Recent insights into the pathophysiology of narcolepsy type 1.

Narcolepsy type 1 (NT1) is a sleep-wake disorder in which people typically experience excessive daytime sleepiness, cataplexy and other sleep-wake disturbances impairing daily life activities. NT1 symptoms are due to hypocretin deficiency. The cause for the observed hypocretin deficiency remains unclear, even though the most likely hypothesis is that this is due to an auto-immune process. The search for autoantibodies and autoreactive T-cells has not yet produced conclusive evidence for or against the auto-immune hypothesis. Other mechanisms, such as reduced corticotrophin-releasing hormone production in the paraventricular nucleus have recently been suggested. There is no reversive treatment, and the therapeutic approach is symptomatic. Early diagnosis and appropriate NT1 treatment is essential, especially in children to prevent impaired cognitive, emotional and social development. Hypocretin receptor agonists have been designed to replace the attenuated hypocretin signalling. Pre-clinical and clinical trials have shown encouraging initial results. A better understanding of NT1 pathophysiology may contribute to faster diagnosis or treatments, which may cure or prevent it.

Sleep in the intensive and intermediate care units: Exploring related factors of delirium, benzodiazepine use and mortality.

AIM OF THE STUDY: The primary purpose was to examine sleep difficulties and delirium in the Intensive and Intermediate Care Unit. Secondarily, factors impacting night-time sleep duration and quality, mortality, and the impact of benzodiazepine use on sleep outcomes were investigated. MATERIALS AND METHODS: This retrospective study encompassed data from 323 intensive and intermediate care unit admissions collected in the Netherlands, spanning from November 2018 to May 2020. Sleep quality was measured using the Richards-Campbell Sleep Questionnaire. Night-time sleep duration was nurse-reported. We investigated associations of these sleep outcomes with age, sex, length-of-stay, natural daylight, disease severity, mechanical ventilation, benzodiazepine use, and delirium using Generalized Estimating Equations models. Associations with one-year post-discharge mortality were analyzed using Cox regression. RESULTS: Night-time sleep duration was short (median 4.5 hours) and sleep quality poor (mean score 4.9/10). Benzodiazepine use was common (24 % of included nights) and was negatively associated with night-time sleep duration and quality (B = -0.558 and -0.533, p <.001). Delirium and overnight transfers were negatively associated with sleep quality (B = -0.716 and -1.831, p <.05). The day-to-night sleep ratio was higher in the three days before delirium onset than in non-delirious individuals (p <.05). Age, disease severity and female sex were associated with increased one-year mortality. Sleep quality was negatively, but not-significantly, associated with mortality (p =.070). CONCLUSIONS: Night-time sleep in the critical care environment has a short duration and poor quality. Benzodiazepine use was not associated with improved sleep. Sleep patterns change ahead of delirium onset. IMPLICATIONS FOR CLINICAL PRACTICE: Consistent sleep monitoring should be part of routine nursing practice, using a validated instrument like the Richards-Campbell Sleep Questionnaire. Given the lack of proven efficacy of benzodiazepines in promoting sleep in critical care settings, it is vital to develop more effective sleep treatments that include non-benzodiazepine medication and sleep hygiene strategies.

An observed population of intermediate-mass helium stars that have been stripped in binaries.

The hydrogen-rich outer layers of massive stars can be removed by interactions with a binary companion. Theoretical models predict that this stripping produces a population of hot helium stars of ~2 to 8 solar masses (M☉), however, only one such system has been identified thus far. We used ultraviolet photometry to identify potential stripped helium stars then investigated 25 of them using optical spectroscopy. We identified stars with high temperatures (~60,000 to 100,000 kelvin), high surface gravities, and hydrogen-depleted surfaces; 16 stars also showed binary motion. These properties match expectations for stars with initial masses of 8 to 25 M☉ that were stripped by binary interaction. Their masses fall in the gap between subdwarf helium stars and Wolf-Rayet stars. We propose that these stars could be progenitors of stripped-envelope supernovae.

