Publications by authors named "Debbie van Baarle"

124 Publications

Limited effect of duration of CMV infection on adaptive immunity and frailty: insights from a 27-year-long longitudinal study.

Clin Transl Immunology 2020 14;9(10):e1193. Epub 2020 Oct 14.

Centre for Infectious Disease Control National Institute for Public Health and the Environment Bilthoven The Netherlands.

Objectives: Cytomegalovirus infection is thought to affect the immune system and to impact general health during ageing. Higher CMV-specific antibody levels in the elderly are generally assumed to reflect experienced viral reactivation during life. Furthermore, high levels of terminally differentiated and CMV-specific T cells are hallmarks of CMV infection, which are thought to expand over time, a process also referred to as memory inflation.

Methods: We studied CMV-specific antibody levels over ~ 27 years in 268 individuals (aged 60-89 years at study endpoint), and to link duration of CMV infection to T-cell numbers, CMV-specific T-cell functions, frailty and cardiovascular disease at study endpoint.

Results: In our study, 136/268 individuals were long-term CMV seropositive and 19 seroconverted during follow-up (seroconversion rate: 0.56%/year). CMV-specific antibody levels increased slightly over time. However, we did not find an association between duration of CMV infection and CMV-specific antibody levels at study endpoint. No clear association between duration of CMV infection and the size and function of the memory T-cell pool was observed. Elevated CMV-specific antibody levels were associated with the prevalence of cardiovascular disease but not with frailty. Age at CMV seroconversion was positively associated with CMV-specific antibody levels, memory CD4 T-cell numbers and frailty.

Conclusion: Cytomegalovirus-specific memory T cells develop shortly after CMV seroconversion but do not seem to further increase over time. Age-related effects other than duration of CMV infection seem to contribute to CMV-induced changes in the immune system. Although CMV-specific immunity is not evidently linked to frailty, it tends to associate with higher prevalence of cardiovascular disease.
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http://dx.doi.org/10.1002/cti2.1193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586993PMC
October 2020

How age and infection history shape the antigen-specific CD8 T-cell repertoire: Implications for vaccination strategies in older adults.

Aging Cell 2020 11 20;19(11):e13262. Epub 2020 Oct 20.

Center for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, the Netherlands.

Older adults often show signs of impaired CD8 T-cell immunity, reflected by weaker responses against new infections and vaccinations, and decreased protection against reinfection. This immune impairment is in part thought to be the consequence of a decrease in both T-cell numbers and repertoire diversity. If this is indeed the case, a strategy to prevent infectious diseases in older adults could be the induction of protective memory responses through vaccination at a younger age. However, this requires that the induced immune responses are maintained until old age. It is therefore important to obtain insights into the long-term maintenance of the antigen-specific T-cell repertoire. Here, we review the literature on the maintenance of antigen-experienced CD8 T-cell repertoires against acute and chronic infections. We describe the complex interactions that play a role in shaping the memory T-cell repertoire, and the effects of age, infection history, and T-cell avidity. We discuss the implications of these findings for the development of new vaccination strategies to protect older adults.
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http://dx.doi.org/10.1111/acel.13262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681067PMC
November 2020

Sickness absenteeism, work performance, and healthcare use due to respiratory infections for shift and non-shift workers.

Chronobiol Int 2020 Oct 13:1-10. Epub 2020 Oct 13.

Centre for Nutrition,Prevention and Health Services, National Institute for Public Health and the Environment , Bilthoven, The Netherlands.

This study aimed to compare sickness absenteeism, work performance, and healthcare use due to respiratory infections, as well as general sickness absenteeism and work performance between shift and non-shift workers. In this study, 589 shift and non-shift workers employed in hospitals were included. For 6 months, participants kept a daily record of their influenza-like illness/acute respiratory infection (ILI/ARI) symptoms using a diary application. After an episode of ILI/ARI symptoms ended, participants (n = 531) were questioned about their sickness absenteeism (occurrence and duration in hours), work performance (on a 10 point scale), and healthcare use during the ILI/ARI episode. At the end of the 6 months follow-up, participants (n = 498) were also asked about general sickness absenteeism and work performance in the past 4 weeks. Mixed-model and regression analyses were used to compare absenteeism, work performance, and healthcare use between shift and non-shift workers. No differences were found in sickness absenteeism [Odds Ratio (OR) = 1.00 (95%‒Confidence Interval (CI): 0.61‒1.64)] and work performance [Regression coefficient (B) = -0.19 (95%‒CI: -0.65‒0.26)] due to ILI/ARI between shift and non-shift workers. In addition, healthcare use due to ILI/ARI was similar between shift and non-shift workers. Furthermore, similar general sickness absenteeism rates and work performance levels were found between shift and non-shift workers. As this is the first study that examined the associations with shift work due to ILI/ARI, further studies are needed to confirm our findings.
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http://dx.doi.org/10.1080/07420528.2020.1825468DOI Listing
October 2020

Preventing infectious diseases for healthy ageing: The VITAL public-private partnership project.

Vaccine 2020 08 24;38(37):5896-5904. Epub 2020 Jul 24.

