Personalized sleep and nutritional strategies to combat adverse effects of night shift work: a controlled intervention protocol.

BACKGROUND: Working during the night interferes with the timing of normal daily activities and is associated with an increased risk of chronic diseases. Under controlled experimental conditions, interventions focusing on sleep and nutrition can mitigate the short-term adverse effects of shift work. However, it is unclear how these results translate to real-life, how they can be targeted to individual conditions, and how they relate to long-term health. Therefore, the current study aims to implement a personalized sleep and nutritional intervention among night shift workers in the field. METHODS: A non-blinded controlled intervention study is used, consisting of a run-in period, an intervention of 3 months, post-intervention measurements, and a follow-up after 12 months. Three study arms are included: sleep intervention, nutritional intervention, and control group (n = 25 each). Participants are healthy 18-60-year male night shift workers, with at least one year of experience in night shift work. Information from the run-in period will be used to personalize the interventions. The main outcomes are sleep measurements and continuous interstitial glucose levels. Furthermore, general health biomarkers and parameters will be determined to further evaluate effects on long-term health. DISCUSSION: This study aims to mitigate negative health consequences associated with night shift work by introducing two personalized preventive interventions. If proven effective, the personalized interventions may serve as practical solutions that can have a meaningful impact on the sustainable health and employability of night shift workers. This study will thereby contribute to the current need for high-quality data on preventative strategies for night shift work in a real-life context. TRIAL REGISTRATION: This trial has been registered under ClinicalTrials.gov Identifier NCT06147089. Registered 27 November 2023.

Impact of Simulated Rotating Shift Work on Mammary Tumor Development in the p53R270H©/+WAPCre Mouse Model for Breast Cancer.

Epidemiological studies associate night shift work with increased breast cancer risk. However, the underlying mechanisms are not clearly understood. To better understand these mechanisms, animal models that mimic the human situation of different aspects of shift work are needed. In this study, we used "timed sleep restriction" (TSR) cages to simulate clockwise and counterclockwise rotating shift work schedules and investigated predicted sleep patterns and mammary tumor development in breast tumor-prone female p53R270H©/+WAPCre mice. We show that TSR cages are effective in disturbing normal activity and estimated sleep patterns. Although circadian rhythms were not shifted, we observed effects of the rotating schedules on sleep timing and sleep duration. Sleep loss during a simulated shift was partly compensated after the shift and also partly during the free days. No effects were observed on body weight gain and latency time of breast cancer development. In summary, our study shows that the TSR cages can be used to model shift work in mice and affect patterns of activity and sleep. The effect of disturbing sleep patterns on carcinogenesis needs to be further investigated.

Time-restricted feeding attenuates hypercholesterolaemia and atherosclerosis development during circadian disturbance in APOE∗3-Leiden.CETP mice.

BACKGROUND: Circadian disturbance (CD) is the consequence of a mismatch between endogenous circadian rhythms, behaviour, and/or environmental cycles, and frequently occurs during shift work. Shift work has been associated with elevated risk for atherosclerotic cardiovascular disease (asCVD) in humans, but evidence for the effectiveness of prevention strategies is lacking. METHODS: Here, we applied time-restricted feeding (TRF) as a strategy to counteract atherosclerosis development during CD in female APOE∗3-Leiden.CETP mice, a well-established model for humanized lipoprotein metabolism. Control groups were subjected to a fixed 12:12 h light-dark cycle, while CD groups were subjected to 6-h phase advancement every 3 days. Groups had either ad libitum (AL) access to food or were subjected to TRF with restricted food access to the dark phase. FINDINGS: TRF did not prevent the increase in the relative abundance of circulating inflammatory monocytes and elevation of (postprandial) plasma triglycerides during CD. Nonetheless, TRF reduced atherosclerotic lesion size and prevented an elevation in macrophage content of atherosclerotic lesions during CD, while it increased the relative abundance of anti-inflammatory monocytes, prevented activation of T cells, and lowered plasma total cholesterol levels and markers of hepatic cholesterol synthesis. These effects were independent of total food intake. INTERPRETATION: We propose that time restricted eating could be a promising strategy for the primary prevention of asCVD risk in shift workers, which warrants future study in humans. FUNDING: This work was funded by the Novo Nordisk Foundation, the Netherlands Ministry of Social Affairs and Employment, Amsterdam Cardiovascular Sciences, and the Dutch Heart Foundation.