Narcolepsy type 1 and Sydenham chorea - Report of 3 cases and review of the literature.

OBJECTIVES/BACKGROUND: Narcolepsy type 1 (NT1) is an immune-mediated disorder characterized by excessive daytime sleepiness, cataplexy, low levels of hypocretin-1 in the cerebrospinal fluid, and a strong association with the HLA DQB1*06:02 allele. There is evidence for streptococcal infections as one pathogenic factor that may lead to NT1 as part of a multifactorial pathogenesis. Elevated titers of Antistreptolysin-O antibodies and increased inflammatory activity in response to streptococci antigens have been described in patients with NT1. Sydenham chorea (SC) results from a post-streptococcal autoimmune process targeting basal ganglia neurons. Despite this common trigger, SC has been interpreted as a misdiagnosis in a few described cases of patients who were first diagnosed with SC and later with NT1. Our goal was to analyze the association between SC and NT1. PATIENTS/METHODS: We reviewed the literature and report three patients from three European sleep centers who were diagnosed with both SC and NT1 within a few months. RESULTS: We describe the cases of one male (age 10) and two female (age 22 and 10) patients. CONCLUSIONS: We argue that in those cases both diagnoses are justified, unlike reports of previous cases in which SC was considered a misdiagnosis in patients with NT1. It remains, however, unclear if the conditions occur independently or if there is an overlap disorder- an SC-like subtype of narcolepsy with a particular sequence of symptoms. Further studies need to clarify the causality of the relationship and the pathophysiology of the reported rare association.

Skin temperature as a predictor of on-the-road driving performance in people with central disorders of hypersomnolence.

Excessive daytime sleepiness is the core symptom of central disorders of hypersomnolence (CDH) and can directly impair driving performance. Sleepiness is reflected in relative alterations in distal and proximal skin temperature. Therefore, we examined the predictive value of skin temperature on driving performance. Distal and proximal skin temperature and their gradient (DPG) were continuously measured in 44 participants with narcolepsy type 1, narcolepsy type 2 or idiopathic hypersomnia during a standardised 1-h driving test. Driving performance was defined as the standard deviation of lateral position (SDLP) per 5 km segment (equivalent to 3 min of driving). Distal and proximal skin temperature and DPG measurements were averaged over each segment and changes over segments were calculated. Mixed-effect model analyses showed a strong, quadratic association between proximal skin temperature and SDLP (p < 0.001) and a linear association between DPG and SDLP (p < 0.021). Proximal skin temperature changes over 3 to 15 min were predictive for SDLP. Moreover, SDLP increased over time (0.34 cm/segment, p < 0.001) and was higher in men than in women (3.50 cm, p = 0.012). We conclude that proximal skin temperature is a promising predictor for real-time assessment of driving performance in people with CDH.

The therapeutic potential of opioids in narcolepsy type 1: A systematic literature review and questionnaire study.

OBJECTIVE: Narcolepsy type 1 is a primary sleep disorder caused by deficient hypocretin transmission leading to excessive daytime sleepiness and cataplexy. Opioids have been suggested to increase the number of hypocretin-producing neurons. We aimed to assess opioid use and its self-reported effect on narcolepsy type 1 symptom severity through a literature review and questionnaire study. METHODS: We systematically reviewed literature on opioid use in narcolepsy. We also recruited 100 people with narcolepsy type 1 who completed an online questionnaire on opioid use in the previous three years. The main questionnaire topics were the indication for use, and the possible effects on narcolepsy symptom severity. Structured follow-up interviews were conducted when opioid use was reported. RESULTS: The systematic literature review mainly showed improvements in narcolepsy symptom severity. Recent opioid use was reported by 16/100 questionnaire respondents, who had used 20 opioids (codeine: 7/20, tramadol: 6/20, oxycodone: 6/20, fentanyl: 1/20). Narcolepsy symptom changes were reported in 11/20. Positive effects on disturbed nocturnal sleep (9/20), excessive daytime sleepiness (4/20), hypnagogic hallucinations (3/17), cataplexy (2/18), and sleep paralysis (1/13) were most pronounced for oxycodone (4/6) and codeine (4/7). CONCLUSIONS: Opioids were relatively frequently used compared to a similarly young general Dutch sample. Oxycodone and, to a lesser extent, codeine were associated with self-reported narcolepsy symptom severity improvements. Positive changes in disturbed nocturnal sleep and daytime sleepiness were most frequently reported, while cataplexy effects were less pronounced. Randomised controlled trials are now needed to verify the potential of opioids as therapeutic agents for narcolepsy.

