Effects of low-dose acetylsalicylic acid on the inflammatory response to experimental sleep restriction in healthy humans.

BACKGROUND: Sleep deficiencies, such as manifested in short sleep duration or insomnia symptoms, are known to increase the risk for multiple disease conditions involving immunopathology. Inflammation is hypothesized to be a mechanism through which deficient sleep acts as a risk factor for these conditions. Thus, one potential way to mitigate negative health consequences associated with deficient sleep is to target inflammation. Few interventional sleep studies investigated whether improving sleep affects inflammatory processes, but results suggest that complementary approaches may be necessary to target inflammation associated with sleep deficiencies. We investigated whether targeting inflammation through low-dose acetylsalicylic acid (ASA, i.e., aspirin) is able to blunt the inflammatory response to experimental sleep restriction. METHODS: 46 healthy participants (19F/27M, age range 19-63 years) were studied in a double-blind randomized placebo-controlled crossover trial with three protocols each consisting of a 14-day at-home monitoring phase followed by an 11-day (10-night) in-laboratory stay (sleep restriction/ASA, sleep restriction/placebo, control sleep/placebo). In the sleep restriction/ASA condition, participants took low-dose ASA (81 mg/day) daily in the evening (22:00) during the at-home phase and the subsequent in-laboratory stay. In the sleep restriction/placebo and control sleep/placebo conditions, participants took placebo daily. Each in-laboratory stay started with 2 nights with a sleep opportunity of 8 h/night (23:00-07:00) for adaptation and baseline measurements. Under the two sleep restriction conditions, participants were exposed to 5 nights of sleep restricted to a sleep opportunity of 4 h/night (03:00-07:00) followed by 3 nights of recovery sleep with a sleep opportunity of 8 h/night. Under the control sleep condition, participants had a sleep opportunity of 8 h/night throughout the in-laboratory stay. During each in-laboratory stay, participants had 3 days of intensive monitoring (at baseline, 5th day of sleep restriction/control sleep, and 2nd day of recovery sleep). Variables, including pro-inflammatory immune cell function, C-reactive protein (CRP), and actigraphy-estimated measures of sleep, were analyzed using generalized linear mixed models. RESULTS: Low-dose ASA administration reduced the interleukin (IL)-6 expression in LPS-stimulated monocytes (p<0.05 for condition*day) and reduced serum CRP levels (p<0.01 for condition) after 5 nights of sleep restriction compared to placebo administration in the sleep restriction condition. Low-dose ASA also reduced the amount of cyclooxygenase (COX)-1/COX-2 double positive cells among LPS-stimulated monocytes after 2 nights of recovery sleep following 5 nights of sleep restriction compared to placebo (p<0.05 for condition). Low-dose ASA further decreased wake after sleep onset (WASO) and increased sleep efficiency (SE) during the first 2 nights of recovery sleep (p<0.001 for condition and condition*day). Baseline comparisons revealed no differences between conditions for all of the investigated variables (p>0.05 for condition). CONCLUSION: This study shows that inflammatory responses to sleep restriction can be reduced by preemptive administration of low-dose ASA. This finding may open new therapeutic approaches to prevent or control inflammation and its consequences in those experiencing sleep deficiencies. TRIAL REGISTRATION: ClinicalTrials.gov NCT03377543.

Prolonged experimental sleep disturbance affects the inflammatory resolution pathways in healthy humans.

