IL-4/13 Blockade and sleep-related adverse drug reactions in over 37,000 Dupilumab reports from the World Health Organization Individual Case Safety reporting pharmacovigilance database (VigiBase™): a big data and machine learning analysis (Preprint)

BACKGROUND Atopic dermatitis displays a relevant sleep burden sustained by clinical (i.e., itch), psychological (i.e., inadequate coping strategies) and therapeutic (i.e. frequent loss of drug response) triggers. Dupilumab, the first biologic approved for atopic dermatitis, showed excellent effects on improving pruritus and sleep after only two weeks of treatment but, in some cases, may have paradoxical effects. OBJECTIVE The rate of sleep-related side-effects remains unknown. More specifically, adverse-drug reactions (ADRs) related to dupilumab have been investigated during the safety phase of randomized clinical trials or in small retrospective epidemiological surveys, but little is known about sleep-related ADRs in real-life settings. Therefore, we took advantage of a global large-scale pharmacovigilance database, carrying out a comprehensive data mining analysis to look at different sleep-related ADRs reported among patients under anti IL-4/13 therapy. METHODS We analysed individual case study reports (ICSRs) in VigiBase, the World Health Organization (WHO) global pharmacovigilance database of ADRs collected by national drug authorities in >140 countries (>90% of the world population). We looked for patterns of potentially sleep-related ADRs and we applied a disproportionality analysis based on Bayesian Confidence Propagation Neural Network (BCPNN). A meta-analytical approach was used to synthesize the overall effect size of sleep-related ADRs potentially associated to Dupilumab administration. RESULTS From inception up to March 9, 2021, 94,065 ADRs from 37,848 unique reports were included and analyzed in the present paper: 1,294 of them (1.4%) concerned sleep disturbances (n=27). Most of sleep-related complaints were generic sleep disorders (n=630), followed by insomnia (n=312), somnolence (n=81), lethargy (n=60), night sweats (n=30), middle insomnia (n=39), hypersomnia (n=25), poor quality sleep (n=21), initial insomnia (n=17), sleep apnoea syndrome (n=13), nightmares (n=11) and sleep deficit (n=11). Interestingly, restlessness and restless leg syndrome, nocturnal dyspnoea, narcolepsy and bruxism were reported in 7, 6, 5, 4 and 3 cases, respectively. Only sleep deficit (OR 15.67 [CrI 8.61-28.51]; IC 3.24 [CrI 2.26-3.97]), generic sleep disorder (OR 6.22 [CrI 5.74-6.73]; IC 2.60 [CrI 2.48-2.71]), and nocturnal dyspnoea (OR 3.68 [CrI 1.53-8.87]; IC 1.56 [CrI 0.03-2.56]) achieved the statistical significance threshold. CONCLUSIONS In this work, we identified over 37,000 unique case-reports of Dupilumab side-effects reported on the WHO pharmacovigilance database. We specifically categorised those related to sleep issues, which were 1,294. Our findings from large numbers of cases provide data supporting the clinical observations that Dupilumab is usually effective in improving sleep quality and sleep disturbances/impairments but sometimes may impair circadian rhythm and sleep. Further work is needed to closely scrutinise the impact of Dupilumab on sleep, in terms of underlying mechanisms, and to better understand residual sleep disorders in patients with atopic dermatitis and other allergic diseases treated with Dupilumab. Thus, sleep monitoring may be helpful for dermatologists in managing atopic dermatitis patients treated with dupilumab. The limitations of spontaneous reporting systems including underreporting and reporting bias, heterogeneity of sources and impossibility to infer any causal relationship merit consideration and further research is needed.

Parents’ Sleep Across Weekdays and Weekends: The Influence of Work, Housework, and Childcare Time

Children increase time demands with important consequences for sleep. Here, we test whether parents’ paid and unpaid time demands and the presence of young children equally reduce mothers’ and fathers’ sleep, comparing the married/cohabiting to unmarried. Applying data from the American Time Use Survey (ATUS, 2003–2016), we find married/cohabiting mothers report less sleep when young children or multiple children are present; they are employed; their spouses are employed; and they spend more time in housework and childcare. By contrast, unmarried mothers report less sleep when children are present because of their larger domestic loads. For married/cohabiting fathers, the presence of multiple children is associated with less sleep but doing more housework results in more sleep. Finally, unmarried fathers’ employment time explains the association of children on their sleep. Parents report a sleep deficit relative to the childless but the reasons vary by gender and the co-presence of a partner.

