Different Methods to Detect Stress in Knowledge Workers: A Pilot Study for Long-term Monitoring.

Stress is a common part of working life, but knowledge is lacking on how to identify it early and with little effort on the part of the employee. We investigated whether simple stress reports and computer usage data could be useful tools for long-term assessment of stress in real life. 38 experts responded to a baseline questionnaire on need for recovery (NFR) and psychological distress (General Health Questionnaire, GHQ12). Their computer usage for work was recorded for 5 months, during which they filled in a 4-month simple diary and a 2-week detailed diary on, for example, stress and productivity. Salivary cortisol and heart rate variability were collected on 3 consecutive days. Generalized estimating equations models were used for the analyses. High NFR and GHQ12 predicted self-reported stress during work, and a decrease in (some) mouse usage features, but not keyboard usage features, over the following months. Some mouse usage features were associated with stress and productivity. The results provide some support for the usefulness of simple stress questions and mouse usage features in assessing long-term stress in real life.

Do holidays change subjective sleep length or sleep debt in shift work disorder?

In shift work disorder (SWD), disturbed sleep acutely impairs employees' recovery, but little attention has been paid to sleep during longer recovery periods. We examined how holidays affect self-estimated sleep length, sleep debt, and recovery in cases of SWD. Twenty-one shift workers with questionnaire-based SWD and nine reference cases without SWD symptoms completed a questionnaire on recovery and sleep need. They also reported sleep length on two separate occasions: during a work period and after ≥ 2 weeks of holidays. Sleep debt was calculated by subtracting sleep length from sleep need. We used parametric tests to compare the groups and the periods. The groups reported shorter sleep on workdays than during holidays (median difference: SWD group 1.7 h, p<0.001; reference group 1.5 h; p<0.05). The SWD group's self-estimated sleep during holidays increased less above the sleep need (median 0.0 h) than the reference group's sleep (1.0 h, p<0.05). In addition, the SWD group reported good recovery from irregular working hours less often (14%) than the reference group (100%, p<0.001). Although holidays were generally associated with longer sleep estimates than workdays, employees with SWD experienced consistently less efficient recovery than those without SWD.

Impact of sleep timing on attention, sleepiness, and sleep quality among real-life night shift workers with shift work disorder: a cross-over clinical trial.

STUDY OBJECTIVES: To examine the effect of sleep timing intervention on sleep quality, attention, and sleepiness at work among night shift workers with shift work disorder. METHODS: We recruited 60 real-life night shift workers through advertisements to participate this cross-over clinical trial. Shift work disorder was confirmed with interview and sleep log. Participants were designated to follow evening sleep (15:00-23:00) and morning sleep (09:00-17:00) schedules in a randomized order. Chronotype was confirmed by the Munich Chronotype Questionnaire. Sleep behaviors and light exposure were recorded using actigraphy. Outcome measures were sleepiness evaluated by the Karolinska Sleepiness Scale, sleep quality evaluated by the Pittsburgh Sleep Quality Index, and attention performance assessed with psychomotor vigilance test. Differences in outcome between the morning and evening sleep schedules were compared using repeated measures ANOVA. RESULTS: The participants slept for longer durations during evening sleep schedules compared with morning sleep schedules. Lower sleepiness scores, higher sleep quality, and shorter reaction times and less lapse numbers in the psychomotor vigilance test were observed for participants during evening sleep schedules than morning sleep schedules after adjustment for light exposure and sleep duration. Significant interaction effects were observed for reaction time and lapse number between chronotype and sleep schedule, where the differences between sleep schedules were most prominent among those with late chronotypes. CONCLUSIONS: It is recommended that night shift workers with shift work disorder arrange to sleep in the evening instead of the morning for better sleep and attention performance, especially those with late chronotypes. TRIAL REGISTRATION: Sleep Schedule Intervention Study Among Night Shift Workers, https://clinicaltrials.gov/ct2/show/NCT04160572, ClinicalTrials.gov Identifier: NTC04160572.

Association of shift work with mood disorders and sleep problems according to chronotype: a 17-year cohort study.

Both evening chronotype and shift work are associated with depressive symptoms. This study examined whether the association between shift work and mood disorders and sleep problems varies by chronotype. The study population included 10637 participants from the Finnish Hospital Personnel Cohort Study. Work schedule was assessed using repeated questionnaires between 2000 and 2017. Chronotype, assessed using a single item from the Diurnal Type Scale, was categorized into definite morning, somewhat morning, somewhat evening, and definite evening types. The presence of mood disorders was identified by the 12-item General Health Questionnaire. Sleep problems were assessed by self-reported frequency of difficulty falling asleep and maintaining asleep. Longitudinal fixed effects models were used to examine the associations between shift work and the presence of mood disorders and sleep problems, stratified by chronotype. We found that fixed night work was associated with mood disorders among somewhat evening (adjusted odds ratio [OR] 1.91, 95% CI 1.09-3.34) and definite evening-type workers (adjusted OR 2.05, 95% CI 1.06-3.98). Shift work with night shifts was associated with mood disorders among definite evening-type workers (adjusted OR 1.75, 95% CI 1.18-2.60). Similarly, fixed night work was associated with difficulty maintaining sleep only among evening-type workers. In conclusion, evening chronotype increase the vulnerability to mood disorders and sleep disturbances related to night work.

