 6-8 h per night, with the longest sleep durations in winter. The prevalence of insomnia in hunter-gatherer populations is low (around 2%) compared with the prevalence of insomnia in industrial societies (around 10-30%). Sleep deprivation studies, which are done to gain insights into sleep function, are often confounded by the effects of stress. Consideration of the duration of spontaneous daily sleep across species of mammals, which ranges from 2 h to 20 h, can provide important insights into sleep function without the stress of deprivation. Sleep duration is not related to brain size or cognitive ability. Rather, sleep duration across species is associated with their ecological niche and feeding requirements, indicating a role for wake-sleep balance in food acquisition and energy conservation. Brain temperature drops from waking levels during non-rapid eye movement (non-REM) sleep and rises during REM sleep. Average daily REM sleep time of homeotherm orders is negatively correlated with average body and brain temperature, with the largest amount of REM sleep in egg laying (monotreme) mammals, moderate amounts in pouched (marsupial) mammals, lower amounts in placental mammals, and the lowest amounts in birds. REM sleep might, therefore, have a key role in the regulation of temperature and metabolism of the brain during sleep and in the facilitation of alert awakening., Competing Interests: Declaration of interests I declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Our understanding of the causes and natural course of restless legs syndrome (RLS) is incomplete. The lack of objective diagnostic biomarkers remains a challenge for clinical research and for the development of valid animal models. As a task force of preclinical and clinical scientists, we have previously defined face validity parameters for rodent models of RLS. In this article, we establish new guidelines for the construct validity of RLS rodent models. To do so, we first determined and agreed on the risk, and triggering factors and pathophysiological mechanisms that influence RLS expressivity. We then selected 20 items considered to have sufficient support in the literature, which we grouped by sex and genetic factors, iron-related mechanisms, electrophysiological mechanisms, dopaminergic mechanisms, exposure to medications active in the central nervous system, and others. These factors and biological mechanisms were then translated into rodent bioequivalents deemed to be most appropriate for a rodent model of RLS. We also identified parameters by which to assess and quantify these bioequivalents. Investigating these factors, both individually and in combination, will help to identify their specific roles in the expression of rodent RLS-like phenotypes, which should provide significant translational implications for the diagnosis and treatment of RLS., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

The mouse-deer or chevrotains are the smallest of the ungulates and ruminants. They are characterized by a number of traits which are considered plesiomorphic for the Artiodactyla order. The objective of this study was to examine sleep in the lesser mouse-deer (Tragulus kanchil), which is the smallest in this group (body mass < 2.2 kg). Electroencephalogram, nuchal electromyogram, electrooculogram, and body acceleration were recorded in four adult mouse-deer females using a telemetry system in Bu Gia Map National Park in Vietnam. The mouse-deer spent on average 49.7 ± 3.0% of 24 h in non-rapid eye movement (NREM) sleep. REM sleep occupied 1.7 ± 0.3% of 24 h or 3.2 ± 0.5% of total sleep time. The average duration of REM sleep episodes was 2.0 ± 0.2 min, the average maximum was 5.1 ± 1.1 min, and the longest episodes lasted 8 min. NREM sleep occurred in sternal recumbency with the head held above the ground while 64.7 ± 6.4% of REM sleep occurred with the head resting on the ground. The eyes were open throughout most of the NREM sleep period. The mouse-deer displayed polyphasic sleep and crepuscular peaks in activity (04:00-06:00 and 18:00-19:00). The largest amounts of NREM occurred in the morning (06:00-09:00) and the smallest before dusk (at 04:00-06:00). REM sleep occurred throughout most of the daylight hours (08:00-16:00) and in the first half of the night (19:00-02:00). We suggest that the pattern and timing of sleep in the lesser mouse-deer is adapted to the survival of a small herbivorous animal, subject to predation, living in high environmental temperatures in the tropical forest undergrowth., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Study Objectives: Brain iron deficiency has been reported to be associated with the restless legs syndrome (RLS). However, 30%-50% of RLS patients do not respond to iron therapy, indicating that mechanisms other than brain iron deficiency may also participate in this disease. The striatum is known to be involved in the modulation of motor activity. We speculated that dysfunction of the striatum may induce RLS., Methods: Two groups, wild-type (WT) and iron-deficient (ID) rats were used. Each group was divided into two