Effects of Nightshift Work on Blood Metabolites in Female Nurses and Paramedic Staff: A Cross-sectional Study.

Nightshift work disturbs the circadian rhythm, which might contribute to the development of cardio-metabolic disorders. In this cross-sectional study, we aimed to gain insight into perturbations of disease relevant metabolic pathways due to nightshift work. We characterized the metabolic profiles of 237 female nurses and paramedic staff participating in the Klokwerk study using the Nightingale Health platform. We performed analyses on plasma levels of 225 metabolites, including cholesterol, triglycerides, fatty acids, and amino acids. Using both principal component- and univariate-regression, we compared metabolic profiles of nightshift workers to metabolic profiles from workers that did not work night shifts (defined as day workers). We also assessed whether differential effects were observed between recently started versus more experienced workers. Within the group of nightshift workers, we compared metabolic profiles measured right after a nightshift with metabolic profiles measured on a day when no nightshift work was conducted. We observed evidence for an impact of nightshift work on the presence of unfavorable fatty acid profiles in blood. Amongst the fatty acids, effects were most prominent for PUFA/FA ratios (consistently decreased) and SFA/FA ratios (consistently elevated). This pattern of less favorable fatty acid profiles was also observed in samples collected directly after a night shift. Amino acid levels (histidine, glutamine, isoleucine, and leucine) and lipoproteins (especially HDL-cholesterol, VLDL-cholesterol, and triglycerides) were elevated when comparing nightshift workers with day workers. Amino acid levels were decreased in the samples that were collected directly after working a nightshift (compared to levels in samples that were collected during a non-nightshift period). The observed effects were generally more pronounced in samples collected directly after the nightshift and among recently started compared to more experienced nightshift workers. Our finding of a suggested impact of shift work on impaired lipid metabolism is in line with evidence that links disruption of circadian rhythmicity to obesity and metabolic disorders.

Exploration of genome-wide DNA methylation profiles in night shift workers.

The past decades, studies indicated that night shift work is associated with adverse health effects, however, molecular mechanisms underlying these effects are poorly understood. A few previous studies have hypothesized a role for DNA-methylation (DNAm) in this relationship. We performed a cross-sectional epigenome-wide association study, to investigate if night shift work is associated with genome-wide DNAm changes and DNAm-based biological age acceleration, based on previously developed so-called 'epigenetic clocks.' Short term (2-6 years) and intermediate term (10-16 years) night shift workers, along with age and sex matched dayworkers (non-shift workers) were selected from the Lifelines Cohort Study. For genome-wide methylation analysis the Infinium Methylation EPIC array (Ilumina) was used. Linear regression analyses were used to detect differences in methylation at individual CpG-sites associated with night shift work. Pathway analysis was performed based on KEGG pathways and predictions of age acceleration in night shift workers were performed based on four previously developed epigenetic age calculators. Only in women, differences in methylation at individual CpG-sites were observed between night shift workers and non-shift workers. Most of these differentially methylated positions (DMPs) were observed in intermediate term night shift workers. Pathway analysis shows involvement of pathways related to circadian rhythm and cellular senescence. Increased age acceleration was observed only in short-term night shift workers (men and women). This might be indicative of adaptation to night shift work or a so-called healthy worker effect. In conclusion, these results show that DNA methylation changes are associated with night shift work, specifically in women.

GlycA, a Biomarker of Low-Grade Inflammation, Is Increased in Male Night Shift Workers.