BACKGROUND: Sleep disturbances, as manifested in insomnia symptoms of difficulties falling asleep or frequent nighttime awakenings, are a strong risk factor for a diverse range of diseases involving immunopathology. Low-grade systemic inflammation has been frequently found associated with sleep disturbances and may mechanistically contribute to increased disease risk. Effects of sleep disturbances on inflammation have been observed to be long lasting and remain after recovery sleep has been obtained, suggesting that sleep disturbances may not only affect inflammatory mediators, but also the so-called specialized pro-resolving mediators (SPMs) that actively resolve inflammation. The goal of this investigation was to test for the first time whether the omega-3 fatty acid-derived D- (RvD) and E-series (RvE) resolvins are impacted by prolonged experimental sleep disturbance (ESD). METHODS: Twenty-four healthy participants (12 F, age 20-42 years) underwent two 19-day in-hospital protocols (ESD/control), separated by > 2 months. The ESD protocol consisted of repeated nights of short and disrupted sleep with intermittent nights of undisturbed sleep, followed by three nights of recovery sleep at the end of the protocol. Under the control sleep condition, participants had an undisturbed sleep opportunity of 8 h/night throughout the protocol. The D- and E-series resolvins were measured in plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: The precursor of the D-series resolvins, 17-HDHA, was downregulated in the ESD compared to the control sleep condition (p <.001 for condition), and this effect remained after the third night of recovery sleep has been obtained. This effect was also observed for the resolvins RvD3, RvD4, and RvD5 (p <.001 for condition), while RvD1 was higher in the ESD compared to the control sleep condition (p <.01 for condition) and RvD2 showed a mixed effect of a decrease during disturbed sleep followed by an increase during recovery sleep in the ESD condition (p <.001 for condition*day interaction). The precursor of E-series resolvins, 18-HEPE, was downregulated in the ESD compared to the control sleep condition (p <.01 for condition) and remained low after recovery sleep has been obtained. This effect of downregulation was also observed for RvE2 (p <.01 for condition), while there was no effect for RvE1 (p >.05 for condition or condition*day interaction). Sex-differential effects were found for two of the D-series resolvins, i.e., RvD2 and RvD4. CONCLUSION: This first investigation on the effects of experimental sleep disturbance on inflammatory resolution processes shows that SPMs, particularly resolvins of the D-series, are profoundly downregulated by sleep disturbances and remain downregulated after recovery sleep has been obtained, suggesting a longer lasting impact of sleep disturbances on these mediators. These findings also suggest that sleep disturbances contribute to the development and progression of a wide range of diseases characterized by immunopathology by interfering with processes that actively resolve inflammation. Pharmacological interventions aimed at promoting inflammatory resolution physiology may help to prevent future disease risk as a common consequence of sleep disturbances. TRIAL REGISTRATION: ClinicalTrials.gov NCT02484742.

Sleep Duration and Blood Pressure: Recent Advances and Future Directions.

PURPOSE OF REVIEW: This review discusses the recent literature on subjectively and objectively assessed sleep duration in relation to hypertension risk and out-of-clinic blood pressure (BP) measures and highlights critical areas for future research. RECENT FINDINGS: Sleep duration, particularly short sleep, may influence BP through disturbed autonomic balance, hormonal imbalances, increased adiposity and metabolic dysfunction, and disrupted circadian rhythms. Observational studies indicate that short and long sleep are associated with hypertension risk, reduced nocturnal dipping, and elevated morning BP, but evidence is stronger for short sleep. Experimental sleep restriction increases BP, while sleep extension may lower BP in prehypertensive individuals. Women and racial/ethnic minorities are more prone to the detrimental effects of short sleep on BP. Additional studies are warranted to clarify the association of objectively assessed sleep with BP level and diurnal pattern and to determine the sex- and race-specific effects of sleep restriction and extension on BP.

Repeating patterns of sleep restriction and recovery: Do we get used to it?

Despite its prevalence in modern society, little is known about the long-term impact of restricting sleep during the week and 'catching up' on weekends. This common sleep pattern was experimentally modeled with three weeks of 5 nights of sleep restricted to 4h followed by two nights of 8-h recovery sleep. In an intra-individual design, 14 healthy adults completed both the sleep restriction and an 8-h control condition, and the subjective impact and the effects on physiological markers of stress (cortisol, the inflammatory marker IL-6, glucocorticoid receptor sensitivity) were assessed. Sleep restriction was not perceived to be subjectively stressful and some degree of resilience or resistance to the effects of sleep restriction was observed in subjective domains. In contrast, physiological stress response systems remain activated with repeated exposures to sleep restriction and limited recovery opportunity. Morning IL-6 expression in monocytes was significantly increased during week 2 and 3 of sleep restriction, and remained increased after recovery sleep in week 2 (p<0.05) and week 3 (p<0.09). Serum cortisol showed a significantly dysregulated 24h-rhythm during weeks 1, 2, and 3 of sleep restriction, with elevated morning cortisol, and decreased cortisol in the second half of the night. Glucocorticoid sensitivity of monocytes was increased, rather than decreased, during the sleep restriction and sleep recovery portion of each week. These results suggest a disrupted interplay between the hypothalamic-pituitary-adrenal and inflammatory systems in the context of repeated exposure to sleep restriction and recovery. The observed dissociation between subjective and physiological responses may help explain why many individuals continue with the behavior pattern of restricting and recovering sleep over long time periods, despite a cumulative deleterious physiological effect.

