Publications by authors named "Kurt Rasmussen"

47 Publications

Causes of irritant contact dermatitis after occupational skin exposure: a systematic review.

Int Arch Occup Environ Health 2021 Oct 19. Epub 2021 Oct 19.

Department of Occupational Medicine, Danish Ramazzini Centre, Regional Hospital West Jutland, University Research Clinic, Herning, Denmark.

Purpose: Irritant contact dermatitis (ICD) is a major cause of occupational disease. The aim was to review the relation between exposure to occupational irritants and ICD and the prognosis of ICD.

Methods: Through a systematic search, 1516 titles were identified, and 48 studies were included in the systematic review.

Results: We found that the evidence for an association between ICD and occupational irritants was strong for wet work, moderate for detergents and non-alcoholic disinfectants, and strong for a combination. The highest quality studies provided limited evidence for an association with use of occlusive gloves without other exposures and moderate evidence with simultaneous exposure to other wet work irritants. The evidence for an association between minor ICD and exposure to metalworking fluids was moderate. Regarding mechanical exposures, the literature was scarce and the evidence limited. We found that the prognosis for complete healing of ICD is poor, but improves after decrease of exposure through change of occupation or work tasks. There was no substantial evidence for an influence of gender, age, or household exposures. Inclusion of atopic dermatitis in the analysis did not alter the risk of ICD. Studies were at risk of bias, mainly due to selection and misclassification of exposure and outcome. This may have attenuated the results.

Conclusion: This review reports strong evidence for an association between ICD and a combination of exposure to wet work and non-alcoholic disinfectants, moderate for metalworking fluids, limited for mechanical and glove exposure, and a strong evidence for a poor prognosis of ICD.
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http://dx.doi.org/10.1007/s00420-021-01781-0DOI Listing
October 2021

Translating Pharmacology into Therapeutics to Fight the Opioid Crisis.

J Pharmacol Exp Ther 2019 11;371(2):394-395

Astellas Pharma Global Development, Northbrook, Illinois (G.J.M.); University of Texas Medical Branch, Galveston, Texas (K.A.C.); and NIDA, Bethesda, Maryland (K.R.).

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http://dx.doi.org/10.1124/jpet.119.262477DOI Listing
November 2019

The Opioid Crisis and the Future of Addiction and Pain Therapeutics.

J Pharmacol Exp Ther 2019 11 3;371(2):396-408. Epub 2019 Sep 3.

National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland (N.P.C., G.S.S., S.G.J., M.D.H.); Orvos Communications, LLC (H.E.G.); National Institute of Neurologic Disorders and Stroke (A.P.T.) and National Institute on Drug Abuse (K.R.), National Institutes of Health, Bethesda, Maryland; Q-State Biosciences, Cambridge, Massachusetts (O.B.M.); and VP Discovery Research, Karuna Therapeutics, Boston, Massachusetts (C.C.F.)

Opioid misuse and addiction are a public health crisis resulting in debilitation, deaths, and significant social and economic impact. Curbing this crisis requires collaboration among academic, government, and industrial partners toward the development of effective nonaddictive pain medications, interventions for opioid overdose, and addiction treatments. A 2-day meeting, , was held at the National Institutes of Health (NIH) to address these concerns and to chart a collaborative path forward. The meeting was supported by the NIH Helping to End Addiction Long-Term (HEAL) Initiative, an aggressive, trans-agency effort to speed scientific solutions to stem the national opioid crisis. The event was unique in bringing together two research disciplines, addiction and pain, in order to create a forum for crosscommunication and collaboration. The output from the symposium will be considered by the HEAL Initiative; this article summarizes the scientific presentations and key takeaways. Improved understanding of the etiology of acute and chronic pain will enable the discovery of novel targets and regulatable pain circuits for safe and effective therapeutics, as well as relevant biomarkers to ensure adequate testing in clinical trials. Applications of improved technologies including reagents, assays, model systems, and validated probe compounds will likely increase the delivery of testable hypotheses and therapeutics to enable better health outcomes for patients. The symposium goals were achieved by increasing interdisciplinary collaboration to accelerate solutions for this pressing public health challenge and provide a framework for focused efforts within the research community. SIGNIFICANCE STATEMENT: This article summarizes key messages and discussions resulting from a 2-day symposium focused on challenges and opportunities in developing addiction- and pain-related medications. Speakers and attendees came from 40 states in the United States and 15 countries, bringing perspectives from academia, industry, government, and healthcare by researchers, clinicians, regulatory experts, and patient advocates.
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http://dx.doi.org/10.1124/jpet.119.259408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863454PMC
November 2019

Evaluation of 5-HT receptor antagonism for the treatment of anxiety, depression, and schizophrenia through the use of receptor-deficient mice.