GSK, Wavre, Belgium.

Prevention of infectious diseases through immunisation of the growing ageing adult population is essential to improve healthy ageing. However, many licenced and recommended vaccines for this age group show signs of waning of the protective effect due to declining immune responses (immuno-senescence) and decreasing vaccine uptake. Today's major challenge is to improve vaccine effectiveness and uptake and to deploy efficient vaccination strategies for this age group. The Vaccines and InfecTious diseases in the Ageing popuLation (VITAL) project, with partners from 17 academic & research groups and public institutes as well as seven industry collaborators, aims to address this challenge. The ambition is to provide evidence-based knowledge to local decision makers. Using a holistic and multidisciplinary approach and novel analytical methods, VITAL will provide tools that allow the development of targeted immunisation programs for ageing adults in European countries. The project is based on four pillars focussing on the assessment of the burden of vaccine-preventable diseases in ageing adults, the dissection of the mechanisms underlying immuno-senescence, the analysis of the clinical and economic public health impact of vaccination strategies and the development of educational resources for healthcare professionals. By the end of the project, a clear, detailed, and integrated program should be available for implementing a consistent, affordable, and sustainable vaccination strategy for ageing adults with regular evaluations of its impact over time.
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http://dx.doi.org/10.1016/j.vaccine.2020.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378501PMC
August 2020

Short- and long-term impact of vaccination against cytomegalovirus: a modeling study.

BMC Med 2020 07 2;18(1):174. Epub 2020 Jul 2.

Center for Infectious Disease Control, National Institute of Public Health and the Environment, Bilthoven, The Netherlands.

Background: Infection with cytomegalovirus (CMV) is highly prevalent worldwide and can cause severe disease in immunocompromised persons and congenitally infected infants. The disease burden caused by congenital CMV infection is high, especially in resource-limited countries. Vaccines are currently under development for various target groups.

Methods: We evaluated the impact of vaccination strategies and hygiene intervention using transmission models. Model parameters were estimated from a cross-sectional serological population study (n=5179) and a retrospective birth cohort (n=31,484), providing information on the age- and sex-specific CMV prevalence and on the birth prevalence of congenital CMV (cCMV).

Results: The analyses show that vertical transmission and infectious reactivation are the main drivers of transmission. Vaccination strategies aimed at reducing transmission from mother to child (vaccinating pregnant women or women of reproductive age) can yield substantial reductions of cCMV in 20 years (31.7-71.4% if 70% of women are effectively vaccinated). Alternatively, hygiene intervention aimed at preventing CMV infection and re-infection of women of reproductive age from young children is expected to reduce cCMV by less than 2%. The effects of large-scale vaccination on CMV prevalence can be substantial, owing to the moderate transmissibility of CMV at the population level. However, as CMV causes lifelong infection, the timescale on which reductions in CMV prevalence are expected is in the order of several decades. Elimination of CMV infection in the long run is only feasible for a vaccine with a long duration of protection and high vaccination coverage.

Conclusions: Vaccination is an effective intervention to reduce the birth prevalence of cCMV. Population-level reductions in CMV prevalence can only be achieved on a long timescale. Our results stress the value of vaccinating pregnant women and women of childbearing age and provide support for the development of CMV vaccines and early planning of vaccination scenarios and rollouts.
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http://dx.doi.org/10.1186/s12916-020-01629-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331215PMC
July 2020

Vaccines to Protect Older Adults against Pneumococcal Disease.

Interdiscip Top Gerontol Geriatr 2020 9;43:113-130. Epub 2020 Apr 9.

Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands,

Determining the optimal vaccination strategy for the protection of the elderly population against pneumococcal disease remains a challenge. Older adults are, second to young infants, most susceptible to become colonized and invaded by Streptococcus pneumoniae, causing serious disease such as bacteremic pneumonia, sepsis, and meningitis. In an era with increasing antimicrobial resistance and the growing susceptible population of aged adults, S. pneumoniae is a priority bacterial pathogen for research and development of new intervention strategies. While elderly indirectly profit from infant immunization programs through herd immunity, vaccination of older age groups can offer more direct protection. Two types of pneumococcal vaccines for adults, both based on capsular polysaccharide serotypes, are currently available but have limitations, such as short-lived protection or limited serotype coverage. These vaccine limitations and the biological aging of the immune system call for novel vaccination strategies for the older adults. Here, we highlight how host-pathogen interactions, immune protection, and effectiveness of currently available vaccines shift with increasing age, and how future pneumococcal vaccine strategies could be tailored for the elderly.
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http://dx.doi.org/10.1159/000504490DOI Listing
June 2020

The mediating role of sleep, physical activity, and diet in the association between shift work and respiratory infections.

Scand J Work Environ Health 2020 09 7;46(5):516-524. Epub 2020 Apr 7.

Center for Nutrition, Prevention and Health Services, National Institute for Public Health and the Environment; P.O. Box 1, 3720 BA Bilthoven, The Netherlands.