Heart rate variability during sleep onset in patients with insomnia with or without comorbid sleep apnea.

OBJECTIVES: Pre-sleep stress or hyperarousal is a known key etiological component in insomnia disorder. Despite this, physiological alterations during the sleep onset are not well-understood. In particular, insomnia and obstructive sleep apnea (OSA) are highly prevalent co-morbid conditions, where autonomic regulation may be altered. We aimed to characterize heart rate variability (HRV) during sleep onset as a potential measure of pre-sleep hyperarousal. METHODS: We described the profile of pre-sleep HRV measures and explore autonomic differences in participants with self-reported insomnia disorder (with no OSA, n = 69; with mild OSA, n = 70; with moderate or severe OSA, n = 66), compared to normal sleep controls (n = 123). Heart rate data during the sleep onset process were extracted for HRV analyses. RESULTS: During the sleep onset process, compared to normal sleep controls, participants with insomnia had altered HRV, indicated by higher heart rate (p = 0.004), lower SDNN (p = 0.003), reduced pNN20 (p < 0.001) and pNN50 (p = 0.010) and lower powers (p < 0.001). Participants with insomnia and moderate/severe OSA may have further deteriorated HRV outcomes compared to no/mild OSA patients with insomnia but differences were not significant. Insomnia itself was associated with significantly higher heart rate, lower pNN20, and lower high frequency power even after adjustment for age, gender, BMI and OSA severity. CONCLUSIONS: Participants with insomnia had lower vagal activity during the sleep onset period, which may be compounded by OSA, reflected in higher heart rates and lower HRV. These altered heart rate dynamics may serve as a physiological biomarker for insomnia during bedtime wakefulness, or as a potential tool to evaluate the efficacy of behavioral interventions which target bedtime stress.

Nirmatrelvir-Ritonavir for Acute COVID-19 in Patients With Cardiovascular Disease and Postacute Sequelae of SARS-CoV-2 Infection.

Background: There is limited evidence of association of nirmatrelvir-ritonavir (NMV-r) and incidence of postacute sequelae of SARS-CoV-2 infection (PASC) in patients with pre-existing cardiovascular disease (CVD). Objectives: The objective of this study was to assess the association of NMV-r in nonhospitalized, vaccinated patients with pre-existing CVD and occurrence of PASC. Methods: We conducted a retrospective cohort study utilizing the TriNetX research network, including vaccinated patients with pre-existing CVD who developed COVID-19 between December 2021 and December 2022. Two cohorts were created based on NMV-r administration within 5 days of diagnosis: NMV-r and non-NMV-r cohort. The main outcome was presence of PASC, assessed between 30 to 90 days and 90 to 180 days after index COVID-19 infection. After propensity score matching, both cohorts were compared using t-test and chi-square test for continuous and categorical variables, respectively. Results: A total of 26,953 patients remained in each cohort after propensity score matching. Broadly defined PASC occurred in 6,925 patients (26%) in the NMV-r cohort vs 8,150 patients (30.6%) in the non-NMV-r cohort (OR: 0.80; 95% CI: 0.76-0.82; P < 0.001) from 30 to 90 days and in 6,692 patients (25.1%) as compared to 8,910 patients (33.5%) (OR: 0.25, 95% CI: 0.23-0.29; P < 0.001) from 90 to 180 days. Similarly, narrowly defined PASC occurred in 5,335 patients (20%) in the NMV-r cohort vs 6,271 patients (23.6%) in the non-NMV-r cohort between 30 and 90 days (OR: 0.81, 95% CI: 0.78-0.84, P < 0.001) and in 5,121 patients (19.2%) as compared to 6,964 patients (26.1%) (OR: 0.67, 95% CI: 0.64-0.70, P < 0.001) between 90 and 180 days. Conclusions: NMV-r in nonhospitalized vaccinated patients with pre-existing CVD with COVID-19 was associated with a reduction in PASC and health care utilization.