Differential DNA methylation in recovery from shift work disorder.

The human DNA methylome is responsive to our environment, but its dynamics remain underexplored. We investigated the temporal changes to DNA methylation (DNAme) in relation to recovery from a shift work disorder (SWD) by performing a paired epigenome-wide analysis in an occupational cohort of 32 shift workers (25 men, age = 43.8 ± 8.8 years, 21 SWD cases). We found that the effect of vacation on DNAme was more prominent in the SWD-group as compared to controls, with respect to the amount of significantly differentially methylated positions (DMPs; Punadj < 0.05) 6.5 vs 3.7%, respectively. The vast majority (78%) of these DMPs were hypomethylated in SWD but not in controls (27%) during the work period. The Gene Ontology Cellular component "NMDA glutamate receptor" (PFDR < 0.05) was identified in a pathway analysis of the top 30 genes in SWD. In-depth pathway analyses revealed that the Reactome pathway "CREB phosphorylation through the activation of CaMKII" might underlie the recovery. Furthermore, three DMPs from this pathway, corresponding to GRIN2C, CREB1, and CAMK2B, correlated with the degree of recovery (Punadj < 0.05). Our findings provide evidence for the dynamic nature of DNAme in relation to the recovery process from a circadian disorder, with biological relevance of the emerging pathways.

Employees with shift work disorder experience excessive sleepiness also on non-work days: a cross-sectional survey linked to working hours register in Finnish hospitals.

A considerable proportion of shift workers have work schedule-related insomnia and/or excessive sleepiness, a phenomenon described as shift work disorder (SWD). There is yet a lack of evidence on whether or not employees recover from symptoms of SWD between work shifts. We studied whether SWD and its subtypes are associated with insomnia and excessive sleepiness during weekly non-work days and with 24-h sleep time. Hospital employees answered a survey on SWD, insomnia and excessive sleepiness on weekly non-work days, and 24-h sleep. To identify shift workers with night shifts (n=2,900, 18% with SWD) and SWD, we linked survey responses to employers' register on working hours. SWD included three subtypes: insomnia only (SWD-I, 4%, n=102), excessive sleepiness only (SWD-Es, 8%, n=244), and both insomnia and excessive sleepiness (SWD-IEs, 6%, n=183). Based on regression analyses, SWD was associated with excessive sleepiness on non-work days (OR: 1.42, 95% CI: 1.07-1.88) and with insomnia on non-work days (0.53, 0.31-0.91). SWD-I was associated with excessive sleepiness on non-work days (2.25, 1.31-3.87) and with shorter sleep (7-7.5 h: 1.96, 1.06-3.63; ≤6.5h: 2.39, 1.24-4.59; reference: ≥8 h). The results suggest that especially employees with SWD-I may need longer time to overcome excessive sleepiness than allowed by their roster.

Prevalence of shift work disorder among hospital personnel: A cross-sectional study using objective working hour data.

The prevalence of shift work disorder (SWD) has been studied using self-reported data and the International Classification of Sleep Disorders, Second Edition (ICSD-2) criteria. We examined the prevalence in relation to ICSD-2 and ICSD-3 criteria, work schedules and the number of non-day shifts (work outside 06:00-18:00 hours) using objective working-hours data. Secondly, we explored a minimum cut-off for the occurrence of SWD symptoms. Hospital shift workers without (n = 1,813) and with night shifts (n = 2,917) and permanent night workers (n = 84) answered a survey (response rate 69%) on SWD and fatigue on days off. The prevalence of SWD was calculated for groups with ≥1, ≥3, ≥5 and ≥7 monthly non-day shifts utilizing the working hours registry. ICSD-3-based SWD prevalence was 2.5%-3.7% (shift workers without nights), 2.6%-9.5% (shift workers with nights) and 6.0% (permanent night workers), depending on the cut-off of non-day shifts (≥7-1/month, respectively). The ICSD-2-based prevalence was higher: 7.1%-9.2%, 5.6%-33.5% and 16.7%, respectively. The prevalence was significantly higher among shift workers with than those without nights (p-values <.001) when using the cut-offs of ≥1-3 non-day shifts. Shift workers with nights who had ≥3 days with ICSD-3-based SWD symptoms/month more commonly had fatigue on days off (49.3%) than those below the cut-off (35.8%, p < .05). The ICSD-3 criteria provided lower estimates for SWD prevalence than ISCD-2 criteria, similarly to exclusion of employees with the fewest non-day shifts. The results suggest that a plausible cut-off for days with ICSD-3-based SWD symptoms is ≥3/month, resulting in 3%-6% prevalence of SWD.