Behav Brain Res 2019 03 10;360:270-278. Epub 2018 Dec 10.

Neuroscience Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA. Electronic address:

The 5-HT receptor is the most recently identified receptor subtype within a family of 5-HT receptors activated by the neurotransmitter serotonin. There has been significant interest in investigating the potential role of this receptor in psychiatric disorders including depression, anxiety, and schizophrenia. Behaviors of 5-HT +/+ (wild-type or WT) and 5-HT -/- (receptor knockout or KO) mice were compared across 10 different assays (7 for anxiety, 1 for depression, 2 for psychosis) to identify differences that could indicate clinical potential for 5-HT receptor antagonism. Evaluation of KO vs. WT mice demonstrated significant differences between the genotypes in the fear conditioning, shock-probe burying, novelty-suppressed feeding, punishment memory, forced swim test, and d-amphetamine hyperactivity assays. There was not consistency in either the direction of behavioral effects across genotypes or across assays. Thus, data from these behavioral assays did not uniformly support the idea that 5-HT receptors constitute an important drug target for these psychiatric disorders. The present findings are generally congruent with the mixed results in the literature on the behaviors of 5-HT -/-mice and with the data on effects of 5-HT receptor antagonists in rodent models that detect activity of anxiolytic, antidepressant, and antipsychotic effects.
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http://dx.doi.org/10.1016/j.bbr.2018.12.019DOI Listing
March 2019

NIDA's medication development priorities in response to the Opioid Crisis: ten most wanted.

Neuropsychopharmacology 2019 03 7;44(4):657-659. Epub 2018 Dec 7.

Division of Therapeutics and Medical Consequences, National Institute on Drug Abuse, 6001 Executive Blvd, Bethesda, MD, 20892, USA.

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http://dx.doi.org/10.1038/s41386-018-0292-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372702PMC
March 2019

Collaboration and patient safety at an emergency department - a qualitative case study.

J Health Organ Manag 2018 Mar 22;32(1):25-38. Epub 2018 Jan 22.

Department of Occupational Medicine, Regional Hospital West Jutland University Research Clinic , Herning, Denmark.

Purpose The purpose of this paper is to examine how conflicts about collaboration between staff at different departments arose during the establishment of a new emergency department and how these conflicts affected the daily work and ultimately patient safety at the emergency department. Design/methodology/approach This qualitative single case study draws on qualitative semi-structured interviews and participant observation. The theoretical concepts "availability" and "receptiveness" as antecedents for collaboration will be applied in the analysis. Findings Close collaboration between departments was an essential precondition for the functioning of the new emergency department. The study shows how a lack of antecedents for collaboration affected the working relation and communication between employees and departments, which spurred negative feelings and reproduced conflicts. This situation was seen as a potential threat for the safety of the emergency patients. Research limitations/implications This study presents a single case study, at a specific point in time, and should be used as an illustrative example of how contextual and situational factors affect the working environment and through that patient safety. Originality/value Few studies provide an in-depth investigation of what actually takes place when collaboration between professional groups goes wrong and escalates, and how problems in collaboration may affect patient safety.
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http://dx.doi.org/10.1108/JHOM-09-2016-0174DOI Listing
March 2018

Costs associated with adverse events among acute patients.

BMC Health Serv Res 2017 Sep 13;17(1):651. Epub 2017 Sep 13.

Department of Occupational Medicine, University Research Clinic, Herning Regional Hospital, Herning, Denmark.

Background: The aim of this study was to analyse the additional treatment costs of acute patients admitted to a Danish hospital who suffered an adverse event (AE) during in-hospital treatment.

Methods: A matched case-control design was utilised. Using a combination of trigger words and patient record reviews 91 patients exposed to AEs were identified. Controls were identified among patients admitted to the same department during the same 20-month period. The matching was based on age, gender, and main diagnosis. Cost data was extracted from the Danish National Cost Database for four different periods after beginning of the admission.

Results: Patients exposed to an AE were associated with higher mean cost of EUR 9505 during their index admission (p = 0.014). For the period of 6 months from the beginning of the admission minus the admission itself they were associated with higher mean cost of EUR 4968 (p = 0.016). For the period from the 7th month until the end of the 12th month there was no statistically significant difference (p = 0.104). For the total period of 12 month, patients exposed to an AE were associated with statistically significant higher mean cost of EUR 13,930 (p = 0.001).