Increasing sleep duration to lower beat-to-beat blood pressure: a pilot study.

Strong evidence has accumulated over the last several years, showing that low sleep quantity and/or quality plays an important role in the elevation of blood pressure. We hypothesized that increasing sleep duration serves as an effective behavioral strategy to reduce blood pressure in prehypertension or type 1 hypertension. Twenty-two participants with prehypertension or stage 1 hypertension, and habitual sleep durations of 7 h or less, participated in a 6-week intervention study. Subjects were randomized to a sleep extension group (48 ± 12 years, N = 13) aiming to increase bedtime by 1 h daily over a 6-week intervention period, or to a sleep maintenance group (47 ± 12 years, N = 9) aiming to maintain habitual bedtimes. Both groups received sleep hygiene instructions. Beat-to-beat blood pressure was monitored over 24 h, and 24-h urine and a fasting blood sample were collected pre- and post-intervention. Subjects in the sleep extension group increased their actigraphy-assessed daily sleep duration by 35 ± 9 min, while subjects in the sleep maintenance condition increased slightly by 4 ± 9 min (P = 0.03 for group effect). Systolic and diastolic beat-to-beat blood pressure averaged across the 24-h recording period significantly decreased from pre- to post-intervention visit in the sleep extension group by 14 ± 3 and 8 ± 3 mmHg, respectively (P < 0.05). Though the reduction of 7 ± 5 and 3 ± 4 mmHg in the sleep maintenance group was not significant, it did not differ from the blood pressure reduction in the sleep extension group (P = 0.15 for interaction effect). These changes were not paralleled by pre- to post-intervention changes in inflammatory or sympatho-adrenal markers, nor by changes in caloric intake. While these preliminary findings have to be interpreted with caution due to the small sample size, they encourage future investigations to test whether behavioral interventions designed to increase sleep duration serve as an effective strategy in the treatment of hypertension.

Timing of restricted sleep: mood and neurobehavioral outcomes in healthy sleepers.

Study Objective: To evaluate how nocturnal timing of sleep restriction affects vigilant attention and mood in healthy controls with normal sleep-wake patterns. Methods: A convenience sample from two controlled sleep restriction protocols were used to investigate the difference between 4 hours of sleep early in the night, versus 4 hours late in the night. Volunteers stayed in a hospital setting and were randomized to one of the three conditions: a control (8 hours of sleep each night), an early short sleep (ESS, 2300-0300 hours), and a late short sleep (LSS, 0300-0700 hours). Participants were evaluated with psychomotor vigilance task (PVT) and mood ratings via visual analog scales. Results: Short sleep conditions led to greater performance decrements than control on PVT. LSS performance impairments were greater than control (lapses, p = 0.011; median RT, p = 0.029; fastest 10%, p = 0.038; reciprocal RT, p = 0.014; and reciprocal 10%, p = 0.005), but had higher positive mood ratings (p = 0.005). LSS also had higher positive mood ratings compared with ESS (p < 0.001). Conclusions: The data underscore the negative mood impact of waking at an adverse circadian phase, for healthy controls. In addition, the paradoxical relationship between mood and performance seen in LSS raises concerns that staying up late and waking at the usual rise time may be rewarding in terms of mood, but nonetheless have performance consequences that may not be fully recognized.

Monitoring sleep using smartphone data in a population of college students.