Objectives Shift work may be associated with an increased incidence of respiratory infections. However, underlying mechanisms are unclear. Therefore, our aim was to examine the mediating role of sleep, physical activity, and diet in the association between shift work and respiratory infections. Methods This prospective cohort study included 396 shift and non-shift workers employed in hospitals. At baseline, sleep duration and physical activity were measured using actigraphy and sleep/activity diaries, sleep quality was reported, and frequency of meal and snack consumption was measured using food diaries. In the following six months, participants used a smartphone application to report their influenza-like illness/acute respiratory infection (ILI/ARI) symptoms daily. Mediation analysis of sleep, physical activity, and diet as potential mediators of the effect of shift work on ILI/ARI incidence rate was performed using structural equation modeling with negative binomial and logistic regression. Results Shift workers had a 23% [incidence rate ratio (IRR) 1.23, 95% CI 1.01-1.49] higher incidence rate of ILI/ARI than non-shift workers. After adding the potential mediators to the model, this reduced to 15% (IRR 1.15, 95% CI 0.94-1.40). The largest mediating (ie, indirect) effect was found for poor sleep quality, with shift workers having 29% more ILI/ARI episodes via the pathway of poorer sleep quality (IRR 1.29, 95% CI 1.02-1.95). Conclusions Compared to non-shift workers, shift workers had a higher incidence rate of ILI/ARI that was partly mediated by poorer sleep quality. Therefore, it may be relevant for future research to focus on perceived sleep quality as an underlying mechanism in the relation between shift work and increased infection susceptibility.
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http://dx.doi.org/10.5271/sjweh.3896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737798PMC
September 2020

Gene expression profiles classifying clinical stages of tuberculosis and monitoring treatment responses in Ethiopian HIV-negative and HIV-positive cohorts.

PLoS One 2019 10;14(12):e0226137. Epub 2019 Dec 10.

Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.

Background: Validation of previously identified candidate biomarkers and identification of additional candidate gene expression profiles to facilitate diagnosis of tuberculosis (TB) disease and monitoring treatment responses in the Ethiopian context is vital for improving TB control in the future.

Methods: Expression levels of 105 immune-related genes were determined in the blood of 80 HIV-negative study participants composed of 40 active TB cases, 20 latent TB infected individuals with positive tuberculin skin test (TST+), and 20 healthy controls with no Mycobacterium tuberculosis (Mtb) infection (TST-), using focused gene expression profiling by dual-color Reverse-Transcription Multiplex Ligation-dependent Probe Amplification assay. Gene expression levels were also measured six months after anti-TB treatment (ATT) and follow-up in 38 TB patients.

Results: The expression of 15 host genes in TB patients could accurately discriminate between TB cases versus both TST+ and TST- controls at baseline and thus holds promise as biomarker signature to classify active TB disease versus latent TB infection in an Ethiopian setting. Interestingly, the expression levels of most genes that markedly discriminated between TB cases versus TST+ or TST- controls did not normalize following completion of ATT therapy at 6 months (except for PTPRCv1, FCGR1A, GZMB, CASP8 and GNLY) but had only fully normalized at the 18 months follow-up time point. Of note, network analysis comparing TB-associated host genes identified in the current HIV-negative TB cohort to TB-associated genes identified in our previously published Ethiopian HIV-positive TB cohort, revealed an over-representation of pattern recognition receptors including TLR2 and TLR4 in the HIV-positive cohort which was not seen in the HIV-negative cohort. Moreover, using ROC cutoff ≥ 0.80, FCGR1A was the only marker with classifying potential between TB infection and TB disease regardless of HIV status.

Conclusions: Our data indicate that complex gene expression signatures are required to measure blood transcriptomic responses during and after successful ATT to fully diagnose TB disease and characterise drug-induced relapse-free cure, combining genes which resolve completely during the 6-months treatment phase of therapy with genes that only fully return to normal levels during the post-treatment resolution phase.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226137PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6903757PMC
April 2020

Immunological effects of shift work in healthcare workers.

Sci Rep 2019 12 3;9(1):18220. Epub 2019 Dec 3.

Centre for Immunology of Infectious Diseases and Vaccines, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.

The immune system potentially plays an important mechanistic role in the relation between shift work and adverse health effects. To better understand the immunological effects of shift work, we compared numbers and functionality of immune cells between night-shift and non-shift workers. Blood samples were collected from 254 night-shift and 57 non-shift workers employed in hospitals. Absolute numbers of monocytes, granulocytes, lymphocytes, and T cell subsets were assessed. As read out of immune function, monocyte cytokine production and proliferative capacity of CD4 and CD8 T cells in response to various stimuli were analysed. The mean number of monocytes was 1.15 (95%-CI = 1.05-1.26) times higher in night-shift than in non-shift workers. Furthermore, night-shift workers who worked night shifts in the past three days had a higher mean number of lymphocytes (B = 1.12 (95%-CI = 1.01-1.26)), T cells (B = 1.16 (95%-CI = 1.03-1.31)), and CD8 T cells (B = 1.23 (95%-CI = 1.05-1.45)) compared to non-shift workers. No differences in functional parameters of monocytes and lymphocytes were observed. The differences in numbers of monocytes and T cells suggest that chronic exposure to night-shift work as well as recent night-shift work may influence the immune status of healthcare workers. This knowledge could be relevant for preventive initiatives in night-shift workers, such as timing of vaccination.
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http://dx.doi.org/10.1038/s41598-019-54816-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890754PMC
December 2019

Author Correction: Impact of delivery mode-associated gut microbiota dynamics on health in the first year of life.