Warm ears, a red flag for sleepiness?

Core body and skin temperatures are intimately linked to sleep and alertness. The distal-to-proximal skin temperature gradient has been described as a good physiological predictor for sleep onset. Increased ear skin temperature is often caused by increased blood flow reflected in redness, which is commonly noticed in people who are sleepy, especially anecdotally in children. Nonetheless, no prior study investigated the possible relation between sleepiness and ear skin temperature as a separate measurement. We assessed the relation between ear skin temperature and sleepiness in patients undergoing regular electroencephalographic examinations, because of suspicion of epilepsy, both without and after sleep deprivation. Subjective sleepiness was measured using the Stanford Sleepiness Scale, and objective sleepiness by determining sleep onset with electroencephalography. Distal, proximal and ear skin temperature were measured repeatedly using wireless measurement devices (iButtons). Forty-four adult patients were included. Ear skin temperature correlates weakly with distal skin temperature (r = 0.174, p < 0.001) and distal-to-proximal gradient (r = 0.160, p < 0.001), but not with proximal skin temperature (r = -0.001, p = 0.975). Ear skin temperature increased significantly in a subgroup of 13 patients, between 5 and 1 min before sleep onset (p = 0.002; η2  = 0.059), even though this increase was also associated with supine posture. iButtons is a valid method to measure ear skin temperature, which appears to function partly like a distal and partly like a proximal skin temperature measurement. Change in ear skin temperature is associated with sleep onset and supine posture.

A highly magnified star at redshift 6.2.

Galaxy clusters magnify background objects through strong gravitational lensing. Typical magnifications for lensed galaxies are factors of a few but can also be as high as tens or hundreds, stretching galaxies into giant arcs1,2. Individual stars can attain even higher magnifications given fortuitous alignment with the lensing cluster. Recently, several individual stars at redshifts between approximately 1 and 1.5 have been discovered, magnified by factors of thousands, temporarily boosted by microlensing3-6. Here we report observations of a more distant and persistent magnified star at a redshift of 6.2 ± 0.1, 900 million years after the Big Bang. This star is magnified by a factor of thousands by the foreground galaxy cluster lens WHL0137-08 (redshift 0.566), as estimated by four independent lens models. Unlike previous lensed stars, the magnification and observed brightness (AB magnitude, 27.2) have remained roughly constant over 3.5 years of imaging and follow-up. The delensed absolute UV magnitude, -10 ± 2, is consistent with a star of mass greater than 50 times the mass of the Sun. Confirmation and spectral classification are forthcoming from approved observations with the James Webb Space Telescope.

Conventional autoantibodies against brain antigens are not routinely detectable in serum and CSF of narcolepsy type 1 and 2 patients.