Sleep is fundamental to all health, especially mental health. Monitoring sleep is thus critical to delivering effective healthcare. However, measuring sleep in a scalable way remains a clinical challenge because wearable sleep-monitoring devices are not affordable or accessible to the majority of the population. However, as consumer devices like smartphones become increasingly powerful and accessible in the United States, monitoring sleep using smartphone patterns offers a feasible and scalable alternative to wearable devices. In this study, we analyze the sleep behavior of 67 college students with elevated levels of stress over 28 days. While using the open-source mindLAMP smartphone app to complete daily and weekly sleep and mental health surveys, these participants also passively collected phone sensor data. We used these passive sensor data streams to estimate sleep duration. These sensor-based sleep duration estimates, when averaged for each participant, were correlated with self-reported sleep duration (r = 0.83). We later constructed a simple predictive model using both sensor-based sleep duration estimates and surveys as predictor variables. This model demonstrated the ability to predict survey-reported Pittsburgh Sleep Quality Index (PSQI) scores within 1 point. Overall, our results suggest that smartphone-derived sleep duration estimates offer practical results for estimating sleep duration and can also serve useful functions in the process of digital phenotyping.

Dismantling the Component-Specific Effects of Yogic Breathing: Feasibility of a Fully Remote Three-Arm RCT with Virtual Laboratory Visits and Wearable Physiology.

Despite the growing research base examining the benefits and physiological mechanisms of slow-paced breathing (SPB), mindfulness (M), and their combination (as yogic breathing, SPB + M), no studies have directly compared these in a "dismantling" framework. To address this gap, we conducted a fully remote three-armed feasibility study with wearable devices and video-based laboratory visits. Eighteen healthy participants (age 18-30 years, 12 female) were randomized to one of three 8-week interventions: slow-paced breathing (SPB, N = 5), mindfulness (M, N = 6), or yogic breathing (SPB + M, N = 7). The participants began a 24-h heart rate recording with a chest-worn device prior to the first virtual laboratory visit, consisting of a 60-min intervention-specific training with guided practice and experimental stress induction using a Stroop test. The participants were then instructed to repeat their assigned intervention practice daily with a guided audio, while concurrently recording their heart rate data and completing a detailed practice log. The feasibility was determined using the rates of overall study completion (100%), daily practice adherence (73%), and the rate of fully analyzable data from virtual laboratory visits (92%). These results demonstrate feasibility for conducting larger trial studies with a similar fully remote framework, enhancing the ecological validity and sample size that could be possible with such research designs.

Impact of Pulmonary and Sleep Disorders on COVID-19 Infection Severity in a Large Clinical Biobank.

Rationale: Multiple pulmonary, sleep, and other disorders are associated with the severity of Covid-19 infections but may or may not directly affect the etiology of acute Covid-19 infection. Identifying the relative importance of concurrent risk factors may prioritize respiratory disease outbreaks research. Objectives: To identify associations of common preexisting pulmonary and sleep disease on acute Covid-19 infection severity, investigate the relative contributions of each disease and selected risk factors, identify sex-specific effects, and examine whether additional electronic health record (EHR) information would affect these associations. Methods: 45 pulmonary and 6 sleep diseases were examined in 37,020 patients with Covid-19. We analyzed three outcomes: death; a composite measure of mechanical ventilation and/or ICU admission; and inpatient admission. The relative contribution of pre-infection covariates including other diseases, laboratory tests, clinical procedures, and clinical note terms was calculated using LASSO. Each pulmonary/sleep disease model was then further adjusted for covariates. Measurements and main results: 37 pulmonary/sleep diseases were associated with at least one outcome at Bonferroni significance, 6 of which had increased relative risk in LASSO analyses. Multiple prospectively collected non-pulmonary/sleep diseases, EHR terms and laboratory results attenuated the associations between preexisting disease and Covid-19 infection severity. Adjustment for counts of prior "blood urea nitrogen" phrases in clinical notes attenuated the odds ratio point estimates of 12 pulmonary disease associations with death in women by ≥1. Conclusions: Pulmonary diseases are commonly associated with Covid-19 infection severity. Associations are partially attenuated by prospectively-collected EHR data, which may aid in risk stratification and physiological studies.

