Comprehensive flow cytometric reference intervals of leukocyte subsets from six study centers across Europe.

A group of European FOCIS Centers of Excellence adapted panels of the Human Immunophenotyping Consortium (HIPC) for whole blood analysis. Using four core panels [T/regulatory T cell/B/natural killer (T/Treg /B/NK) and myeloid cells] the main leukocyte populations were analyzed in a clinical-diagnostic setting in a harmonized manner across different platforms. As a first step, the consortium presents here the absolute and relative frequencies of the leukocyte subpopulations in the peripheral blood of more than 300 healthy volunteers across six different European centers.

Blood immune cell biomarkers in lung cancer.

Characterization of host immune cell parameters prior to treatment is expected to identify biomarkers predictive of clinical outcome as well as to elucidate why some patients fail to respond to immunotherapy. We monitored blood immune cells from 58 patients with non-small- cell lung cancer (NSCLC) undergoing surgery of the primary tumor and from 50 age-matched healthy volunteers. Complete leukocyte blood count, the number of circulating dendritic cells (DC), HLA-DRlow monocytes and several lymphocytic subpopulations were determined by eight-color flow cytometry. Furthermore, the prognostic value of the immune cell parameters investigated was evaluated by patients' survival analysis. Compared to the control group, blood of NSCLC patients contained more neutrophils resulting in a higher neutrophil-to-lymphocyte ratio (NLR), but a lower number of blood DC, in particular of plasmacytoid DC (pDC), natural killer (NK) cells and naive CD4+ and CD8+ T cells. Furthermore, a higher frequency of CD4+ regulatory T cells (Treg) and HLA-DRlow monocytes was detected, and smoking had a significant impact on these values. HLA-DRlow monocytes were positively correlated to the number of neutrophils, monocytes and NLR, but negatively associated with the number of pDC and naive CD4+ T cells. The frequency of Treg, HLA-DRlow monocytes and naive CD4+ and CD8+ T cells as well as the ratios of CD4/HLA-DRlow monocytes and HLA-DRlow monocytes/pDC correlated with patient's overall survival. Next to Treg, HLA-DRlow monocytes and naive T cells represent prognostic markers for NSCLC patients and might be useful for monitoring of patients' responses to immunotherapies in future studies.

[Prevalence of sleep-related breathing disorders of inpatients with psychiatric disorders]. / Prävalenz schlafbezogener Atmungsstörungen bei stationären Patienten mit psychischen Erkrankungen.

BACKGROUND: Sleep-related breathing disorders seriously impair well-being and increase the risk for relevant somatic and psychiatric disorders. Moreover, risk factors for sleep-related breathing disorders are highly prevalent in psychiatric patients. The aim of this study was for the first time in Germany to study the prevalence of obstructive sleep apnea syndrome (OSAS) as the most common form of sleep-related breathing disorder in patients with psychiatric disorders. METHODS: In 10 psychiatric hospitals in Germany and 1 hospital in Switzerland, a total of 249 inpatients underwent an 8­channel sleep polygraphy to investigate the prevalence of sleep apnea in this group of patients. RESULTS: With a conspicuous screening result of 23.7% of the subjects, a high prevalence of sleep-related breathing disorders was found to occur among this group of patients. Male gender, higher age and high body mass index (BMI) were identified as positive risk factors for the detection of OSAS. DISCUSSION: The high prevalence indicates that sleep apnea is a common sleep disorder among psychiatric patients. Although OSAS can lead to substantial disorders of the mental state and when untreated is accompanied by serious somatic health problems, screening procedures are not part of the routine work-up in psychiatric hospitals; therefore, sleep apnea is presumably underdiagnosed in psychiatric patients. In view of the results of this and previous studies, this topic complex should be the subject of further research studies.

Insomnia symptoms, perceived stress and coping strategies in patients with systemic lupus erythematosus.