A distinctive DNA methylation pattern in insufficient sleep.

Short sleep duration or insomnia may lead to an increased risk of various psychiatric and cardio-metabolic conditions. Since DNA methylation plays a critical role in the regulation of gene expression, studies of differentially methylated positions (DMPs) might be valuable for understanding the mechanisms underlying insomnia. We performed a cross-sectional genome-wide analysis of DNA methylation in relation to self-reported insufficient sleep in individuals from a community-based sample (79 men, aged 39.3 ± 7.3), and in relation to shift work disorder in an occupational cohort (26 men, aged 44.9 ± 9.0). The analysis of DNA methylation data revealed that genes corresponding to selected DMPs form a distinctive pathway: "Nervous System Development" (FDR P value < 0.05). We found that 78% of the DMPs were hypomethylated in cases in both cohorts, suggesting that insufficient sleep may be associated with loss of DNA methylation. A karyoplot revealed clusters of DMPs at various chromosomal regions, including 12 DMPs on chromosome 17, previously associated with Smith-Magenis syndrome, a rare condition comprising disturbed sleep and inverse circadian rhythm. Our findings give novel insights into the DNA methylation patterns associated with sleep loss, possibly modifying processes related to neuroplasticity and neurodegeneration. Future prospective studies are needed to confirm the observed associations.

Sleep and alertness in shift work disorder: findings of a field study.

PURPOSE: Although shift work disorder (SWD) affects a major part of the shift working population, little is known about its manifestation in real life. This observational field study aimed to provide a detailed picture of sleep and alertness among shift workers with a questionnaire-based SWD, by comparing them to shift workers without SWD during work shifts and free time. METHODS: SWD was determined by a questionnaire. Questionnaires and 3-week field monitoring, including sleep diaries, actigraphy, the Karolinska Sleepiness Scale (KSS), EEG-based sleep recordings, and Psychomotor Vigilance Tasks (PVT), were used to study 22 SWD cases and 9 non-SWD workers. RESULTS: The SWD group had a shorter subjective total sleep time and greater sleep debt before morning shifts than the non-SWD group. Unlike the non-SWD group, the SWD group showed little compensatory sleep on days off. The SWD group had lower objective sleep efficiency and longer sleep latency on most days, and reported poorer relaxation at bedtime and sleep quality across all days than the non-SWD group. The SWD group's average KSS-sleepiness was higher than the non-SWD group's sleepiness at the beginning and end of morning shifts and at the end of night shifts. The SWD group also had more lapses in PVT at the beginning of night shifts than the non-SWD group. CONCLUSIONS: The results indicate that SWD is related to disturbed sleep and alertness in association with both morning and night shifts, and to less compensatory sleep on days off. SWD seems to particularly associate with the quality of sleep.

Inhibition of Homophilic Interactions and Ligand Binding of the Receptor for Advanced Glycation End Products by Heparin and Heparin-Related Carbohydrate Structures.

Background: Heparin and heparin-related sulphated carbohydrates inhibit ligand binding of the receptor for advanced glycation end products (RAGE). Here, we have studied the ability of heparin to inhibit homophilic interactions of RAGE in living cells and studied how heparin related structures interfere with RAGE⁻ligand interactions. Methods: Homophilic interactions of RAGE were studied with bead aggregation and living cell protein-fragment complementation assays. Ligand binding was analyzed with microwell binding and chromatographic assays. Cell surface advanced glycation end product binding to RAGE was studied using PC3 cell adhesion assay. Results: Homophilic binding of RAGE was mediated by V1- and modulated by C2-domain in bead aggregation assay. Dimerisation of RAGE on the living cell surface was inhibited by heparin. Sulphated K5 carbohydrate fragments inhibited RAGE binding to amyloid ß-peptide and HMGB1. The inhibition was dependent on the level of sulfation and the length of the carbohydrate backbone. α-d-Glucopyranosiduronic acid (glycyrrhizin) inhibited RAGE binding to advanced glycation end products in PC3 cell adhesion and protein binding assays. Further, glycyrrhizin inhibited HMGB1 and HMGB1 A-box binding to heparin. Conclusions: Our results show that K5 polysaccharides and glycyrrhizin are promising candidates for RAGE targeting drug development.