Beyond the symptom: the biology of fatigue.

A workshop titled "Beyond the Symptom: The Biology of Fatigue" was held virtually September 27-28, 2021. It was jointly organized by the Sleep Research Society and the Neurobiology of Fatigue Working Group of the NIH Blueprint Neuroscience Research Program. For access to the presentations and video recordings, see: https://neuroscienceblueprint.nih.gov/about/event/beyond-symptom-biology-fatigue. The goals of this workshop were to bring together clinicians and scientists who use a variety of research approaches to understand fatigue in multiple conditions and to identify key gaps in our understanding of the biology of fatigue. This workshop summary distills key issues discussed in this workshop and provides a list of promising directions for future research on this topic. We do not attempt to provide a comprehensive review of the state of our understanding of fatigue, nor to provide a comprehensive reprise of the many excellent presentations. Rather, our goal is to highlight key advances and to focus on questions and future approaches to answering them.

Vascular endothelial growth factor is an important determinant of sepsis morbidity and mortality.

Sepsis, the systemic inflammatory response to infection, is a leading cause of morbidity and mortality. The mechanisms of sepsis pathophysiology remain obscure but are likely to involve a complex interplay between mediators of the inflammatory and coagulation pathways. An improved understanding of these mechanisms should provide an important foundation for developing novel therapies. In this study, we show that sepsis is associated with a time-dependent increase in circulating levels of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) in animal and human models of sepsis. Adenovirus-mediated overexpression of soluble Flt-1 (sFlt-1) in a mouse model of endotoxemia attenuated the rise in VEGF and PlGF levels and blocked the effect of endotoxemia on cardiac function, vascular permeability, and mortality. Similarly, in a cecal ligation puncture (CLP) model, adenovirus-sFlt-1 protected against cardiac dysfunction and mortality. When administered in a therapeutic regimen beginning 1 h after the onset of endotoxemia or CLP, sFlt peptide resulted in marked improvement in cardiac physiology and survival. Systemic administration of antibodies against the transmembrane receptor Flk-1 but not Flt-1 protected against sepsis mortality. Adenovirus-mediated overexpression of VEGF but not PlGF exacerbated the lipopolysaccharide-mediated toxic effects. Together, these data support a pathophysiological role for VEGF in mediating the sepsis phenotype.

Changes in Sleep Regularity and Perceived Life Stress across the COVID-19 Pandemic: A Longitudinal Analysis of a Predominately Female United States Convenience Sample.

The Coronavirus Disease 2019 (COVID-19) pandemic had a profound impact on sleep and psychological well-being for individuals worldwide. This pre-registered investigation extends our prior study by tracking self-reported social jetlag (SJL), social sleep restriction (SSR), and perceived life stress from May 2020 through October 2021. Using web-based surveys, we collected self-reported sleep information with the Ultrashort Munich Chronotype Questionnaire at three additional timepoints (September 2020, February 2021 and October 2021). Further, we measured perceived life stress with the Perceived Stress Scale at two additional timepoints (February 2021 and October 2021). In a subsample of 181, predominantly female (87%), United States adults aged 19-89 years, we expanded our prior findings by showing that the precipitous drop in SJL during the pandemic first wave (May 2020), compared to pre-pandemic (February, 2020), rapidly rose with loosening social restrictions (September 2020), though never returned to pre-pandemic levels. This effect was greatest in young adults, but not associated with self-reported chronotype. Further, perceived life stress decreased across the pandemic, but was unrelated to SJL or SSR. These findings suggest that sleep schedules were sensitive to pandemic-related changes in social restrictions, especially in younger participants. We posit several possible mechanisms supporting these findings.

Differential effects of an experimental model of prolonged sleep disturbance on inflammation in healthy females and males.