OBJECTIVE: The aim of this study is to evaluate perceived stress and coping strategies in individuals with systemic lupus erythematosus (SLE) according to the presence of insomnia symptoms, using a set of variables that include anxiety and depressive symptoms evaluation. METHODS: Ninety SLE women were evaluated in a cross-sectional study using the Perceived Stress Scale (PSS), Brief COPE, Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), Beck Depression Inventory (BDI) and Self-rating Anxiety Scale (SAS). RESULTS: Individuals with insomnia symptoms (n = 57, 66%) presented higher PSS (p < 0.001), PSQI (p < 0.0001), BDI, (p < 0.0001) scores and showed less-effective coping strategies such as the use of behavioral disengagement (p = 0.04), self-blame (p = 0.02) and emotional-focused coping (p = 0.001). In a multi-regression model ISI was the independent determinant of high PSS and of behavioral disengagement; PSQI was the only determinant of self-blame (p = 0.02) and emotional-focused coping. CONCLUSIONS: SLE individuals with insomnia symptoms show high levels of perceived stress and more frequent use of disengaging and emotional-focused coping strategies. This body of evidence suggests that individuals with SLE and comorbid insomnia symptoms may therefore require additional interventions for insomnia.

Neurology and psychiatry: waking up to opportunities of sleep. : State of the art and clinical/research priorities for the next decade.

In recent years, evidence has emerged for a bidirectional relationship between sleep and neurological and psychiatric disorders. First, sleep-wake disorders (SWDs) are very common and may be the first/main manifestation of underlying neurological and psychiatric disorders. Secondly, SWDs may represent an independent risk factor for neuropsychiatric morbidities. Thirdly, sleep-wake function (SWF) may influence the course and outcome of neurological and psychiatric disorders. This review summarizes the most important research and clinical findings in the fields of neuropsychiatric sleep and circadian research and medicine, and discusses the promise they bear for the next decade. The findings herein summarize discussions conducted in a workshop with 26 European experts in these fields, and formulate specific future priorities for clinical practice and translational research. More generally, the conclusion emerging from this workshop is the recognition of a tremendous opportunity offered by our knowledge of SWF and SWDs that has unfortunately not yet entered as an important key factor in clinical practice, particularly in Europe. Strengthening pre-graduate and postgraduate teaching, creating academic multidisciplinary sleep-wake centres and simplifying diagnostic approaches of SWDs coupled with targeted treatment strategies yield enormous clinical benefits for these diseases.

Poor sleep quality in systemic lupus erythematosus: does it depend on depressive symptoms?

OBJECTIVES: Sleep disturbances are frequently observed in rheumatic diseases including systemic lupus erythematosus (SLE). This study aimed at evaluating the prevalence of insomnia, poor sleep quality and their determinants in a cohort of SLE patients. METHODS: Eighty-one consecutive SLE female patients were evaluated in a cross-sectional study. The Pittsburgh Sleep Quality Index (PSQI), the Insomnia Severity Index (ISI), the Beck Depression Inventory (BDI) and the Self-rating Anxiety Scale (SAS) were administered. Patients with previous diagnosis of obstructive sleep apnea or restless legs syndrome were excluded. Fifty-three women with hypertension (without SLE) were enrolled as control group (H). RESULTS: In the SLE cohort poor sleep quality (65.4% vs 39.6%, p < 0.01) and difficulty in maintaining sleep and/or early morning awakening (65.4% vs 22.6%, p < 0.001), but not insomnia (33.3% vs 22.6%, p = ns), were more prevalent than in H. Depressive symptoms were present in 34.6% of SLE vs 13.2% H patients (p < 0.001) while state anxiety was more common in H patients (H 35.8% vs SLE 17.3%, p < 0.005). SLE was associated with a 2.5-times higher probability of presenting poor sleep quality in comparison to H (OR 2.5 [CI 1.21-5.16]). After adjusting for confounders, both depressive symptoms (OR 4.4, [1.4-14.3]) and use of immunosuppressive drugs (OR 4.3 [CI 1.3-14.8]) were significantly associated with poor sleep quality in SLE patients. Furthermore, poor sleep quality was not associated either with disease duration or activity. CONCLUSIONS: In a cohort of SLE women, insomnia and poor sleep quality, especially difficulties in maintaining sleep, were common. Depressive symptoms might be responsible for the higher prevalence of poor sleep quality in SLE.

The influence of 8 and 16 mg nicotine patches on sleep in healthy non-smokers.