POS0998 SPONDYLOARTHRITIS AND SLEEP DISORDERS

Background:Spondyloarthropathies (SpA) are a group of chronic and progressive diseases, characterized in particular by a progressive stiffening of the spine, spreading to neighboring joints or to certain tissues, which could lead in the long term to progressive stiffening and functional impairment. This conditioncancauseinsomnia problems and impaired sleep quality.Objectives:To assess the impact of SpA on the quality of sleep.Methods:This is a retrospective study over a period of 4 years from January 2015 to December 2019, including all the medical records of patients with SpA followed in the Department of Rheumatology of the University Hospital of Ibn Rochd, Casablanca. We evaluated for each patient two validated scores: the Epworth somnolence scale rated from 0 to 24, and the Pittsburgh sleep score rated from 0 to 21 with 7 components. Patients with a psychiatric history or who were followed up for neurological pathologies were excluded.Results:178 patients were included. 60.67% were men with an average age of 36.32 years (14-68 years). 45.01% had axial SpA, 29.77% had psoriatic arthritis, and 25.22% were followed for SpA associated with inflammatory bowel disease. 45% had associated comorbidities: there were 18 diabetics and 34 hypertensive, 16.58% were smokers. Clinically, 85.42% presented a back pain initially on examination, 55% presented a polyarthralgia, and 39.88% an oligoarthritis. 63% had radiological sacroiliitis, and 35.14% had bilateral coxitis. 13.48% had a positive HLA B27 and 58.89% had a positive inflammatory assessment with very high activity indices,with a mean of 4.6. 64.66% of the patients received NSAIDs,of which 11% responded well. 57% were treated with csDMARDs, and 17.86% were treated with biologics. At the time of our study, the mean visual analog scale was 5.84 ± 1.7 out of 10 (2-9). The mean Epworth score was 8.38 ± 5.2 (0-21). 56.1% of patients had no sleep debt, 33.3% had a sleep deficit, and only 10.6% had signs of drowsiness. For the overall Pittsburgh score, the mean was 7.02 ± 3.6 (1-18). The mean of “subjective quality of sleep” was 1.12, “sleep latency” was 1.22, “duration of sleep” was 1.06, “usual sleep efficiency” was 0.74, “Sleep disturbance” of 1.28, “use of a sleep medication” of 0.54, and the average of the component concerning “poor shape during the day” was 1.03 out of 3. The LEQUESNE index went from an average of 6 to 8, which corresponds to an average handicap (P = 0.2) over a period of 3 years. 68% of the patients had an alteration in the quality of sleep, starting on average three years after the onset of symptoms. 11% reported having experiencedanxiety and depressive symptoms, and reported having used antidepressants or anxiolytics in the past 5 years.Conclusion:Our study showed the negative impact of SpA on the duration and overall quality of sleep. The degree of pain as well as functional impairment can cause and worsen sleep disturbances in SpA. We have shown that the Pittsburg score increases significantly with the increase of pain.The Lequesne score and that the Epworth score increase with disease activity[1].References:[1]StolwijkC,vanTubergenA,Castillo-OrtizJD,BoonenA.Prevalenceofextra-articularmanifestationsinpatientswithankylosingspondylitis:asystematicreviewandmeta-analysis.AnnRheumDis2015;74:65—73.Disclosure of Interests:None declared.

149 Perceived sleep need, cumulative sleep deficit, and associations with daily affect in adolescents: 28 days over school & vacation

Introduction This study aimed to describe trajectories of daily perceived sleep need and sleep deficit across 28 consecutive days, and examine if cumulative sleep deficit predicts next-day affect. Methods Daily sleep and affect were measured over 2 weeks of school and 2 weeks of vacation in 205 adolescents (54.1% females, Mage = 16.9 years). Each day, participants completed actigraphy and self-reported the amount of sleep needed to function well the next day (i.e., perceived sleep need), sleep duration, and high- and low-arousal positive and negative affect. Cumulative actigraphy and diary sleep deficit were calculated as difference between perceived sleep need and sleep duration, weighted by sleep deficit over the past 3 days. Cross-lagged, multilevel models were used to test cumulative sleep deficit as a predictor of next-day affect. Lagged affect, day of the week, study day, and sociodemographics were controlled. Results Perceived sleep need was lower early in the school week, before increasing in the second half of the week. Adolescents accumulated sleep deficit across school days and reduced it during weekends. During weekends and vacations, adolescents’ self-reported, but not actigraphy sleep duration, met perceived sleep need. Higher cumulative actigraphy sleep deficit predicted higher next-day high arousal negative affect; higher cumulative diary sleep deficit predicted higher negative affect (regardless of arousal), and lower low arousal positive affect the following day. Conclusion Adolescents experienced sustained cumulative sleep deficit across school days, and whilst non-school nights appeared to be opportunities for reducing sleep deficit. Trajectories of sleep deficit during vacation suggested recovery from school-related sleep restriction. Cumulative sleep deficit was related to affect on a daily basis, highlighting the value of this measure for future research and interventions. Support (if any):