Sustained night shift work is associated with various adverse health risks, including an increased risk of cardiovascular disease, type II diabetes, and susceptibility to infectious respiratory diseases. The extent of these adverse health effects, however, seems to greatly vary between night shift workers, yet the underlying reasons and the mechanisms underlying these interindividual differences remain poorly understood. Metabolomics assays in the blood have recently gained much attention as a minimally invasive biomarker platform capturing information predictive of metabolic and cardiovascular diseases. In this cross-sectional study, we explored and compared the metabolic profiles of 1010 night shift workers and 1010 age- and sex-matched day workers (non-shift workers) from the Lifelines Cohort Study. The metabolic profiles were determined using the 1H-NMR Nightingale platform for the quantification of 250 parameters of metabolism, including routine lipids, extensive lipoprotein subclasses, fatty acid composition, and various low-molecular metabolites, including amino acids, ketone bodies, and gluconeogenesis-related metabolites. Night shift workers had an increased BMI (26.6 vs. 25.9 kg/m2) compared with day workers (non-shift workers) in both sexes, were slightly more likely to be ever smokers (only in males) (54% vs. 46%), worked on average 5.9 ± 3.7 night shifts per month, and had been working in night shifts for 18.3 ± 10.5 years on average. We observed changes in several metabolic markers in male night shift workers compared with non-shift workers, but no changes were observed in women. In men, we observed higher levels of glycoprotein acetyls (GlycA), triglycerides, and fatty acids compared with non-shift workers. The changes were seen in the ratio of triglycerides and cholesterol(esters) to total lipids in different sizes of VLDL particles. Glycoprotein acetyls (GlycAs) are of particular interest as markers since they are known as biomarkers for low-grade chronic inflammation. When the analyses were adjusted for BMI, no significant associations were observed. Further studies are needed to better understand the relationship between night shift work and metabolic profiles, particularly with respect to the role of sex and BMI in this relationship.

A randomized crossover trial assessing time of day snack consumption and resulting postprandial glycemic response in a real-life setting among healthy adults.

The postprandial glycemic response is an important metabolic health factor, which, from laboratory studies, is known to change from low to high over the course of the day, and from which negative health outcomes have been linked to nightly eating. We applied interstitial continuous glucose monitoring to examine the glycemic response to a standardized carbohydrate-rich snack (198 kcal) across the day in a real-life setting. Twenty-four healthy participants (12 men, 12 women, 27-61 y old) consumed the snack nine times during 6 d in a crossover design, altering the time of consumption between morning, afternoon and evening. The snack was consumed in the participant's own environment with a preceding fast of at least 2.5 h between their customary main meals and practices. Linear mixed models were used with fixed effect of timing, and participant as random effect, to assess incremental area under the curve, peak value and time-to-peak of the glycemic response. Overall, the highest glycemic excursions were observed in the morning, while a more dampened but prolonged response was observed in the evening. These findings do not concur with previously published laboratory studies. This implies that results obtained under controlled experimental conditions in laboratories cannot be generalized directly to predict chrononutritional effects on the glycemic response in healthy individuals and their daily routines.

Night-shift work is associated with increased susceptibility to SARS-CoV-2 infection.

Night-shift workers experience disturbances of their circadian rhythm and sleep, which may make them more susceptible to infectious diseases. Therefore, we studied whether night-shift workers are at higher risk of testing positive for SARS-CoV-2 infection than day workers. In this prospective study, data were used from 20 questionnaire rounds of the Dutch Lifelines COVID-19 cohort that was initiated in March 2020. In the different questionnaire rounds, 2285 night-shift workers and 23,766 day workers reported whether they had tested positive for SARS-CoV-2. Cox proportional hazards regression models adjusted for demographic, work, and health covariates were used to compare SARS-CoV-2 incidence between night-shift and day workers. From March 2020-January 2021, 3.4% of night-shift workers and 2.2% of day workers reported to have tested positive for SARS-CoV-2 (p < .001). After adjustment for covariates, night-shift workers had a 37% higher risk of testing positive for SARS-CoV-2 (hazard ratio: 1.37, 95% confidence interval: 1.05-1.77). In this study, we show that night-shift workers were more likely to test positive for SARS-CoV-2 than day workers, which adds to the growing evidence that night-shift work may influence the complex processes involved in infection susceptibility. Further mechanistic insight is needed to understand the relation between night-shift work and (SARS-CoV-2) infection susceptibility.

Night shift work characteristics are associated with several elevated metabolic risk factors and immune cell counts in a cross-sectional study.