subgroups, control and N-methyl-d-aspartate striatal-lesioned. After baseline recording, striatal-lesioned wild-type (WT-STL) and striatal-lesioned iron-deficient (ID-STL) rats were given pramipexole and thioperamide injections. Iron-deficient and ID-STL rats were then given a standard rodent diet for 4 weeks, and their sleep and motor activity were recorded., Results: WT-STL rats showed periodic leg movements (PLM) in wake, an increase in PLM in slow wave sleep (SWS), a decrease in rapid-eye-movement sleep, and a decrease in the daily average duration of episodes in SWS. The sleep-wake pattern and motor activity did not differ between ID and ID-STL rats. Thioperamide or pramipexole injection decreased PLM in sleep and in wake in WT-STL rats and ID-STL rats. Unlike ID rats, whose motor hyperactivity can be reversed by iron replacement, PLM in wake and in sleep in ID-STL rats were not fully corrected by iron treatment., Conclusions: Lesions of the striatum generate RLS-like activity in rats. Dysfunction of the striatum may be responsible for failure to respond to iron treatment in some human RLS patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Employing orexin-A immunohistochemical staining we describe the nuclear parcellation of orexinergic neurons in the hypothalami of a lar gibbon and a chimpanzee. The clustering of orexinergic neurons within the hypothalamus and the terminal networks follow the patterns generally observed in other mammals, including laboratory rodents, strepsirrhine primates and humans. The orexinergic neurons were found within three distinct clusters in the ape hypothalamus, which include the main cluster, zona incerta cluster and optic tract cluster. In addition, the orexinergic neurons of the optic tract cluster appear to extend to a more rostral and medial location than observed in other species, being observed in the tuberal region in the anterior ventromedial aspect of the hypothalamus. While orexinergic terminal networks were observed throughout the brain, high density terminal networks were observed within the hypothalamus, medial and intralaminar nuclei of the dorsal thalamus, and within the serotonergic and noradrenergic regions of the midbrain and pons, which is typical for mammals. The expanded distribution of orexinergic neurons into the tuberal region of the ape hypothalamus, is a feature that needs to be investigated in other primate species, but appears to correlate with orexin gene expression in the same region of the human hypothalamus, but these neurons are not revealed with immunohistochemical staining in humans. Thus, it appears that apes have a broader distribution of orexinergic neurons compared to other primate species, but that the neurons within this extension of the optic tract cluster in humans, while expressing the orexin gene, do not produce the neuropeptide., (© 2021 American Association for Anatomy.)

Background: Few treatment options exist for second-line treatment of malignant pleural mesothelioma. We aimed to assess the antibody-drug conjugate anetumab ravtansine versus vinorelbine in patients with unresectable locally advanced or metastatic disease overexpressing mesothelin who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab., Methods: In this phase 2, randomised, open-label study, done at 76 hospitals in 14 countries, we enrolled adults (aged ≥18 years) with unresectable locally advanced or metastatic malignant pleural mesothelioma, an Eastern Cooperative Oncology Group performance status of 0-1, and who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab. Participants were prospectively screened for mesothelin overexpression (defined as 2+ or 3+ mesothelin membrane staining intensity on at least 30% of viable tumour cells by immunohistochemistry) and were randomly assigned (2:1), using an interactive voice and web response system provided by the sponsor, to receive intravenous anetumab ravtansine (6·5 mg/kg on day 1 of each 21-day cycle) or intravenous vinorelbine (30 mg/m 2 once every week) until progression, toxicity, or death. The primary endpoint was progression-free survival according to blinded central radiology review, assessed in the intention-to-treat population, with safety assessed in all participants who received any study treatment. This study is registered with ClinicalTrials.gov, NCT02610140, and is now completed., Findings: Between Dec 3, 2015, and May 31, 2017, 589 patients were enrolled and 248 mesothelin-overexpressing patients were randomly allocated to the two treatment groups (166 patients were randomly assigned to receive anetumab ravtansine and 82 patients were randomly assigned to receive vinorelbine). 