Nat Commun 2019 Nov 25;10(1):5352. Epub 2019 Nov 25.

Department of Paediatric Immunology and Infectious Diseases, Wilhelmina Children's Hospital of University Medical Centre, Utrecht, the Netherlands.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-019-13373-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877559PMC
November 2019

Impact of delivery mode-associated gut microbiota dynamics on health in the first year of life.

Nat Commun 2019 11 1;10(1):4997. Epub 2019 Nov 1.

Department of Paediatric Immunology and Infectious Diseases, Wilhelmina Children's Hospital of University Medical Centre, Utrecht, the Netherlands.

The early-life microbiome appears to be affected by mode of delivery, but this effect may depend on intrapartum antibiotic exposure. Here, we assess the effect of delivery mode on gut microbiota, independent of intrapartum antibiotics, by postponing routine antibiotic administration to mothers until after cord clamping in 74 vaginally delivered and 46 caesarean section born infants. The microbiota differs between caesarean section born and vaginally delivered infants over the first year of life, showing enrichment of Bifidobacterium spp., and reduction of Enterococcus and Klebsiella spp. in vaginally delivered infants. The microbiota composition at one week of life is associated with the number of respiratory infections over the first year. The taxa driving this association are more abundant in caesarean section born children, providing a possible link between mode of delivery and susceptibility to infectious outcomes.
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http://dx.doi.org/10.1038/s41467-019-13014-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825150PMC
November 2019

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

J Pineal Res 2020 Jan 10;68(1):e12614. Epub 2019 Oct 10.

Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands.

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.
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http://dx.doi.org/10.1111/jpi.12614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916424PMC
January 2020

The hallmarks of CMV-specific CD8 T-cell differentiation.

Med Microbiol Immunol 2019 Aug 13;208(3-4):365-373. Epub 2019 Apr 13.

Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.

Upon cytomegalovirus (CMV) infection, large T-cell responses are elicited that remain high or even increase over time, a phenomenon named memory T-cell inflation. Besides, the maintained robust T-cell response, CMV-specific T cells seem to have a distinctive phenotype, characterized by an advanced differentiation state. Here, we will review this "special" differentiation status by discussing the cellular phenotype based on the expression of CD45 isoforms, costimulatory, inhibitory and natural killer receptors, adhesion and lymphocyte homing molecules, transcription factors, cytokines and cytotoxic molecules. In addition, we focus on whether the differentiation state of CMV-specific CD8 T cells is unique in comparison with other chronic viruses and we will discuss the possible impact of factors such as antigen exposure and aging on the advanced differentiation status of CMV-specific CD8 T cells.
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http://dx.doi.org/10.1007/s00430-019-00608-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647465PMC
August 2019

Early Measles Vaccination During an Outbreak in the Netherlands: Short-Term and Long-Term Decreases in Antibody Responses Among Children Vaccinated Before 12 Months of Age.

J Infect Dis 2019 07;220(4):594-602

Center for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven.

Background: The majority of infants will not be protected by maternal antibodies until their first measles vaccination, between 12 and 15 months of age. This provides incentive to reduce the age at measles vaccination, but immunological consequences are insufficiently understood, and long-term effects are largely unknown.

Methods: A total of 79 infants who received early measles vaccination between 6 and 12 months age and a second dose at 14 months of age were compared to 44 children in a control group who received 1 dose at 14 months of age. Measles virus-specific neutralizing antibody concentrations and avidity were determined up to 4 years of age.

Results: Infants who first received measles vaccination before 12 months of age had a long-term decrease in the concentration and avidity of measles virus-specific neutralizing antibodies, compared with infants in the control group. For 11.1% of children with a first dose before 9 months of age, antibody levels at 4 years of age had dropped below the cutoff for clinical protection.

Conclusions: Early measles vaccination provides immediate protection in the majority of infants but yields a long-term decrease in neutralizing antibody responses, compared to vaccination at a later age. Additional vaccination at 14 months of age does not improve this. Over the long term, this may result in an increasing number of children susceptible to measles.
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http://dx.doi.org/10.1093/infdis/jiz159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639599PMC
July 2019

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

PLoS One 2019 1;14(2):e0211557. Epub 2019 Feb 1.

Center for Nutrition, Prevention and Health Services, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211557PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358078PMC
November 2019

Shift Work and Respiratory Infections in Health-Care Workers.

Am J Epidemiol 2019 03;188(3):509-517

Center for Nutrition, Prevention and Health Services, National Institute for Public Health and the Environment, Bilthoven, the Netherlands.