Sleep deficit in COVID-19 health-care workers may increase the infection risk

The COVID-19 pandemic has had negative effects on health-care workers. The rapid growth of the disease has led to overwhelmed health-care systems, overcrowded hospitals, an insufficient number of health-care professionals and shortages of medical equipment. The potential exposure of front-line health-care workers during the COVID-19 outbreak has led to self-isolation and the appearance of adverse feelings such as stress, anxiety and fear. All these factors, combined with an increased workload and extra and changed shifts, are determinants of a sleep-loss process that may result in insomnia. The exacerbated pro-inflammatory milieu caused by insomnia and sleep deprivation present in health professionals may therefore make them more prone to developing severe COVID-19 if infected and/or aggravate the symptoms of the disease. Keeping these professionals healthy and doing everything possible to prevent them from being infected with COVID-19 should be a top priority. As part of this effort, we must be aware of the important effects of insomnia on the immune systems of these professionals and take all possible measures to counter these effects.

Does Work after Retirement Matter? Sleep Features among Workers in the Brazilian Longitudinal Study of Adult Health

A growing number of people keep working after retirement, a phenomenon known as bridge employment. Sleep features, which are related to morbidity and mortality outcomes, are expected to be influenced by bridge employment or permanent retirement. The objective of this study was to analyze sleep duration and quality of bridge employees and permanent retirees compared to nonretired, i.e., active workers, from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Participants (second wave of ELSA-Brasil, 2012–2014) comprised permanently retired (n = 2348), career bridge workers (n = 694), bridge workers in a different place (n = 760), and active workers (n = 6271). The associations of all studied retirement schemes and self-reported sleep quality and duration were estimated through logistic and linear regression analysis. Workers from all studied retirement schemes showed better sleep patterns than active workers. In comparison to active workers, bridge workers who had changed workplace also showed a reduced chance of difficulty falling asleep and too-early awakenings, which were not found among career bridge workers. Bridge employment and permanent retirement were associated with a reduced chance of reporting sleep deficit. Bridge work at a different place rather than staying at the same workplace seems to be favorable for sleep. Further study is needed to explain mechanisms.

Eyeblink Detection in the Field: A Proof of Concept Study of Two Mobile Optical Eye-Trackers

ABSTRACT Introduction High physical and cognitive strain, high pressure, and sleep deficit are part of daily life for military professionals and civilians working in physiologically demanding environments. As a result, cognitive and physical capacities decline and the risk of illness, injury, or accidents increases. Such unfortunate outcomes could be prevented by tracking real-time physiological information, revealing individuals’ objective fatigue levels. Oculometrics, and especially eyeblinks, have been shown to be promising biomarkers that reflect fatigue development. Head-mounted optical eye-trackers are a common method to monitor these oculometrics. However, studies measuring eyeblink detection in real-life settings have been lacking in the literature. Therefore, this study aims to validate two current mobile optical eye-trackers in an unrestrained military training environment. Materials and Method Three male participants (age 20.0 ± 1.0) of the Swiss Armed Forces participated in this study by wearing three optical eye-trackers, two VPS16s (Viewpointsystem GmbH, Vienna, Austria) and one Pupil Core (Pupil Labs GmbH, Berlin, Germany), during four military training events: Healthcare education, orienteering, shooting, and military marching. Software outputs were analyzed against a visual inspection (VI) of the video recordings of participants’ eyes via the respective software. Absolute and relative blink numbers were provided. Each blink detected by the software was classified as a “true blink” (TB) when it occurred in the software output and the VI at the same time, as a “false blink” (FB) when it occurred in the software but not in the VI, and as a “missed blink” (MB) when the software failed to detect a blink that occurred in the VI. The FBs were further examined for causes of the incorrect recordings, and they were divided into four categories: “sunlight,” “movements,” “lost pupil,” and “double-counted”. Blink frequency (i.e., blinks per minute) was also analyzed. Results Overall, 49.3% and 72.5% of registered eyeblinks were classified as TBs for the VPS16 and Pupil Core, respectively. The VPS16 recorded 50.7% of FBs and accounted for 8.5% of MBs, while the Pupil Core recorded 27.5% of FBs and accounted for 55.5% of MBs. The majority of FBs—45.5% and 73.9% for the VPS16 and Pupil Core, respectively—were erroneously recorded due to participants’ eye movements while looking up, down, or to one side. For blink frequency analysis, systematic biases (±limits of agreement) stood at 23.3 (±43.5) and −4.87 (±14.1) blinks per minute for the VPS16 and Pupil Core, respectively. Significant differences in systematic bias between devices and the respective VIs were found for nearly all activities (P < .05). Conclusion An objective physiological monitoring of fatigue is necessary for soldiers as well as civil professionals who are exposed to higher risks when their cognitive or physical capacities weaken. However, optical eye-trackers’ accuracy has not been specified under field conditions—especially not in monitoring fatigue. The significant overestimation and underestimation of the VPS16 and Pupil Core, respectively, demonstrate the general difficulty of blink detection in the field.