105 (63%) of 166 patients treated with anetumab ravtansine (median follow-up 4·0 months [IQR 1·4-5·5]) versus 43 (52%) of 82 patients treated with vinorelbine (3·9 months [1·4-5·4]) had disease progression or died (median progression-free survival 4·3 months [95% CI 4·1-5·2] vs 4·5 months [4·1-5·8]; hazard ratio 1·22 [0·85-1·74]; log-rank p=0·86). The most common grade 3 or worse adverse events were neutropenia (one [1%] of 163 patients for anetumab ravtansine vs 28 [39%] of 72 patients for vinorelbine), pneumonia (seven [4%] vs five [7%]), neutrophil count decrease (two [1%] vs 12 [17%]), and dyspnoea (nine [6%] vs three [4%]). Serious drug-related treatment-emergent adverse events occurred in 12 (7%) patients treated with anetumab ravtansine and 11 (15%) patients treated with vinorelbine. Ten (6%) treatment-emergent deaths occurred with anetumab ravtansine: pneumonia (three [2%]), dyspnoea (two [1%]), sepsis (two [1%]), atrial fibrillation (one [1%]), physical deterioration (one [1%]), hepatic failure (one [1%]), mesothelioma (one [1%]), and renal failure (one [1%]; one patient had 3 events). One (1%) treatment-emergent death occurred in the vinorelbine group (pneumonia)., Interpretation: Anetumab ravtansine showed a manageable safety profile and was not superior to vinorelbine. Further studies are needed to define active treatments in relapsed mesothelin-expressing malignant pleural mesothelioma., Funding: Bayer Healthcare Pharmaceuticals., Competing Interests: Declarations of interests HLK reports grants paid to the University of Chicago to support clinical trials for Aduro, AstraZeneca, Bayer, Blueprint, Bristol Myers Squibb, Deciphera, GlaxoSmithKline, Harpoon, Inhibrx, MacroGenics, Merck, Polaris, Seattle Genetics, and Vivace; consulting fees from Bristol Myers Squibb, Deciphera, Inventiva, Novocure, and Seattle Genetics; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events for AstraZeneca; support for attending meetings, travel, or both from AstraZeneca and Inventiva; participation on a data safety monitoring board or advisory board for Bristol Myers Squibb, Inventiva, and Seattle Genetics; and leadership or fiduciary role on board of directors for the International Mesothelioma Interest Group. SN reports personal payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Abbvie, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Pfizer, Pharmamar, Roche, and Takeda; and personal fees for participation on a data safety monitoring board or advisory board from AstraZeneca, Bayer, Daiichi Sanko, Eli Lilly, Pfizer, Roche, Sanofi, and Takeda. AB reports payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from AstraZeneca, Boehringer Ingelheim, Eli-Lilly, Pfizer, Roche, and Takeda; and support for attending meetings, travel, or both for Boehringer Ingelheim, Merck Sharp and Dohme, and Roche. GLC reports personal consulting fees for their advisory role for Novocure and Zai Lab; personal speaker engagements for Astellas, AstraZeneca, Merck Sharp and Dohme, Novocure, and Zai Lab; and support for attending meetings, travel, or both for Astellas, Novocure, and Merck Sharp and Dohme. JGJVA reports consulting fees for the advisory boards for Amphera, Bayer, Bristol Myers Squibb, Eli-Lilly, and Merck Sharp and Dohme; patents issued on allogenic tumour cell lysate and on combination immuno-oncology, owned by Erasmus MC Cancer Centre; participation on a data safety monitoring board or advisory board for Biocad; unpaid leadership role for the International Association for the Study of Lung Cancer; and stock or stock options for Amphera. JSp reports clinical trial reimbursement to Guy's & St Thomas’ NHS Foundation Trust from Bayer, BergenBio, Boehringer Ingelheim, Bristol Myers Squibb, Genmab, IO Biotech, Lytix, Seattle Genetics, and Starpharma; consulting fees paid to King's College London from Apobec, AVACTA, Bristol Myers Squibb, IO Biotech, and Seattle Genetics; support for attending meetings, travel, or both from Amgen and Janssen; participation on a data safety monitoring board or advisory board for AstraZeneca and Merck; and stock or stock options (co-founder) for Epsilogen. PT reports fees for a symposium presentation from AstraZeneca; and a conference registration fee from AstraZeneca. KN reports personal fees for advisory boards from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb Belgium, and Roche Belgium; personal fees for lectures from Roche Belgium; and support for attending meetings, travel, or both from AstraZeneca, Merck Sharpe and Dohme, and Pfizer. AG reports payment to Newcastle upon Tyne Hospitals NHS Foundation Trust for the care of patients on a study from Bayer (support for this manuscript). JAB reports institutional payment to the Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital for support of investigator-initiated study from Merck Sharp and Dohme, consulting fees paid to the Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital from Bristol Myers Squibb, and payment to the Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital for participation on a data safety monitoring board or advisory board for Roche. AS reports consulting fees from ArQule and Sanofi; payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Abbvie, Amgen, ArQule, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Eisai, Eli-Lilly, Gilead, Merck Sharp and Dohme, Novartis, Pfizer, Roche, Sandoz, Servier, and Takeda; and participation on a data safety monitoring board or advisory board for Bayer, Bristol Myers Squibb, Eisai, Gilead, Merck Sharp and Dohme, Pfizer, and