Sleep disturbances, including disrupted sleep and short sleep duration, are highly prevalent and are prospectively associated with an increased risk for various widespread diseases, including cardiometabolic, neurodegenerative, chronic pain, and autoimmune diseases. Systemic inflammation, which has been observed in populations experiencing sleep disturbances, may mechanistically link disturbed sleep with increased disease risks. To determine whether sleep disturbances are causally responsible for the inflammatory changes reported in population-based studies, we developed a 19-day in-hospital experimental model of prolonged sleep disturbance inducing disrupted and shortened sleep. The model included delayed sleep onset, frequent nighttime awakenings, and advanced sleep offset, interspersed with intermittent nights of undisturbed sleep. This pattern aimed at providing an ecologically highly valid experimental model of the typical sleep disturbances often reported in the general and patient populations. Unexpectedly, the experimental sleep disturbance model reduced several of the assessed proinflammatory markers, namely interleukin(IL)-6 production by monocytes and plasma levels of IL-6 and C-reactive protein (CRP), presumably due to intermittent increases in the counterinflammatory hormone cortisol. Striking sex differences were observed with females presenting a reduction in proinflammatory markers and males showing a predominantly proinflammatory response and reductions of cortisol levels. Our findings indicate that sleep disturbances causally dysregulate inflammatory pathways, with opposing effects in females and males. These results have the potential to advance our mechanistic understanding of the pronounced sexual dimorphism in the many diseases for which sleep disturbances are a risk factor.

Sleep and circadian informatics data harmonization: a workshop report from the Sleep Research Society and Sleep Research Network.

The increasing availability and complexity of sleep and circadian data are equally exciting and challenging. The field is in constant technological development, generating better high-resolution physiological and molecular data than ever before. Yet, the promise of large-scale studies leveraging millions of patients is limited by suboptimal approaches for data sharing and interoperability. As a result, integration of valuable clinical and basic resources is problematic, preventing knowledge discovery and rapid translation of findings into clinical care. To understand the current data landscape in the sleep and circadian domains, the Sleep Research Society (SRS) and the Sleep Research Network (now a task force of the SRS) organized a workshop on informatics and data harmonization, presented at the World Sleep Congress 2019, in Vancouver, Canada. Experts in translational informatics gathered with sleep research experts to discuss opportunities and challenges in defining strategies for data harmonization. The goal of this workshop was to fuel discussion and foster innovative approaches for data integration and development of informatics infrastructure supporting multi-site collaboration. Key recommendations included collecting and storing findable, accessible, interoperable, and reusable data; identifying existing international cohorts and resources supporting research in sleep and circadian biology; and defining the most relevant sleep data elements and associated metadata that could be supported by early integration initiatives. This report introduces foundational concepts with the goal of facilitating engagement between the sleep/circadian and informatics communities and is a call to action for the implementation and adoption of data harmonization strategies in this domain.

Causes and Consequences of Chronic Sleep Deficiency and the Role of Orexin.

Sleep is one of the pillars of health. Experimental models of acute sleep loss, of chronic partial sleep deprivation, and of sleep fragmentation in healthy sleepers are helpful models of sleep deficiency produced by insufficient sleep duration, sleep timing, and sleep disorders. Sleep deficiency is associated with changes in markers associated with risk for disease. These include metabolic, inflammatory, and autonomic markers of risk. In addition, sleep disruption and sleep deficits lead to mood instability, lack of positive outlook, and impaired neurobehavioral functioning. On a population level, insufficient sleep is associated with increased risk for hypertension and diabetes. Sleep disturbance is very common, and about half the population will report that they have experienced insomnia at some time in their lives. Approximately 10% of the population describe daytime impairment due to sleep disturbance at night, consistent with a diagnosis of insomnia disorder. The hypothalamic neuropeptides, orexin-A and orexin-B, act through G-protein-coupled receptors (orexin-1 and orexin-2 receptors). Dual and selective orexin-2 receptor antagonists have shown efficacy in inducing sleep in men and women with insomnia disorder by accelerating sleep onset and improving sleep efficiency and total sleep time. Further study comparing these medications, in short- and longer-term use models, is recommended. Greater understanding of comparative effects on mood, neurobehavioral, and physiological systems will help determine the extent of clinical utility of dual versus selective orexin receptor antagonists.