Night shift work is associated with increased health risks. Here we examined the association of metabolic risk factors and immune cell counts, with both night shift work and particular characteristics thereof: frequency, duration and consecutive night shifts. We performed a cross-sectional study using data from 10,201 non-shift workers and 1062 night shift workers of the Lifelines Cohort study. Linear regression analyses, adjusted for demographic, lifestyle and occupational factors, were used to study associations of night shift work characteristics with metabolic risk factors and immune cell counts. Night shift workers had an increased BMI, waist circumference and immune cell counts compared to non-shift workers. This was especially seen in night shift workers who had a higher frequency of night shifts per month (≥ 5: BMI: B = 0.81 kg/m2 (95%-CI = 0.43-1.10); waist circumference: B = 1.58 cm (95%-Cl = 0.34-1.71; leukocytes: B = 0.19 × 109 cells/L (95%-CI = 0.04-0.34 × 109)) and worked more consecutive night shifts (> 3: BMI: B = 0.92 kg/m2 (95%-CI = 0.41-1.43); waist circumference: B = 1.85 cm (95%-Cl = 0.45-3.24); leukocytes: B = 0.32 × 109 cells/L (95%-CI = 0.09-0.55 × 109)). This association was less pronounced in long-term night shift workers (≥ 20 years). Our findings provide evidence for the association between night shift work characteristics and BMI, waist circumference and leukocytes (including, monocytes, lymphocytes, and basophil granulocytes).

Social Jetlag and Related Risks for Human Health: A Timely Review.

The term social jetlag is used to describe the discrepancy between biological time, determined by our internal body clock, and social times, mainly dictated by social obligations such as school or work. In industrialized countries, two-thirds of the studying/working population experiences social jetlag, often for several years. Described for the first time in 2006, a considerable effort has been put into understanding the effects of social jetlag on human physiopathology, yet our understanding of this phenomenon is still very limited. Due to its high prevalence, social jetlag is becoming a primary concern for public health. This review summarizes current knowledge regarding social jetlag, social jetlag associated behavior (e.g., unhealthy eating patterns) and related risks for human health.

Disruption of circadian rhythm by alternating light-dark cycles aggravates atherosclerosis development in APOE*3-Leiden.CETP mice.

Disruption of circadian rhythm by means of shift work has been associated with cardiovascular disease in humans. However, causality and underlying mechanisms have not yet been established. In this study, we exposed hyperlipidemic APOE*3-Leiden.CETP mice to either regular light-dark cycles, weekly 6 hours phase advances or delays, or weekly alternating light-dark cycles (12 hours shifts), as a well-established model for shift work. We found that mice exposed to 15 weeks of alternating light-dark cycles displayed a striking increase in atherosclerosis, with an approximately twofold increase in lesion size and severity, while mice exposed to phase advances and delays showed a milder circadian disruption and no significant effect on atherosclerosis development. We observed a higher lesion macrophage content in mice exposed to alternating light-dark cycles without obvious changes in plasma lipids, suggesting involvement of the immune system. Moreover, while no changes in the number or activation status of circulating monocytes and other immune cells were observed, we identified increased markers for inflammation, oxidative stress, and chemoattraction in the vessel wall. Altogether, this is the first study to show that circadian disruption by shifting light-dark cycles directly aggravates atherosclerosis development.

Plasma sCD36 as non-circadian marker of chronic circadian disturbance in shift workers.

Shift work induces chronic circadian disturbance, which might result in increased health risks, including cardio-metabolic diseases. Previously, we identified sCD36 as a potential non-circadian biomarker of chronic circadian disturbance in mice. The aim of the current study (n = 232 individuals) was to identify whether sCD36 measured in plasma can be used as a non-circadian marker of chronic circadian disturbance in humans, which would allow its use to measure the effects of interventions and monitoring in large-scale studies. We compared levels of plasma sCD36 of day workers with recent (< 2 years) and experienced (> 5 years) night-shift workers within the Klokwerk study. We detected no differences in sCD36 levels between day workers and recent or experienced night-shift workers, measured during a day or afternoon shift. In addition, sCD36 levels measured directly after a night shift were not different from sCD36 levels measured during day or afternoon shifts, indicating no acute effect of night shifts on sCD36 levels in our study. In summary, our study does not show a relation between night-shift work experience (recent or long-term) and plasma levels of sCD36. Since we do not know if and for which time span night-shift work is associated with changes in sCD36 levels, and our study was relatively small and cross-sectional, further evidence for an association between chronic circadian disruption and this candidate biomarker sCD36 should be gathered from large cohort studies.