Recently, there has been interest in whether shift work may enhance susceptibility to infection. Our aim was to determine whether shift workers in the health-care field have a higher incidence, duration, and/or severity of influenza-like illness (ILI) and acute respiratory infection (ARI) than non-shift workers. From September 2016 to June 2017, 501 rotating and/or night-shift workers and 88 non-shift workers from the Klokwerk+ Study (the Netherlands, 2016-2017) registered the occurrence of ILI/ARI symptoms daily using a smartphone application. The incidence rate of ILI/ARI (defined as ≥2 symptoms on the same day/≥1 symptom on 2 consecutive days), the mean duration of each episode, and the incidence rate of severe episodes were compared between shift workers and non-shift workers using negative binomial regression and linear mixed-model analysis. In total, participants completed 110,347 diaries. Shift workers' incidence rate of ILI/ARI was 1.20 (95% confidence interval (CI): 1.01, 1.43) times higher than that of non-shift workers, and for severe ILI/ARI episodes, shift workers' incidence rate was 1.22 (95% CI: 1.01, 1.49) times higher. The mean duration of an ILI/ARI episode did not differ (ratio between means = 1.02, 95% CI: 0.87, 1.19). In conclusion, shift workers in health care had more ILI/ARI episodes and more severe ILI/ARI episodes than non-shift workers, but with a similar duration. Insight into underlying mechanisms connecting shift work and infection susceptibility will contribute to the design of preventive initiatives.
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http://dx.doi.org/10.1093/aje/kwy258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395171PMC
March 2019

Socioeconomic Status Is Associated With Antibody Levels Against Vaccine Preventable Diseases in the Netherlands.

Front Public Health 2018 27;6:209. Epub 2018 Jul 27.

Centre for Immunology of Infectious Diseases and Vaccines, Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, Netherlands.

We investigated whether low socioeconomic status (SES), which is associated with reduced health and life expectancy, might play a role in increased risk for infectious diseases. Therefore, we explored the association between SES and immunoglobulin G (IgG) levels against various pathogens. We analyzed the association between SES [educational level and net household income (NHI)] and serum IgG concentration against measles, mumps, rubella, varicella, Haemophilus influenzae type B (HiB), pneumococcus, meningococcus serogroup C (MenC), and cytomegalovirus (CMV) collected within a national cross-sectional serosurvey (2006/2007) using linear regression analyses among non-vaccinated individuals. Higher educational level was associated with higher IgG concentrations against measles (GMC ratio 1.34, 95% CI 1.18-1.53) and rubella (1.13, 1.02-1.25) compared to low education level. In contrast, higher education level was associated with lower IgG concentrations against pneumococcus (0.78, 0.70-0.88), MenC (0.54, 0.44-0.68), and CMV (0.23, 0.18-0.31) compared to low education level. This pattern was also evident when NHI was used as SES indicator. Our study suggests that socioeconomic status is associated with antibody levels in a pathogen-dependent manner. The results suggest that differences in serological response upon infection or differences in exposure might be involved in the variation in IgG levels between SES groups.
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http://dx.doi.org/10.3389/fpubh.2018.00209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6094970PMC
July 2018

Host Gene Expression Kinetics During Treatment of Tuberculosis in HIV-Coinfected Individuals Is Independent of Highly Active Antiretroviral Therapy.

J Infect Dis 2018 10;218(11):1833-1846

Department of Infectious Diseases, Leiden University Medical Center, Leiden.

Background: Limitations in diagnostic tools to discriminate between active tuberculosis and latent Mycobacterium tuberculosis infection and for monitoring antituberculosis treatment responses are major challenges in tuberculosis control, especially in human immunodeficiency virus (HIV)-coinfected individuals.

Methods: Expression levels of 105 immune-related genes were determined in 131 HIV-infected patients with active tuberculosis (n = 48), patients with latent M. tuberculosis infection (LTBI; n = 37), and controls with no M. tuberculosis infection (n = 46) in Addis Ababa, Ethiopia, using focused gene expression profiling with a dual-color reverse-transcription multiplex ligation-dependent probe amplification assay.

Results: Within the cohort of HIV-positive subjects, the expression profiles of 7 genes at baseline (FCGR1A, RAB24, TLR1, TLR4, MMP9, NLRC4, and IL1B) could accurately discriminate between active tuberculosis and both latent and no M. tuberculosis infection, largely independently of (in)eligibility for highly active antiretroviral therapy (HAART). Six months after antituberculosis treatment, biomarker profiles of patients with tuberculosis became indistinguishable from those of patients with LTBI and controls. Importantly, host gene expression kinetics during antituberculosis treatment in HIV-coinfected individuals was found to be independent of HAART use.

Conclusions: Blood transcriptomic profiles can potentially be used as biomarkers to discriminate the different clinical stages of tuberculosis in HIV-coinfected individuals and to monitor tuberculosis treatment responses in both HAART recipients and untreated individuals.
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http://dx.doi.org/10.1093/infdis/jiy404DOI Listing
October 2018

Negative Effect of Age, but Not of Latent Cytomegalovirus Infection on the Antibody Response to a Novel Influenza Vaccine Strain in Healthy Adults.

Front Immunol 2018 29;9:82. Epub 2018 Jan 29.

Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, Netherlands.