Servier. SC reports payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Amphera, Boehringer Ingelheim, Bristol Myers Squibb, Hoffmann La Roche, Merck Sharp and Dohme Oncology, and Pfizer; and support for attending meetings, travel, or both from Amphera, Boehringer Ingelheim, Bristol Myers Squibb, Hoffmann La Roche, Merck Sharp and Dohme Oncology, and Pfizer. JPVM reports consultancy fees from Amgen, AstraZeneca, Boehringer Ingelheim, Pfizer, and Roche; payment and reimbursement of expenses for services and consultancy from Amgen; registration fees from AstraZeneca, Merck Sharp and Dohme Belgium, Bristol Myers Squibb, GlaxoSmithKline, and Roche; and travel and accommodation support from AstraZeneca, Bristol Myers Squibb, Merck Sharp and Dohme Belgium, and Roche. AKN reports personal fees for consulting for clinical trials, quality of life research, and tumour measurement from Bayer (support for this manuscript); grants or contracts to institution from AstraZeneca and Douglas Pharmaceuticals; consulting fees from Atara Biotherapeutics (personal), Pharmabcine (institutional), and Seagen (personal); personal payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Bristol Myers Squibb; travel support from AstraZeneca; and participation on a data safety monitoring board or advisory board for Bristol Myers Squibb (personal). GBJ reports personal grants or contracts from Adaptimmune, Amgen, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Elelixis, Genentech, GlaxoSmithKline, Immatics, Immunocore, Incyte, Kite Pharma, Macrogenics, MedImmune, Merck, Novartis, Regeneron, Repertoire Immune Medicines, Roche, Tmunity Therapeutics, Torque, Verastem, and Xcovery; personal consulting fees for AbbVie, Adicet, Amgen, Ariad, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Clovis Oncology, Daiichi Sankyo, Genentech, Gilead, Instil Bio, Janssen, Lilly, Maverick Therapeutics, MedImmune, Merck, Novartis, Roche, Tyme Oncology, Viogin Biotech, and Xcovery; participation on a data safety monitoring board or advisory board for Maverick Therapeutics and Virogin Biotech (personal); and stock or stock options for Virogin Biotech. GBJ also has an immediate family member employed by Johnson and Johnson and Janssen. JSi is an employee of Bayer Healthcare Pharmaceuticals with ownership of stock; and reports unpaid leadership roles for the American Statistical Association, International Society for Clinical Biostatistics, and the Pharmaceutical Industry Working Group on Estimands in Oncology. LK is an external employee of Bayer Healthcare Pharmaceuticals. KK is an employee of Bayer AG Pharma with ownership of stock. AOW is an employee of Bayer AG Pharma. BHC and CE are employees of Bayer Healthcare Pharmaceuticals. RH reports institutional support for the conduct of this study via a Cooperative Research and Development Agreement (CRADA) between Bayer and the Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. He also has a CRADA with TCR(2) for conduct of clinical studies unrelated to this manuscript. DAF reports grants from Astex Therapeutics, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, and Merck Sharp and Dohme; personal fees from Aldeyra, Atara, Bristol Myers Squibb, Inventiva, Lab21, Roche, RS Oncology, and Targovax; and non-financial support from Bristol Myers Squibb, Clovis, Eli-Lilly, and Roche. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

We previously found that human heroin addicts and mice chronically exposed to morphine exhibit a significant increase in the number of detected hypocretin/orexin (Hcrt)-producing neurons. However, it remains unknown how this increase affects target areas of the hypocretin system involved in opioid withdrawal, including norepinephrine containing structures locus coeruleus (LC) and A1/A2 medullary regions. Using a combination of immunohistochemical, biochemical, imaging, and behavioral techniques, we now show that the increase in detected hypocretin cell number translates into a significant increase in hypocretin innervation and tyrosine hydroxylase (TH) levels in the LC without affecting norepinephrine-containing neuronal cell number. We show that the increase in TH is completely dependent on Hcrt innervation. The A1/A2 regions were unaffected by morphine treatment. Manipulation of the Hcrt system may affect opioid addiction and withdrawal. SIGNIFICANCE STATEMENT Previously, we have shown that the hypothalamic hypocretin system undergoes profound anatomic changes in human heroin addicts and in mice exposed to morphine, suggesting a role of this system in the development of addictive behaviors. The locus coeruleus plays a key role in opioid addiction. Here we report that the hypothalamic hypocretin innervation of the locus coeruleus increases dramatically with morphine administration to mice. This increase is correlated with a massive increase in tyrosine hydroxylase expression in locus coeruleus. Elimination of hypocretin neurons prevents the tyrosine hydroxylase increase in locus coeruleus and dampens the somatic and affective components of opioid withdrawal., (Copyright © 2022 the authors.)