Narcolepsy with cataplexy (NT1) is a chronic hypothalamic disorder with a presumed immune-mediated etiology leading to a loss of hypocretin neurons. Previous studies reported conflicting results in terms of presence of auto-antibodies involved in narcolepsy pathophysiology. A total of 86 patients with primary/idiopathic narcolepsy (74 NT1, 12 NT2) and 23 control patients with excessive daytime sleepiness due to other causes were tested for the presence of a wide range of anti-neuronal antibodies in both serum and cerebrospinal fluid (CSF). Anti-neuronal antibodies were rarely found in patients with narcolepsy (n = 2) and in controls (n = 1). Our results are in line with previous reports. We can therefore support the current evidence, that conventional anti-neuronal antibodies are not routinely detected during the workup of NT1 and other CDH patients.

Role of Brown Adipose Tissue in Adiposity Associated With Narcolepsy Type 1.

Narcolepsy type 1 is a neurological sleep-wake disorder caused by the destruction of orexin (hypocretin)-producing neurons. These neurons are particularly located in the lateral hypothalamus and have widespread projections throughout the brain, where they are involved, e.g., in the regulation of the sleep-wake cycle and appetite. Interestingly, a higher prevalence of obesity has been reported in patients with narcolepsy type 1 compared to healthy controls, despite a normal to decreased food intake and comparable physical activity. This suggests the involvement of tissues implicated in total energy expenditure, including skeletal muscle, liver, white adipose tissue (WAT), and brown adipose tissue (BAT). Recent evidence from pre-clinical studies with orexin knock-out mice demonstrates a crucial role for the orexin system in the functionality of brown adipose tissue (BAT), probably through multiple pathways. Since BAT is a highly metabolically active organ that combusts fatty acids and glucose toward heat, thereby contributing to energy metabolism, this raises the question of whether BAT plays a role in the development of obesity and related metabolic diseases in narcolepsy type 1. BAT is densely innervated by the sympathetic nervous system that activates BAT, for instance, following cold exposure. The sympathetic outflow toward BAT is mainly mediated by the dorsomedial, ventromedial, arcuate, and paraventricular nuclei in the hypothalamus. This review focuses on the current knowledge on the role of the orexin system in the control of energy balance, with specific focus on BAT metabolism and adiposity in both preclinical and clinical studies.

Decreased body mass index during treatment with sodium oxybate in narcolepsy type 1.

Narcolepsy type 1 is characterised by an increase in body weight after disease onset, frequently leading to obesity. It was suggested that this weight gain may be counteracted by treatment with sodium oxybate. We here provide longitudinal body mass index data of patients with narcolepsy type 1 after starting treatment with sodium oxybate, compared with patients in whom treatment with modafinil was initiated. Eighty-one individuals with narcolepsy type 1 fulfilled the entry criteria for this retrospective study: 59 had newly started treatment with sodium oxybate and 22 had newly started modafinil. Gender-specific differences between both treatment groups were compared using Student's t tests and mixed effect modeling. Patients using sodium oxybate lost weight, with a mean body mass index decrease of 2.56 kg/m2 between the first and last measurement (women; p = .001) and 0.84 kg/m2 (men; p = .006). Patients using modafinil, however, gained weight, with a mean body mass index increase of 0.57 kg/m2 (women; p = .033) and 0.67 kg/m2 (men; p = .122). Medication (p = .006) and baseline body mass index (p = .032) were predictors for body mass index decrease. In conclusion, treatment with sodium oxybate is associated with a body mass index reduction in narcolepsy type 1, whereas modafinil treatment is not. This effect is most pronounced in those who already have a higher baseline body mass index.

Correction to: Radioiodine ablation with 1,850 MBq in association with rhTSH in patients with differentiated thyroid cancer.

Unfortunately, the fourth author's middle name was missed out in the original publication of this article. The complete correct name should read as follows.

An excess of massive stars in the local 30 Doradus starburst.