Older adults are more vulnerable to influenza virus infection and at higher risk for severe complications and influenza-related death compared to younger adults. Unfortunately, influenza vaccine responses tend to be impaired in older adults due to aging of the immune system (immunosenescence). Latent infection with cytomegalovirus (CMV) is assumed to enhance age-associated deleterious changes of the immune system. Although lower responses to influenza vaccination were reported in CMV-seropositive compared to CMV-seronegative adults and elderly, beneficial effects of CMV infection were observed as well. The lack of consensus in literature on the effect of latent CMV infection on influenza vaccination may be due to the presence of pre-existing immunity to influenza in these studies influencing the subsequent influenza vaccine response. We had the unique opportunity to evaluate the effect of age and latent CMV infection on the antibody response to the novel influenza H1N1pdm vaccine strain during the pandemic of 2009, thereby reducing the effect of pre-existing immunity on the vaccine-induced antibody response. This analysis was performed in a large study population ( = 263) in adults (18-52 years old). As a control, memory responses to the seasonal vaccination, including the same H1N1pdm and an H3N2 strain, were investigated in the subsequent season 2010-2011. With higher age, we found decreased antibody responses to the pandemic vaccination even within this age range, indicating signs of immunosenescence to this novel antigen in the study population. Using a generalized estimation equation regression model, adjusted for age, sex, and previous influenza vaccinations, we observed that CMV infection in contrast did not influence the influenza virus-specific antibody titer after H1N1pdm vaccination. Yet, we found higher residual protection rates (antibody level ≥40 hemagglutinin units (HAU)) in CMV-seropositive individuals than in CMV-seronegative individuals 6 months and 1 year after pandemic vaccination. In the subsequent season, no effect of age or CMV infection on seasonal influenza vaccine response was observed. In conclusion, we observed no evidence for CMV-induced impairment of antibody responses to a novel influenza strain vaccine in adults. If anything, our data suggest that there might be a beneficial effect of latent CMV infection on the protection rate after novel influenza vaccination.
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http://dx.doi.org/10.3389/fimmu.2018.00082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796903PMC
February 2019

Objectively measured physical activity of hospital shift workers.

Scand J Work Environ Health 2018 05 22;44(3):265-273. Epub 2018 Jan 22.

Center for Nutrition, Prevention and Health Services, National Institute for Public Health and the Environment, P.O. Box 1, 3720 BA, Bilthoven, The Netherlands.

Objectives Shift work may alter workers' leisure-time and occupational physical activity (PA) levels, which might be one of the potential underlying mechanisms of the negative health effects of shift work. Therefore, we compared objectively measured PA levels between hospital shift and non-shift workers. Methods Data were used from Klokwerk+, a cohort study examining the health effects of shift work among healthcare workers employed in hospitals. In total, 401 shift workers and 78 non-shift workers were included, all of whom wore Actigraph GT3X accelerometers for up to seven days. Time spent sedentary, standing, walking, running, stairclimbing, and cycling during leisure time and at work was estimated using Acti4 software. Linear regression was used to compare proportions of time spent in these activities between hospital shift and non-shift workers. Results Average accelerometer wear-time was 105.9 [standard deviation (SD) 14.0] waking hours over an average of 6.9 (SD 0.6) days. No differences between hospital shift and non-shift workers were found in leisure-time PA (P>0.05). At work, shift workers were less sedentary [B=-10.6% (95% CI -14.3- -6.8)] and spent larger proportions of time standing [B=9.5% (95% CI 6.4-12.6)] and walking [B=1.2% (95% CI 0.1-2.2)] than non-shift workers. However, these differences in occupational PA became smaller when the number of night shifts during accelerometer wear-time increased. Conclusions Leisure-time PA levels of hospital shift workers were similar to those of non-shift workers, but shift workers were less sedentary and more physically active (ie, standing/walking) at work. Future research to the role of occupational activities in the health effects of shift work is recommended.
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http://dx.doi.org/10.5271/sjweh.3709DOI Listing
May 2018

Mumps infection but not childhood vaccination induces persistent polyfunctional CD8 T-cell memory.

J Allergy Clin Immunol 2018 05 12;141(5):1908-1911.e12. Epub 2018 Jan 12.

Center for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.

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http://dx.doi.org/10.1016/j.jaci.2017.11.047DOI Listing
May 2018

VDJdb: a curated database of T-cell receptor sequences with known antigen specificity.

Nucleic Acids Res 2018 01;46(D1):D419-D427

Pirogov Russian National Research Medical University, Moscow 117997, Russia.

The ability to decode antigen specificities encapsulated in the sequences of rearranged T-cell receptor (TCR) genes is critical for our understanding of the adaptive immune system and promises significant advances in the field of translational medicine. Recent developments in high-throughput sequencing methods (immune repertoire sequencing technology, or RepSeq) and single-cell RNA sequencing technology have allowed us to obtain huge numbers of TCR sequences from donor samples and link them to T-cell phenotypes. However, our ability to annotate these TCR sequences still lags behind, owing to the enormous diversity of the TCR repertoire and the scarcity of available data on T-cell specificities. In this paper, we present VDJdb, a database that stores and aggregates the results of published T-cell specificity assays and provides a universal platform that couples antigen specificities with TCR sequences. We demonstrate that VDJdb is a versatile instrument for the annotation of TCR repertoire data, enabling a concatenated view of antigen-specific TCR sequence motifs. VDJdb can be accessed at https://vdjdb.cdr3.net and https://github.com/antigenomics/vdjdb-db.
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http://dx.doi.org/10.1093/nar/gkx760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5753233PMC
January 2018

Infectious reactivation of cytomegalovirus explaining age- and sex-specific patterns of seroprevalence.