Time-restricted feeding improves adaptation to chronically alternating light-dark cycles.

Disturbance of the circadian clock has been associated with increased risk of cardio-metabolic disorders. Previous studies showed that optimal timing of food intake can improve metabolic health. We hypothesized that time-restricted feeding could be a strategy to minimize long term adverse metabolic health effects of shift work and jetlag. In this study, we exposed female FVB mice to weekly alternating light-dark cycles (i.e. 12 h shifts) combined with ad libitum feeding, dark phase feeding or feeding at a fixed clock time, in the original dark phase. In contrast to our expectations, long-term disturbance of the circadian clock had only modest effects on metabolic parameters. Mice fed at a fixed time showed a delayed adaptation compared to ad libitum fed animals, in terms of the similarity in 24 h rhythm of core body temperature, in weeks when food was only available in the light phase. This was accompanied by increased plasma triglyceride levels and decreased energy expenditure, indicating a less favorable metabolic state. On the other hand, dark phase feeding accelerated adaptation of core body temperature and activity rhythms, however, did not improve the metabolic state of animals compared to ad libitum feeding. Taken together, restricting food intake to the active dark phase enhanced adaptation to shifts in the light-dark schedule, without significantly affecting metabolic parameters.

The association between exposure to different aspects of shift work and metabolic risk factors in health care workers, and the role of chronotype.

OBJECTIVE: Shift work has been linked to cardio-metabolic diseases, but insight into different shift work-related aspects and chronotype of shift workers and their relation with metabolic risk factors is limited. This study examined the association between current shift work status, frequency and duration of night shift work, chronotype, and metabolic risk factors in a population of health care workers. METHODS: Anthropometrics, questionnaires, and blood samples were collected from 503 shift working and 93 non-shift working health care workers employed in hospitals. Body mass index, waist circumference, cholesterol (total, HDL, LDL), triglycerides, and high-sensitivity C-reactive protein were measured. Associations of current shift work, frequency (non-night shift worker, 1-2, 3-4, ≥5 night shifts/month) and duration of night shift work (non-night shift workers, <10, 10-19, ≥20 years), and shift workers' chronotype, with metabolic risk factors were studied using linear regression analysis. RESULTS: Compared to non-shift workers, shift workers' total cholesterol level was 0.38 mmol/L lower (95%-CI = -0.73 --0.04) and LDL cholesterol was 0.34 mmol/L lower (95%-CI = -0.60 --0.08). For all other metabolic risk factors, no differences were found. The association between shift work and LDL cholesterol was especially found among shift workers working night shifts for ≥20 years (B = -0.49 (95%-CI = -0.78 --0.19)). No differences were found for night shift frequency and chronotype. CONCLUSION: In this population of health care workers employed in hospitals, no evidence for differences in metabolic risk factors was observed that could underlie a link between shift work and cardio-metabolic diseases. Further research using different aspects of shift work to study the association with metabolic risk factors is recommended.

Shift work, sleep disturbances and social jetlag in healthcare workers.

The aim of this study was to compare chronotype- and age-dependent sleep disturbances and social jetlag between rotating shift workers and non-shift workers, and between different types of shifts. In the Klokwerk+ cohort study, we included 120 rotating shift workers and 74 non-shift workers who were recruited from six Dutch hospitals. Participants wore Actigraph GT3X accelerometers for 24 hr for 7 days. From the Actigraph data, we predicted the sleep duration and social jetlag (measure of circadian misalignment). Mixed models and generalized estimation equations were used to compare the sleep parameters between shift and non-shift workers. Within shift workers, sleep on different shifts was compared with sleep on work-free days. Differences by chronotype and age were investigated using interaction terms. On workdays, shift workers had 3.5 times (95% confidence interval: 2.2-5.4) more often a short (< 7 hr per day) and 4.1 times (95% confidence interval: 2.5-6.8) more often a long (≥ 9 hr per day) sleep duration compared with non-shift workers. This increased odds ratio was present in morning chronotypes, but not in evening chronotypes (interaction p-value < .05). Older shift workers (≥ 50 years) had 7.3 times (95% confidence interval: 2.5-21.8) more often shorter sleep duration between night shifts compared with work-free days, while this was not the case in younger shift workers (< 50 years). Social jetlag due to night shifts increased with increasing age (interaction p-value < .05), but did not differ by chronotype (interaction p-value ≥ .05). In conclusion, shift workers, in particular older workers and morning chronotypes, experienced more sleep disturbances than non-shift workers. Future research should elucidate whether these sleep disturbances contribute to shift work-related health problems.