Macro- and microvascular reactivity during repetitive exposure to shortened sleep: sex differences.

Epidemiological studies have reported strong association between sleep loss and hypertension with unknown mechanisms. This study investigated macrovascular and microcirculation changes and inflammatory markers during repetitive sleep restriction. Sex differences were also explored. Forty-five participants completed a 22-day in-hospital protocol. Participants were assigned to, (1) eight-hour sleep per night (control), or (2) sleep restriction (SR) condition: participants slept from 0300 to 0700 h for three nights followed by a recovery night of 8-h sleep, repeated four times. Macrocirculation assessed by flow mediated dilation (FMD) and microcirculation reactivity tests were performed at baseline, last day of each experimental block and during recovery at the end. Cell adhesion molecules and inflammatory marker levels were measured in blood samples. No duration of deprivation (SR block) by condition interaction effects were found for FMD, microcirculation, norepinephrine, cell adhesion molecules, IL-6 or IL-8. However, when men and women were analyzed separately, there was a statistical trend (p = 0.08) for increased IL-6 across SR blocks in women, but not in men. Interestingly, men showed a significant progressive (dose dependent) increase in skin vasodilatation (p = 0.02). A novel and unexpected finding was that during the recovery period, men that had been exposed to repeated SR blocks had elevated IL-8 and decreased norepinephrine. Macrocirculation, microcirculation, cell adhesion molecules, and markers of inflammation appeared to be resistant to this model of short-term repetitive exposures to the blocks of shortened sleep in healthy sleepers. However, men and women responded differently, with women showing mild inflammatory response and men showing more vascular system sensitivity to the repetitive SR.

Sleep deficiency and chronic pain: potential underlying mechanisms and clinical implications.

Pain can be both a cause and a consequence of sleep deficiency. This bidirectional relationship between sleep and pain has important implications for clinical management of patients, but also for chronic pain prevention and public health more broadly. The review that follows will provide an overview of the neurobiological evidence of mechanisms thought to be involved in the modulation of pain by sleep deficiency, including the opioid, monoaminergic, orexinergic, immune, melatonin, and endocannabinoid systems; the hypothalamus-pituitary-adrenal axis; and adenosine and nitric oxide signaling. In addition, it will provide a broad overview of pharmacological and non-pharmacological approaches for the management of chronic pain comorbid with sleep disturbances and for the management of postoperative pain, as well as discuss the effects of sleep-disturbing medications on pain amplification.

The role of insomnia in the association between posttraumatic stress disorder and hypertension.

OBJECTIVE: Posttraumatic stress disorder (PTSD) is associated with incident hypertension. Although this relationship is poorly understood, PTSD is also associated with insomnia symptoms, which increases the risk for hypertension. Whether insomnia contributes to PTSD-associated risk for hypertension is unknown. METHODS: We examined self-report survey and electronic health record data from 1109 participants in the Women Veterans Cohort Study (mean age: 43.8 ±â€Š10.9 years; 52% women, 81% White) to assess the cross-sectional associations between PTSD symptom severity, recent symptoms of insomnia, and hypertension, defined as self-reported treatment for high blood pressure in the last year. Structural equation modeling was used to examine whether insomnia symptoms mediate the association between PTSD and hypertension. RESULTS: PTSD symptom severity was associated with hypertension (r = 0.09, P < 0.001). PTSD symptom severity and hypertension were each associated with the insomnia symptoms difficulty falling asleep, difficulty staying asleep, and worry/distress about sleep problems (PTSD: rs = 0.58--0.62, P <  0.001; hypertension: rs = 0.07--0.10, P <  0.001). A latent variable derived from those symptoms mediated 9% of the association between PTSD symptom severity and hypertension (P = 0.02). CONCLUSION: In this study of young and middle-aged Veterans, insomnia symptoms mediated the association between PTSD and hypertension. Difficulties falling asleep and maintaining sleep and related distress may be particularly deleterious for cardiovascular health in Veterans. Longitudinal data is required to further investigate the associations between PTSD, insomnia, and hypertension.