PLoS Comput Biol 2017 Sep 26;13(9):e1005719. Epub 2017 Sep 26.

Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, the Netherlands.

Human cytomegalovirus (CMV) is a herpes virus with poorly understood transmission dynamics. Person-to-person transmission is thought to occur primarily through transfer of saliva or urine, but no quantitative estimates are available for the contribution of different infection routes. Using data from a large population-based serological study (n = 5,179), we provide quantitative estimates of key epidemiological parameters, including the transmissibility of primary infection, reactivation, and re-infection. Mixture models are fitted to age- and sex-specific antibody response data from the Netherlands, showing that the data can be described by a model with three distributions of antibody measurements, i.e. uninfected, infected, and infected with increased antibody concentration. Estimates of seroprevalence increase gradually with age, such that at 80 years 73% (95%CrI: 64%-78%) of females and 62% (95%CrI: 55%-68%) of males are infected, while 57% (95%CrI: 47%-67%) of females and 37% (95%CrI: 28%-46%) of males have increased antibody concentration. Merging the statistical analyses with transmission models, we find that models with infectious reactivation (i.e. reactivation that can lead to the virus being transmitted to a novel host) fit the data significantly better than models without infectious reactivation. Estimated reactivation rates increase from low values in children to 2%-4% per year in women older than 50 years. The results advance a hypothesis in which transmission from adults after infectious reactivation is a key driver of transmission. We discuss the implications for control strategies aimed at reducing CMV infection in vulnerable groups.
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http://dx.doi.org/10.1371/journal.pcbi.1005719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630159PMC
September 2017

CMV immune evasion and manipulation of the immune system with aging.

Geroscience 2017 06 24;39(3):273-291. Epub 2017 Jun 24.

Department of Medicine, University of Cambridge, Box 157, Level 5, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK.

Human cytomegalovirus (HCMV) encodes numerous proteins and microRNAs that function to evade the immune response and allow the virus to replicate and disseminate in the face of a competent innate and acquired immune system. The establishment of a latent infection by CMV, which if completely quiescent at the level of viral gene expression would represent an ultimate in immune evasion strategies, is not sufficient for lifelong persistence and dissemination of the virus. CMV needs to reactivate and replicate in a lytic cycle of infection in order to disseminate further, which occurs in the face of a fully primed secondary immune response. Without reactivation, latency itself would be redundant for the virus. It is also becoming clear that latency is not a totally quiescent state, but is characterized by limited viral gene expression. Therefore, the virus also needs immune evasion strategies during latency. An effective immune response to CMV is required or viral replication will cause morbidity and ultimately mortality in the host. There is clearly a complex balance between virus immune evasion and host immune recognition over a lifetime. This poses the important question of whether long-term evasion or manipulation of the immune response driven by CMV is detrimental to health. In this meeting report, three groups used the murine model of CMV (MCMV) to examine if the contribution of the virus to immune senescence is set by the (i) initial viral inoculum, (ii) inflation of T cell responses, (iii) or the balance between functionally distinct effector CD4+ T cells. The work of other groups studying the CMV response in humans is discussed. Their work asks whether the ability to make immune responses to new antigens is compromised by (i) age and HCMV carriage, (ii) long-term exposure to HCMV giving rise to an overall immunosuppressive environment and increased levels of latent virus, or (iii) adapted virus mutants (used as potential vaccines) that have the capacity to elicit conventional and unconventional T cell responses.
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http://dx.doi.org/10.1007/s11357-017-9986-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5505894PMC
June 2017

Differences in T-cell infiltrates and survival between HPV+ and HPV- oropharyngeal squamous cell carcinoma.

Future Sci OA 2016 Mar 7;2(1):FSO88. Epub 2016 Jan 7.

Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands; Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.

Recent studies have suggested that immune cells as part of tumor's microenvironment could partly explain the better outcome in HPV-associated oropharyngeal carcinoma. We performed a systematic review of the literature focused on differences in immune-infiltrate in HPV+ versus HPV- oropharyngeal cancers. This comprehensive search yielded 4308 original papers, of which 20 satisfied our eligibility criteria. Increase in both circulating and tumor infiltrating CD8+ lymphocytes is mainly seen in HPV+ oropharyngeal carcinoma. Interestingly, the survival benefit associated with increase in immune cells is equal both in HPV+ and HPV- oropharyngeal cancer. Based on these results, our review underscores the role of the immune system in the biological and clinical behavior of oropharyngeal squamous cell carcinomas (OPSCC) and might open doors to further investigate immune modulatory treatment options in OPSCC patients.
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http://dx.doi.org/10.4155/fso.15.88DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5137981PMC
March 2016

Discriminative expression of whole blood genes in HIV patients with latent and active TB in Ethiopia.