The 30 Doradus star-forming region in the Large Magellanic Cloud is a nearby analog of large star-formation events in the distant universe. We determined the recent formation history and the initial mass function (IMF) of massive stars in 30 Doradus on the basis of spectroscopic observations of 247 stars more massive than 15 solar masses ([Formula: see text]). The main episode of massive star formation began about 8 million years (My) ago, and the star-formation rate seems to have declined in the last 1 My. The IMF is densely sampled up to 200 [Formula: see text] and contains 32 ± 12% more stars above 30 [Formula: see text] than predicted by a standard Salpeter IMF. In the mass range of 15 to 200 [Formula: see text], the IMF power-law exponent is [Formula: see text], shallower than the Salpeter value of 2.35.

Ejection of the Massive Hydrogen-rich Envelope Timed with the Collapse of the Stripped SN 2014C.

We present multi-wavelength observations of SN 2014C during the first 500 days. These observations represent the first solid detection of a young extragalactic stripped-envelope SN out to high-energy X-rays ~40 keV. SN 2014C shows ordinary explosion parameters (Ek ~ 1.8 × 1051 erg and Mej ~ 1.7 M⊙). However, over an ~1 year timescale, SN 2014C evolved from an ordinary hydrogen-poor supernova into a strongly interacting, hydrogen-rich supernova, violating the traditional classification scheme of type-I versus type-II SNe. Signatures of the SN shock interaction with a dense medium are observed across the spectrum, from radio to hard X-rays, and revealed the presence of a massive shell of ~1 M⊙of hydrogen-rich material at ~6 × 1016 cm. The shell was ejected by the progenitor star in the decades to centuries before collapse. This result challenges current theories of massive star evolution, as it requires a physical mechanism responsible for the ejection of the deepest hydrogen layer of H-poor SN progenitors synchronized with the onset of stellar collapse. Theoretical investigations point at binary interactions and/or instabilities during the last nuclear burning stages as potential triggers of the highly time-dependent mass loss. We constrain these scenarios utilizing the sample of 183 SNe Ib/c with public radio observations. Our analysis identifies SN 2014C-like signatures in ~10% of SNe. This fraction is reasonably consistent with the expectation from the theory of recent envelope ejection due to binary evolution if the ejected material can survive in the close environment for 103-104 years. Alternatively, nuclear burning instabilities extending to core C-burning might play a critical role.

Standard radiotherapy but not chemotherapy impairs systemic immunity in non-small cell lung cancer.

Introduction: Advanced non-small cell lung cancer (NSCLC) is traditionally treated with platinum-based chemotherapy and radiotherapy. Since immunotherapy holds promise for treating advanced NSCLC, we assessed the systemic effects of the traditional therapies for NSCLC on immune cell composition and function. Methods: 84 pulmonary adenocarcinoma patients, treated either with chemotherapy or radiotherapy, were studied. A prospective study of 23 patients was conducted in which the myeloid and lymphoid cell compartments of peripheral blood were analyzed. Changes in cell populations were validated in a retrospective cohort of 61 adenocarcinoma patients using automated differential counts collected throughout therapy. Furthermore, the functional capacity of circulating T cells and antigen-presenting cells (APC) was studied. Blood samples of healthy individuals were used as controls. Results: In comparison to healthy controls, untreated adenocarcinoma patients display an elevated frequency of myeloid cells coinciding with relative lower frequencies of lymphocytes and dendritic cells. Standard chemotherapy had no overt effects on myeloid and lymphoid cell composition nor on T-cell and APC-function. In contrast, patients treated with radiotherapy displayed a decrease in lymphoid cells and a relative increase in monocytes/macrophages. Importantly, these changes were associated with a reduced APC function and an impaired response of T cells to recall antigens. Conclusions: Platinum-based standard of care chemotherapy for NSCLC has no profound negative effect on the immune cell composition and function. The negative effect of prolonged low-dose radiotherapy on the immune system warrants future studies on the optimal dose and fraction of radiotherapy when combined with immunotherapy.

Endosonography for lung cancer staging: predictors for false-negative outcomes.