AIM AND METHODS: The purpose of this study was to determine whether sleep changes are a consequence of nicotine presence or withdrawal during the night, we examined 66 healthy non-smokers (33 males, 33 females, age: 20-25 years) after an adaptation night in a sleep laboratory setting. Subjects were randomized to receive placebo or either 8 or 16 mg nicotine patches during the day or during the night in a double blind, parallel group design. RESULTS: The 16 mg nicotine patch applied during the night caused a reduced sleep period time and sleep efficiency as well as an increased wake time. A reduced REM-sleep latency and subjective sleep quality rating were found in subjects receiving nicotine during the night. Arousals, apneas and periodic leg movements were not affected by nicotine. DISCUSSION: This study documents insomnia-like sleep changes in healthy non-smokers caused by nicotine in a dose-dependent manner. There was no evidence for sleep-related withdrawal symptoms after 13 h of nicotine application.

[Insomnia--state of the science]. / Insomnien--Stand der Forschung.

Diagnostic systems such as the international classification of diseases (ICD-10) or the diagnostic and statistical manual of mental disorders (DSM IV) have frequently been criticized as not adequately reflecting the complexity and heterogeneity of insomnia. Progress was made through the introduction of the international classification of sleep disorders (ICSD-2) and the research diagnostic criteria (RDC). The DSM-5 introduced the new category of insomnia disorder, thus relinquishing the traditional dichotomy of primary versus secondary insomnia. Recent basic research indicates that genetic and epigenetic factors are involved in the etiology of insomnia; the so-called three P model (i.e. predisposing, precipitating and perpetuating factors) and the hyperarousal concept have gained much attention in trying to explain the pathophysiology of insomnia. With respect to the cognitive-behavioral therapy of insomnia (CBT-I), a plethora of empirical evidence supports the first-line character of this type of treatment for insomnia. Unfortunately, CBT-I is still administered to only a minority of afflicted patients, probably due to a lack of resources in the healthcare system. As a consequence, stepped-care models to improve insomnia therapy encompass self-help programs, internet-based treatment avenues, community-centered activities (specially trained nurses) and as a last resort medical specialists/psychotherapists and sleep experts to deal with insomnia.

[Sleep medicine differential diagnostics in psychiatry and psychotherapy]. / Schlafmedizinische Differenzialdiagnostik in Psychiatrie und Psychotherapie.

Complaints about disturbed sleep or increased daytime sleepiness are among the most frequent symptoms reported to psychiatrists by patients. Such complaints can be symptoms of an underlying psychiatric disorder or indicative of a separate or comorbid sleep disorder. Hence, basic knowledge in the differential diagnosis of sleep medicine pathologies is pivotal for psychiatrists and psychotherapists. In the present overview following a description of the diagnostic methods, the diagnostic work-up according to the major symptomatic clusters, namely disturbances in initiating and maintaining sleep, abnormal nocturnal movements and excessive daytime sleepiness will be presented.

Investigating non-inferiority of internet-delivered versus face-to-face cognitive behavioural therapy for insomnia (CBT-I): a randomised controlled trial (iSleep well).

BACKGROUND: Insomnia is a highly prevalent disorder associated with numerous adverse health outcomes. Cognitive behavioural therapy for insomnia (CBT-I) is recommended as first-line treatment by clinical guidelines but is accessible to only a minority of patients suffering from insomnia. Internet-delivered CBT-I (iCBT-I) could contribute to the widespread dissemination of this first-line treatment. As there is insufficient evidence regarding non-inferiority, this study directly aims to compare therapist-guided internet-delivered versus face-to-face CBT-I in terms of insomnia severity post-treatment. Furthermore, a health-economic evaluation will be conducted, and potential benefits and disadvantages of therapist-guided iCBT-I will be examined. METHODS: This study protocol describes a randomised controlled two-arm parallel-group non-inferiority trial comparing therapist-guided iCBT-I with face-to-face CBT-I in routine clinical care. A total of 422 patients with insomnia disorder will be randomised and treated at 16 study centres throughout Germany. Outcomes will be assessed at baseline, 10 weeks after randomisation (post), and 6 months after randomisation (follow-up). The primary outcome is insomnia severity measured using the Insomnia Severity Index. Secondary outcomes include depression-related symptoms, quality of life, fatigue, physical activity, daylight exposure, adverse events related to treatment, and a health-economic evaluation. Finally, potential moderator variables and several descriptive and exploratory outcomes will be assessed (e.g. benefits and disadvantages of internet-delivered treatment). DISCUSSION: The widespread implementation of CBT-I is a significant healthcare challenge. The non-inferiority of therapist-guided iCBT-I versus face-to-face CBT-I will be investigated in an adequately powered sample in routine clinical care, with the same therapeutic content and same level of therapist qualifications provided with both interventions. If this trial demonstrates the non-inferiority of therapist-guided iCBT-I, healthcare providers may be more confident recommending this treatment to their patients, contributing to the wider dissemination of CBT-I. TRIAL REGISTRATION: Trial registration number in the German Clinical Trials Register: DRKS00028153 ( https://drks.de/search/de/trial/DRKS00028153 ). Registered on 16th May 2023.