Diet, Physical Activity, and Daylight Exposure Patterns in Night-Shift Workers and Day Workers.

Background: Night-shift work has been reported to have an impact on nutrition, daylight exposure, and physical activity, which might play a role in observed health effects. Because these exposures show diurnal variation, and shift work has been related with disturbances in the circadian rhythm, the timing of assessment of these factors requires careful consideration. Our aim was to describe the changes in patterns of diet, physical activity, and daylight exposure associated with night-shift work. Methods: We conducted an observational study among female healthcare workers either regularly working night shifts or not working night shifts. We assessed physical activity and daylight exposure using continuous monitoring devices for 48 h. We logged dietary patterns (24 h) and other health- and work-associated characteristics. Two measurement sessions were conducted when participants did 'not' work night shifts, and one session was conducted during a night-shift period. Results: Our study included 69 night-shift workers and 21 day workers. On days in which they conduct work but no night work, night-shift workers had similar physical activity and 24-h caloric intake, yet higher overall daylight exposures than day workers and were more often exposed around noon instead of mainly around 1800h. Night-shift workers were less exposed to daylight during the night-shift session compared to the non-night-shift session. Total caloric intakes did not significantly differ between sessions, but we did observe a shorter maximum fasting interval, more eating moments, and a higher percentage of fat intake during the night-shift session. Conclusion: Observed differences in diet, physical activity, and exposure to daylight primarily manifested themselves through changes in exposure patterns, highlighting the importance of time-resolved measurements in night-shift-work research. Patterns in daylight exposure were primarily related to time of waking up and working schedule, whereas timing of dinner seemed primarily governed by social conventions.

A Diurnal Rhythm in Brown Adipose Tissue Causes Rapid Clearance and Combustion of Plasma Lipids at Wakening.

Many favorable metabolic effects have been attributed to thermogenic activity of brown adipose tissue (BAT). Yet, time of day has rarely been considered in this field of research. Here, we show that a diurnal rhythm in BAT activity regulates plasma lipid metabolism. We observed a high-amplitude rhythm in fatty acid uptake by BAT that synchronized with the light/dark cycle. Highest uptake was found at the onset of the active period, which coincided with high lipoprotein lipase expression and low angiopoietin-like 4 expression by BAT. Diurnal rhythmicity in BAT activity determined the rate at which lipids were cleared from the circulation, thereby imposing the daily rhythm in plasma lipid concentrations. In mice as well as humans, postprandial lipid excursions were nearly absent at waking. We anticipate that diurnal BAT activity is an important factor to consider when studying the therapeutic potential of promoting BAT activity.

Klokwerk + study protocol: An observational study to the effects of night-shift work on body weight and infection susceptibility and the mechanisms underlying these health effects.