OBJECTIVES: Non-small cell lung cancer (NSCLC) guidelines recommend endosonography (endobronchial [EBUS] and/or transesophageal ultrasound [EUS]) as the initial step for mediastinal tissue staging. Identifying predictors for false negative results could help establish which patients should undergo confirmatory surgical staging. MATERIALS AND METHODS: 775 NSCLC patients staged negative by EBUS, EUS or combined EUS/EBUS were retrospectively analyzed. Predictors of false-negative outcomes were identified by logistic regression analysis. RESULTS AND CONCLUSION: Three predictors for false-negative outcomes were identified: central location of the lung tumor (OR 3.7/4.5/3.6 for EBUS, EUS and EUS/EBUS respectively, p<0.05), nodal enlargement on CT (OR 3.2/2.5/4.9 for EBUS, EUS and EUS/EBUS respectively, p<0.05) and FDG-avidity of N2/N3 lymph node stations on PET (OR 4.2/4.0/7.5 for EBUS, EUS and EUS/EBUS respectively, p<0.05). One subgroup (peripheral lung tumor, nodal enlargement on CT without FDG-avidity for N2/N3) had a low predicted probability (7.8%) for false-negative EUS. For combined EUS/EBUS, two subgroups were identified: peripheral located tumor with nodal enlargement on CT but without FDG-avidity for N2/N3 (predicted probability 4.7%) and centrally located tumor without affected lymph nodes on CT or PET (predicted probability 3.4%). In conclusion, for specific well-defined subsets of NSCLC patients the low predicted probability of metastasis after negative endosonography might justify omitting confirmatory surgical staging.

Radioiodine ablation with 1,850 MBq in association with rhTSH in patients with differentiated thyroid cancer.

PURPOSE: The aim of this study was to evaluate the efficacy of post-operative radioiodine ablation with 1,850 MBq after recombinant human thyrotropin (rhTSH) administration in patients with differentiated thyroid carcinoma (DTC). We also aimed to assess the prognostic role of several patient features on the outcome of ablation. METHODS: We retrospectively analyzed data from a total of 125 patients with DTC who underwent post-operative radioiodine ablation with 1,850 MBq of ¹³¹I after preparation with rhTSH. One injection of 0.9 mg rhTSH was administered on each of two consecutive days; ¹³¹I therapy was delivered 24 h after the last injection, followed by a post-therapy whole-body scan. Successful ablation was assessed 6-12 months later and defined as an rhTSH-stimulated serum thyroglobulin (Tg) level ≤1.0 ng/ml and a normal neck ultrasound. RESULTS: Patients were stratified according to the American Thyroid Association (ATA) Management Guidelines for Differentiated Thyroid Cancer. Successful ablation was achieved in 82.4 % of patients, with an ablation rate of 95.1 % in low-risk patients and 76.2 % in intermediate-risk patients. Analyzing the correlation between ablation outcome and patient characteristics, we found a statistically significant association between failure to ablate and class of risk based on ATA guidelines (p = 0.025) and a stimulated Tg value at ablation of above 5 ng/ml (p < 0.001). CONCLUSION: The use of 1,850 MBq post-operative radioiodine thyroid remnant ablation in association with rhTSH is effective for low- and intermediate-risk patients. Moreover, in our study, we found a statistical correlation between failure to ablate and class of risk based on ATA guidelines for DTC and a stimulated Tg value at ablation.

Binary interaction dominates the evolution of massive stars.

The presence of a nearby companion alters the evolution of massive stars in binary systems, leading to phenomena such as stellar mergers, x-ray binaries, and gamma-ray bursts. Unambiguous constraints on the fraction of massive stars affected by binary interaction were lacking. We simultaneously measured all relevant binary characteristics in a sample of Galactic massive O stars and quantified the frequency and nature of binary interactions. More than 70% of all massive stars will exchange mass with a companion, leading to a binary merger in one-third of the cases. These numbers greatly exceed previous estimates and imply that binary interaction dominates the evolution of massive stars, with implications for populations of massive stars and their supernovae.