α-Adrenergic receptor function, arousal and sleep: mechanisms and therapeutic implications.

Noradrenergic (NE) neurotransmission and particularly α-adrenergic receptor function has been identified as a critical component of the sleep/wake regulation in animals and humans. This work (i) provides an update on the impact of NE neurotransmission on the sleep/wake regulation, (ii) summarizes the effects of α-receptor agonists and antagonists on arousal and sleep in animals and healthy humans, and (iii) reviews the current body of evidence for the effectiveness and safety of these compounds in the treatment of clinical conditions characterized by alterations of arousal or sleep, including attention deficit and hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), borderline personality disorder and primary sleep disorders. This systematic evaluation of the potential and limitations of the effects of α-adrenergic compounds might promote novel inroads for the treatment of these highly prevalent clinical conditions.

REM sleep instability--a new pathway for insomnia?

Chronic insomnia afflicts approximately 10% of the adult population and is associated with daytime impairments and an elevated risk for developing somatic and mental disorders. Current pathophysiological models propose a persistent hyperarousal on the cognitive, emotional and physiological levels. However, the marked discrepancy between minor objective alterations in standard parameters of sleep continuity and the profound subjective impairment in patients with insomnia is unresolved. We propose that "instability" of REM sleep contributes to the experience of disrupted and non-restorative sleep and to the explanation of this discrepancy. This concept is based on evidence showing increased micro- and macro-arousals during REM sleep in insomnia patients. As REM sleep represents the most highly aroused brain state during sleep it seems particularly prone to fragmentation in individuals with persistent hyperarousal. The continuity hypothesis of dream production suggests that pre-sleep concerns of patients with insomnia, i. e., worries about poor sleep and its consequences, dominate their dream content. Enhanced arousal during REM sleep may render these wake-like cognitions more accessible to conscious perception, memory storage and morning recall, resulting in the experience of disrupted and non-restorative sleep. Furthermore, chronic fragmentation of REM sleep might lead to dysfunction in a ventral emotional neural network, including limbic and paralimbic areas that are specifically activated during REM sleep. This dysfunction, along with attenuated functioning in a dorsal executive neural network, including frontal and prefrontal areas, might contribute to emotional and cognitive alterations and an elevated risk of developing depression.

Chronic insomnia: clinical and research challenges--an agenda.

Chronic insomnia afflicts up to 10% of the population in Western industrialized countries. It is characterized by delayed sleep onset, problems in maintaining sleep, early morning awakening or the feeling of non-restorative sleep coupled with significant daytime impairments on an emotional, social or professional level. It can occur as a co-morbid condition in any other medical or mental disorder, but also as a primary condition. Within the last decade new diagnostic and differential diagnostic approaches have been suggested that enhance diagnostic precision. Epidemiological data and data relating to the health care and cost situation of chronic insomnia suggest a huge burden for society. Chronic insomnia leads to a clear-cut increased risk for psychopathology (i. e., affective disorders) and probably also for cardiovascular and metabolic dysfunction. The pathophysiology of the condition is still poorly understood and will profit from integrating modern neuroscientific approaches (animal studies, molecular biology, neuroimaging, neurophysiology, etc.). Current treatment strategies are mainly based on cognitive behavioural interventions (CBT-I) and hypnotic treatment with benzodiazepine receptor agonists and sedating antidepressants. Although the effectiveness of these treatments has been clearly demonstrated, a substantial proportion of patients proves to be treatment-resistant or profits only poorly. The question of long-term pharmaceutical treatment of chronic insomnia, at least in Europe, is unresolved and urgently needs answers. Novel rational treatment avenues require clues on causes and mechanisms from integrated neuroscientific approaches. The important issues concerning insomnia treatment in the future especially in Europe will be reviewed and discussed critically.