Effects of modifications to the health and social sector's collective agreement on the objective characteristics of working hours.

This study aimed to evaluate the effects of an intervention on objective working-hour characteristics. The intervention involved making modifications to the collective agreement that would limit employees' entitlement to time off as compensation. The intervention group consisted of 493 and the control group of 2,303 health and social care shift workers, respectively. We analysed the objective pay roll-based working-hour data for 2012-2013, which we obtained from employers' records, using the repeated measures mixed model. The changes in objective working-hour characteristics were small, but systematic. The intervention had some positive effects: the amount of short recovery periods (<28 h) after the last night shift decreased from 5% to 3%, and the amount of working weeks of over 48 h decreased from 19% to 17%. The realization of employees' shift preferences increased from 18% to 20%. However, in contrast, consecutive work shifts and the number of scheduled absences increased and days off decreased, suggesting less time for recovery and thus a negative trend in shift ergonomics. When planning shifts, nursing management should avoid regulations that promote specific unhealthy shift characteristics, that is, consecutive work shifts and less days off.

HMGB4 is expressed by neuronal cells and affects the expression of genes involved in neural differentiation.

HMGB4 is a new member in the family of HMGB proteins that has been characterized in sperm cells, but little is known about its functions in somatic cells. Here we show that HMGB4 and the highly similar rat Transition Protein 4 (HMGB4L1) are expressed in neuronal cells. Both proteins had slow mobility in nucleus of living NIH-3T3 cells. They interacted with histones and their differential expression in transformed cells of the nervous system altered the post-translational modification statuses of histones in vitro. Overexpression of HMGB4 in HEK 293T cells made cells more susceptible to cell death induced by topoisomerase inhibitors in an oncology drug screening array and altered variant composition of histone H3. HMGB4 regulated over 800 genes in HEK 293T cells with a p-value ≤0.013 (n = 3) in a microarray analysis and displayed strongest association with adhesion and histone H2A -processes. In neuronal and transformed cells HMGB4 regulated the expression of an oligodendrocyte marker gene PPP1R14a and other neuronal differentiation marker genes. In conclusion, our data suggests that HMGB4 is a factor that regulates chromatin and expression of neuronal differentiation markers.

Developing register-based measures for assessment of working time patterns for epidemiologic studies.

OBJECTIVES: Epidemiological studies suggest that long working hours and shift work may increase the risk of chronic diseases, but the "toxic" elements remain unclear due to crude assessment of working time patterns based on self-reports. In this methodological paper, we present and evaluate objective register-based algorithms for assessment of working time patterns and validate a method to retrieve standard payroll data on working hours from the employer electronic records. METHODS: Detailed working hour records from employers' registers were obtained for 12 391 nurses and physicians, a total 14.5 million separate work shifts from 2008-2013. We examined the quality and validity of the obtained register data and designed 29 algorithms characterizing four potentially health-relevant working time patterns: (i) length of the working hours; (ii) time of the day; (iii) shift intensity; and (iv) social aspects of the working hours. RESULTS: The collection of the company-based register data was feasible and the retrieved data matched with the originally published shift plans. The transferred working time records included <0.01% missing data. Two percent were duplicates that could be easily removed. The 29 variables of working time patterns, generated for each year, were stable across the follow-up (year-to-year correlation coefficients from r=0.7-0.9 for 23 variables), their distributions were as expected, and correlations of the variables within the four main dimensions of working hours were plausible. CONCLUSION: The developed method and algorithms allow a detailed characterization of four main dimensions of working time patterns potentially relevant for health. We recommend this method for future large-scale epidemiological studies.

HB-GAM inhibits proliferation and enhances differentiation of neural stem cells.

Proliferation of neural stem cells in the embryonic cerebral cortex is regulated by many growth factors and their receptors. Among the key molecules stimulating stem cell proliferation are FGF-2 and the FGF receptor-1. This ligand-receptor system is highly dependent on the surrounding heparan sulfates. We have found that heparin-binding growth-associated molecule (HB-GAM, also designated as pleiotrophin) regulates neural stem cell proliferation in vivo and in vitro. Deficiency of HB-GAM results in a pronounced, up to 50% increase in neuronal density in the adult mouse cerebral cortex. This phenotype arises during cortical neurogenesis, when HB-GAM knockout embryos display an enhanced proliferation rate as compared to wild-type embryos. Further, our in vitro studies show that exogenously added HB-GAM inhibits formation and growth of FGF-2, but not EGF, stimulated neurospheres, restricts the number of nestin-positive neural stem cells, and inhibits FGF receptor phosphorylation. We propose that HB-GAM functions as an endogenous inhibitor of FGF-2 in stem cell proliferation in the developing cortex.