BACKGROUND: Night-shift work may cause severe disturbances in the worker's circadian rhythm, which has been associated with the onset of health problems and diseases. As a substantial part of the workforce is exposed to night-shift work, harmful aspects of night-shift work should not be overlooked. The aim of the Klokwerk + study is to study the effects of night-shift work on body weight and infection susceptibility and the mechanisms underlying these health effects. First, we will study the relation between night-shift work exposure and body weight and between night-shift work exposure and infection susceptibility. Second, we will examine the mechanisms linking night-shift work exposure to body weight and infection susceptibility, with a specific focus on sleep, physical activity, diet, light exposure, vitamin D level, and immunological factors. Lastly, we will focus on the identification of biomarkers for chronic circadian disturbance associated with night-shift work. METHODS/DESIGN: The design of this study is a prospective observational cohort study consisting of 1,960 health care workers aged 18-65 years. The study population will consist of a group of night-shift workers and an equally sized group of non-night-shift workers. During the study, there will be two measurement periods. As one of the main outcomes of this study is infection susceptibility, the measurement periods will take place at approximately the first (September/October) (T0) and the last month (April/May) (T1, after 6 months) of the flu season. The measurements will consist of questionnaires, anthropometric measurements, a smartphone application to determine infection susceptibility, food diaries, actigraphy, light sensors, and blood sample analyses. DISCUSSION: The Klokwerk + study will contribute to the current need for high-quality data on the health effects of night-shift work and its underlying behavioral and physiological mechanisms. The findings can be the starting point for the development of interventions that prevent negative health effects caused by night-shift work. In addition, the identification of biomarkers indicative of loss of homeostasis due to circadian disturbance may be an important asset in monitoring the effects of such interventions.

The Relationship Between Shift Work and Metabolic Risk Factors: A Systematic Review of Longitudinal Studies.

CONTEXT: Although the metabolic health effects of shift work have been extensively studied, a systematic synthesis of the available research is lacking. This review aimed to systematically summarize the available evidence of longitudinal studies linking shift work with metabolic risk factors. EVIDENCE ACQUISITION: A systematic literature search was performed in 2015. Studies were included if (1) they had a longitudinal design; (2) shift work was studied as the exposure; and (3) the outcome involved a metabolic risk factor, including anthropometric, blood glucose, blood lipid, or blood pressure measures. EVIDENCE SYNTHESIS: Eligible studies were assessed for their methodologic quality in 2015. A best-evidence synthesis was used to draw conclusions per outcome. Thirty-nine articles describing 22 studies were included. Strong evidence was found for a relation between shift work and increased body weight/BMI, risk for overweight, and impaired glucose tolerance. For the remaining outcomes, there was insufficient evidence. CONCLUSIONS: Shift work seems to be associated with body weight gain, risk for overweight, and impaired glucose tolerance. Overall, lack of high-methodologic quality studies and inconsistency in findings led to insufficient evidence in assessing the relation between shift work and other metabolic risk factors. To strengthen the evidence, more high-quality longitudinal studies that provide more information on the shift work schedule (e.g., frequency of night shifts, duration in years) are needed. Further, research to the (mediating) role of lifestyle behaviors in the health effects of shift work is recommended, as this may offer potential for preventive strategies.

Contrasting Roles of Dopamine and Noradrenaline in the Motivational Properties of Social Play Behavior in Rats.

Social play behavior, abundant in the young of most mammalian species, is thought to be important for social and cognitive development. Social play is highly rewarding, and as such, the expression of social play depends on its pleasurable and motivational properties. Since the motivational properties of social play have only sporadically been investigated, we developed a setup in which rats responded for social play under a progressive ratio schedule of reinforcement. Dopaminergic neurotransmission plays a key role in incentive motivational processes, and both dopamine and noradrenaline have been implicated in the modulation of social play behavior. Therefore, we investigated the role of dopamine and noradrenaline in the motivation for social play. Treatment with the psychostimulant drugs methylphenidate and cocaine increased responding for social play, but suppressed its expression during reinforced play periods. The dopamine reuptake inhibitor GBR-12909 increased responding for social play, but did not affect its expression, whereas the noradrenaline reuptake inhibitor atomoxetine decreased responding for social play as well as its expression. The effects of methylphenidate and cocaine on responding for social play, but not their play-suppressant effects, were blocked by pretreatment with the dopamine receptor antagonist α-flupenthixol. In contrast, pretreatment with the α2-adrenoceptor antagonist RX821002 prevented the play-suppressant effect of methylphenidate, but left its effect on responding for social play unaltered. In sum, the present study introduces a novel method to study the incentive motivational properties of social play behavior in rats. Using this paradigm, we demonstrate dissociable roles for dopamine and noradrenaline in social play behavior: dopamine stimulates the motivation for social play, whereas noradrenaline negatively modulates the motivation for social play behavior and its expression.