[Substance-induced sleep disorders and abuse of hypnotics]. / Substanzinduzierte Schlafstörungen und Schlafmittelmissbrauch.

The intake of a large variety of substances has a negative impact on sleep. Widely used, readily available substances like alcohol, nicotine, or caffeine need to be mentioned here. Illicit drugs (e.g., heroin or ecstasy) have different mechanisms of action with a high sleep-disrupting potential. Prescription drugs, i.e., corticosteroids or ß-blockers, may also negatively affect sleep. An important question is whether the intake of hypnotics, especially benzodiazepines, may have a negative long-term effect on sleep. Classical benzodiazepines (BZ) initially lead to a reduction of nocturnal wake time and prolong total sleep time as a desired effect. Regarding the microstructure of sleep, BZ lead to a reduction of slow frequencies and an increase of fast frequencies in the EEG. With many BZ, tolerance may occur, thus, leading to unwanted dose increases. Further problems include rebound effects that occur upon discontinuation of BZ, including a drastic deterioration of sleep upon drug withdrawal. This phenomenon may pave the way for the development of drug dependency. Further unwanted side-effects (e.g., nocturnal falls) and the question of BZ abuse and dependency will be discussed.

[Lack of sleep and insomnia. Impact on somatic and mental health]. / Schlafmangel und Insomnie. Einfluss auf die körperliche und psychische Gesundheit.

Lack of sleep and insomnia need to be viewed differently. Lack of sleep implies a shortening of the habitual sleep duration due to external circumstances or motivational factors. Insomnia, in contrast, is defined as a sleep disorder due to unknown reasons for the afflicted subjects. People with insomnia suffer from being unable to sleep, in spite of adequate external circumstances. Research on lack of sleep/shortened sleep duration has focused on relationships with somatic and mental health. Longitudinal studies revealed that a shortening of sleep duration (< 6 h) is associated with an increased risk for the metabolic syndrome and cardiovascular diseases. For sleep duration and mortality, a U-shaped relationship was found, indicating that both shortened (< 6 h) and prolonged sleep durations (> 8 h) are associated with increased mortality. Similar, albeit weaker, correlations were described for insomnia and somatic health. In addition, insomnia is a risk factor for the development of mental disorders, especially depression. These relationships suggest that the area of sleep and sleep disorders should be integrated into everyday medical practice and that preventive approaches to somatic and mental disorders should encompass the topic of sleep to a much stronger extent than currently practiced.

Impact of escitalopram on nocturnal sleep, day-time sleepiness and performance compared to amitriptyline: a randomized, double-blind, placebo-controlled study in healthy male subjects.

INTRODUCTION: Antidepressant drugs vary in their effects on sleep, day-time sedation and performance. Up to now, no data are available for either escitalopram (ESCIT) or amitriptyline (AMI), measuring these by an objective test, such as the MULTIPLE SLEEP LATENCY TEST (MSLT). SUBJECTS AND METHODS: We therefore investigated the impact of a single evening dose of 10 mg ESCIT on polysomnographically recorded nocturnal sleep, day-time sleepiness and performance in comparison to 75 mg AMI and placebo (PLAC) in healthy male subjects. RESULTS: Both antidepressants significantly suppressed REM sleep (p<0.001). Although polysomnographically measured sleep continuity was impaired after ESCIT (p=0.006), subjective estimates of sleep parameters did not differ. Periodic limb movements (PLMS) were increased after AMI (p<0.001) but not after ESCIT. Processing speed and performance were enhanced after ESCIT compared with AMI (p=0.011), but not with PLAC. Next-day alertness was significantly impaired by AMI (p=0.012), but not by ESCIT. Mean day-time sleep onset latencies increased significantly after evening ESCIT (p<0.001). In contrast, AMI led to a pronounced increase of day-time sleepiness (p=0.007). DISCUSSION: This study demonstrates that single evening doses of either AMI or ESCIT exhibit different effects on next-day vigilance and alertness in terms of a slightly stimulating effect of ESCIT and a significant reduction after AMI.

[Sexual dysfunction and its consequences in patients with cardiovascular diseases]. / Sexuelle Funktionsstörungen bei Herzkranken und die Folgen.