Tuberculosis (Edinb) 2016 09 13;100:25-31. Epub 2016 Jun 13.

Department of Internal Medicine and Infectious Diseases, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: Transcriptomic host biomarkers could assist in developing effective diagnostics, vaccines and therapeutics for tuberculosis (TB). However, different biomarkers may be discriminatory in different populations depending on the host and bacillary genetics and HIV infection, and need to be addressed.

Methods: The expression levels of 45 genes that are known to be involved in or affected by TB pathogenesis were analyzed using dual color Reverse Transcriptase Multiplex Ligation-dependent Probe Amplification (dcRT-MLPA) assay in whole blood of 106 HIV positive individuals including active TB patients (TB(+)HIV(+), n = 29), and non TB patients that are tuberculin skin test positive (TST+) (TST(+)HIV(+), n = 26), or TST negative (TST(-)HIV(+), n = 51).

Results: Between the two clinical groups (TB(+)HIV(+) vs. TST(-)HIV(+)) 8 genes were differently expressed (CCL19, CD14, CD8A, FPR1, IL7R, CCL22, TNFRSF1A, and FCGR1A); between TB(+)HIV(+) vs. TST(+)HIV(+), 6 genes (CD14, IL7R, TIMP2, CCL22, TNFRSF1A, and FCGR1A) were differently expressed. Since no difference in gene expression was revealed between TST(+)HIV(+) vs. TST(-)HIV(+), we clustered both the TST(+)HIV(+) and TST(-)HIV(+) individuals as one group (TST(+/-)HIV(+)) and compared gene expression with TB(+)HIV(+) patients. Thus, the results revealed that the levels of five genes (CD8A, TIMP2, CCL22, FCGR1A and TNFRSF1A) were the most accurate single gene markers for differentiation between TB(+)HIV(+) and TST(+/-)HIV(+), with AUCs of 0.71, 0.71, 0.79, 0.83 and 0.73, respectively. However, the combination of two genes (CCL22 + FCGR1A) and FCGR1A alone were the most accurate marker for differentiation between the two groups (TB(+)HIV(+) and TST(+/-)HIV(+)) with AUC of 0.85 and 0.83, respectively.

Conclusions: We showed that five genes (CD8A, TIMP2, CCL22, FCGR1A and TNFRSF1A), specifically FCGR1A and CCL22 have the potential to discriminate active TB from non-active TB in HIV patients in Ethiopia and could be used to improve diagnostic tools for active TB in HIV patients, and to understand the pathogenesis of TB/HIV coinfection.
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http://dx.doi.org/10.1016/j.tube.2016.06.003DOI Listing
September 2016

Editorial: Role of HLA and KIR in Viral Infections.

Front Immunol 2016 27;7:286. Epub 2016 Jul 27.

Department of Immune Mechanisms, Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, Netherlands; Laboratory of Translational Immunology, Department of Immunology, University Medical Center, Utrecht, Netherlands.

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http://dx.doi.org/10.3389/fimmu.2016.00286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4961690PMC
August 2016

Rapid reconstitution of CD4 T cells and NK cells protects against CMV-reactivation after allogeneic stem cell transplantation.

J Transl Med 2016 08 2;14(1):230. Epub 2016 Aug 2.

Laboratory of Translational Immunology, Department of Immunology, Utrecht, The Netherlands.

Background: Epstein-Barr virus and Cytomegalovirus reactivations frequently occur after allogeneic stem cell transplantation (SCT).

Methods: Here we investigated the role of immune cell reconstitution in the onset and subsequent severity of EBV- and CMV-reactivation. To this end, 116 patients were prospectively sampled for absolute T cell (CD4 and CD8), B-cell (CD19) and NK-cell (CD16 and CD56) numbers weekly post-SCT during the first 3 months and thereafter monthly until 6 months post-SCT. Viral load was monitored in parallel.

Results: In contrast to the general belief, we found that early T-cell reconstitution does not play a role in the onset of viral reactivation. CMV reactivation in the first 7 weeks after SCT however resulted in higher absolute CD8(+) T-cell numbers 6 months post-SCT in patients with high-level reactivation, many of which were CMV-specific. Interestingly, rapid reconstitution of CD4(+) T-cells, as well as NK cells and the presence of donor KIR3DL1, are associated with the absence of CMV-reactivation after SCT, suggestive of a protective role of these cells. In contrast, EBV-reactivations were not affected in any way by the level of immune reconstitution after SCT.

Conclusion: In conclusion, these data suggest that CD4(+) T-cells and NK cells, rather than CD8(+) T-cells, are associated with protection against CMV-reactivation.
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http://dx.doi.org/10.1186/s12967-016-0988-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971638PMC
August 2016

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.

BMC Public Health 2016 08 2;16:692. Epub 2016 Aug 2.

Center for Nutrition, Prevention and Health Services, National Institute for Public Health and the Environment, P.O. Box 1, 3720 BA, Bilthoven, The Netherlands.

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.
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http://dx.doi.org/10.1186/s12889-016-3317-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4969645PMC
August 2016