Perceived sleep need, cumulative sleep deficit, and associations with daily affect in adolescents: A 28-day study over school and vacation periods

Study Objectives: To describe trajectories of daily perceived sleep need (PSNeed) and sleep deficit across 28 consecutive days, and examine if cumulative sleep deficit predicts next-day affect.Methods: Daily sleep and affect were measured over 2 weeks of school and 2 weeks of vacation in 205 adolescents (54.1% females, Mage = 16.9 years). Each day, participants wore actigraphs and self-reported the amount of sleep needed to function well the next day (i.e., perceived sleep need), sleep duration, and high- and low-arousal positive and negative affect (PA, NA). Cumulative actigraphy and diary sleep deficit were calculated as the weighted average of the difference between PSNeed and sleep duration over the past 3 days. Cross-lagged, multilevel models were used to test cumulative sleep deficit as a predictor of next-day affect. Lagged affect, day of the week, study day, and sociodemographics were controlled.Results: PSNeed was lower early in the school week, before increasing in the second half of the week. Adolescents accumulated sleep deficit across school days and reduced it during weekends. During weekends and vacations, adolescents’ self-reported, but not actigraphy sleep duration, met PSNeed. Higher cumulative actigraphy sleep deficit predicted higher next-day high arousal NA; higher cumulative diary sleep deficit predicted higher NA (regardless of arousal), and lower low arousal PA the following day.Conclusions: Adolescents experienced sustained cumulative sleep deficit across school days. Non-school nights appeared to be opportunities for reducing sleep deficit. Trajectories of sleep deficit during vacation suggested recovery from school-related sleep restriction.

Effects of Sleep Deprivation on the Brain Electrical Activity in Mice

Sleep plays a crucial role in maintaining brain health. Insufficient sleep leads to an enhanced permeability of the blood–brain barrier and the development of diseases of small cerebral vessels. In this study, we discuss the possibility of detecting changes in the electrical activity of the brain associated with sleep deficit, using an extended detrended fluctuation analysis (EDFA). We apply this approach to electroencephalograms (EEG) in mice to identify signs of changes that can be caused by short-term sleep deprivation (SD). Although the SD effect is usually subject-dependent, analysis of a group of animals shows the appearance of a pronounced decrease in EDFA scaling exponents, describing power-law correlations and the impact of nonstationarity as a fairly typical response. Using EDFA, we revealed an SD effect in 9 out of 10 mice (Mann–Whitney test, p<0.05) that outperforms the DFA results (7 out of 10 mice). This tool may be a promising method for quantifying SD-induced pathological changes in the brain.

Brain reactivity using fMRI to insomnia stimuli in insomnia patients with discrepancy between subjective and objective sleep

Subjective–objective discrepancy of sleep (SODS) might be related to the distorted perception of sleep deficit and hypersensitivity to insomnia-related stimuli. We investigated differences in brain activation to insomnia-related stimuli among insomnia patients with SODS (SODS group), insomnia patients without SODS (NOSODS group), and healthy controls (HC). Participants were evaluated for subjective and objective sleep using sleep diary and polysomnography. Functional magnetic resonance imaging was conducted during the presentation of insomnia-related (Ins), general anxiety-inducing (Gen), and neutral (Neu) stimuli. Brain reactivity to the contrast of Ins vs. Neu and Gen vs. Neu was compared among the SODS (n = 13), NOSODS (n = 15), and HC (n = 16) groups. In the SODS group compared to other groups, brain areas including the left fusiform, bilateral precuneus, right superior frontal gyrus, genu of corpus callosum, and bilateral anterior corona radiata showed significantly increased blood oxygen level dependent (BOLD) signal in the contrast of Ins vs. Neu. There was no brain region with significantly increased BOLD signal in the Gen vs. Neu contrast in the group comparisons. Increased brain activity to insomnia-related stimuli in several brain regions of the SODS group is likely due to these individuals being more sensitive to sleep-related threat and negative cognitive distortion toward insomnia.