PURPOSE: Due to the high prevalence of sexual disorders in men and women with cardiovascular disease, the associations between sexual dysfunction, depression, anxiety, quality of life and partnership were investigated. Studies examining impairments to certain aspects of psychological health and interpersonal life in cardiac patients are still lacking. The SPARK (Sexuality of Patients in Rehabilitation of Cardiovascular Diseases) investigation is the first study which explores these relevant associations in German rehabilitation patients. METHODS: Five rehabilitation centers for cardiovascular diseases took part in our cross-sectional study. Associations between sexual dysfunction and depression, anxiety, quality of life and partnership were tested using z-tests (resulting parameter prevalence rate ratio, PRR) and via multiple binary logistic regressions controlling for age and severity of cardiovascular disease as possible confounders (resulting parameter odds ratio, OR). RESULTS: Sexual function could be assessed in 261 men and 75 women (sexual activity during the previous month; for detailed flow chart see Fig. 1). In total, 43.1% of female patients reported a sexual dysfunction, while 20.2% of male patients stated to have at least moderate erectile dysfunction (ED). The proportion of self-assessed sexual problems is shown in Fig. 2. Women with a sexual dysfunction were impaired to a significantly higher extent compared to women without sexual dysfunction with regard to their quality of partnership (PRR 13.0; p=0.019; OR 25.42, confidence interval, CI, 2.5-254.9), anxiety (PRR 3.2; p=0.053; OR 4.43, CI 1.2-16.4) and psychological quality of life (PRR 2.4; p=0.115; OR 6.08, CI 1.6-22.9). Men with ED reported significantly stronger depression (PRR 3.6; p=0.003; OR 3.63, CI 1.5-8.8) and anxiety (PRR 2.4; p=0.008; OR 2.88, CI 1.4-5.9) compared to men without ED. For detailed information see Tables 1 and 2. CONCLUSION: Due to the high proportion of men and women with cardiovascular disease reporting sexual disorders, depression and anxiety, screening for these disorders should be an integral part of comprehensive rehabilitation programs. In particular, the diagnosis and treatment of psychiatric comorbidity seem to be necessary from a tertiary preventive perspective.

[Disturbances of slow-wave sleep and psychiatric disorders]. / Störungen des Tiefschlafs und psychische Erkrankungen.

Slow-wave sleep is defined as sleep stages 3 and 4 that characteristically show slow delta EEG activity during polysomnography. The percentage of slow-wave sleep normally declines with age. Sleep disorders are a common symptom of many psychiatric disorders. In polysomnographic recordings they mostly manifest as disturbances of sleep continuity. In some disorders changes in REM sleep are also found. A reduction of slow-wave sleep has most often been described in patients with depression and addictive disorders. More recent research implicates slow-wave sleep as an important factor in memory consolidation, especially the contents of declarative memory. Psychotropic drugs influence sleep in different ways. Hypnotic substances can reduce the deep sleep stages (e.g. benzodiazepines), whereas 5-HT2C antagonists increase the percentage of slow-wave sleep. Whether a selective impairment/alteration of slow-wave sleep is clinically relevant has not yet been proved.

[Nicotine. Influence on sleep and its relevance for psychiatry and psychotherapy]. / Nikotin. Einfluss auf den Schlaf und Relevanz für Psychiatrie und Psychotherapie.

BACKGROUND: Nicotine, by its impact on several neurotransmitter systems, influences sleep. Sleep disturbance is a common symptom in different psychiatric disorders and there is a high prevalence of smoking in psychiatric patients. METHODS: Systematic literature search. RESULTS: Symptoms of insomnia are observed during nicotine consumption and its withdrawal. The effects of therapeutic nicotine substitution after smoking cessation on sleep are often masked by withdrawal symptoms. Depressive non-smokers experience an improvement of mood under nicotine administration and in turn, depressive symptoms and sleep impairment during nicotine withdrawal have a negative impact on abstinence rates. CONCLUSION: Sleep disturbance is a comorbid risk factor influencing abstinence during smoking cessation. In depressive patients the complex relationship between affect, sleep, nicotine consumption and its withdrawal should be carefully monitored. In such subgroups of smokers willing to quit this has to be taken care of in therapeutic interventions.