Conclusions: AEs are associated with significant hospital costs. Our findings suggest that a follow-up period of 6 months is necessary when investigating the costs associated with AEs among acute patients. Further research of specific types of AEs and the costs of preventing these types of AEs would improve the understanding of the relationship between adverse events and costs.
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http://dx.doi.org/10.1186/s12913-017-2605-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5598051PMC
September 2017

Costs associated with adverse events among acute patients.

BMC Health Serv Res 2017 Sep 13;17(1):651. Epub 2017 Sep 13.

Department of Occupational Medicine, University Research Clinic, Herning Regional Hospital, Herning, Denmark.

Background: The aim of this study was to analyse the additional treatment costs of acute patients admitted to a Danish hospital who suffered an adverse event (AE) during in-hospital treatment.

Methods: A matched case-control design was utilised. Using a combination of trigger words and patient record reviews 91 patients exposed to AEs were identified. Controls were identified among patients admitted to the same department during the same 20-month period. The matching was based on age, gender, and main diagnosis. Cost data was extracted from the Danish National Cost Database for four different periods after beginning of the admission.

Results: Patients exposed to an AE were associated with higher mean cost of EUR 9505 during their index admission (p = 0.014). For the period of 6 months from the beginning of the admission minus the admission itself they were associated with higher mean cost of EUR 4968 (p = 0.016). For the period from the 7th month until the end of the 12th month there was no statistically significant difference (p = 0.104). For the total period of 12 month, patients exposed to an AE were associated with statistically significant higher mean cost of EUR 13,930 (p = 0.001).

Conclusions: AEs are associated with significant hospital costs. Our findings suggest that a follow-up period of 6 months is necessary when investigating the costs associated with AEs among acute patients. Further research of specific types of AEs and the costs of preventing these types of AEs would improve the understanding of the relationship between adverse events and costs.
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http://dx.doi.org/10.1186/s12913-017-2605-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5598051PMC
September 2017

Forebrain-selective AMPA-receptor antagonism guided by TARP γ-8 as an antiepileptic mechanism.

Nat Med 2016 12 7;22(12):1496-1501. Epub 2016 Nov 7.

Lilly Research Laboratory, Eli Lilly and Company, Indianapolis, Indiana, USA.

Pharmacological manipulation of specific neural circuits to optimize therapeutic index is an unrealized goal in neurology and psychiatry. AMPA receptors are important for excitatory synaptic transmission, and their antagonists are antiepileptic. Although efficacious, AMPA-receptor antagonists, including perampanel (Fycompa), the only approved antagonist for epilepsy, induce dizziness and motor impairment. We hypothesized that blockade of forebrain AMPA receptors without blocking cerebellar AMPA receptors would be antiepileptic and devoid of motor impairment. Taking advantage of an AMPA receptor auxiliary protein, TARP γ-8, which is selectively expressed in the forebrain and modulates the pharmacological properties of AMPA receptors, we discovered that LY3130481 selectively antagonized recombinant and native AMPA receptors containing γ-8, but not γ-2 (cerebellum) or other TARP members. Two amino acid residues unique to γ-8 determined this selectivity. We also observed antagonism of AMPA receptors expressed in hippocampal, but not cerebellar, tissue from an patient with epilepsy. Corresponding to this selective activity, LY3130481 prevented multiple seizure types in rats and mice and without motor side effects. These findings demonstrate the first rationally discovered molecule targeting specific neural circuitries for therapeutic advantage.
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http://dx.doi.org/10.1038/nm.4221DOI Listing
December 2016

Work injuries among migrant workers in Denmark.

Occup Environ Med 2017 03 22;74(4):235-242. Epub 2016 Aug 22.

Department of Occupational Medicine, Danish Ramazzini Centre, University Research Clinic, Regional Hospital West Jutland, Herning, Denmark.

Objectives: Work migration into Denmark has increased during the recent decades, especially after the enlargement of the European Union (EU) in 2004. Whether or not migrant workers experience more work injuries than the native workforce has been debated and results are conflicting, most likely due to methodological difficulties and cultural disparities. We set out to meet these challenges using population-based work injury registers, targeting a specific and representative region in Denmark.

Methods: This population-based study used data on work injuries from an emergency department (ED) and reported injuries from the ED's catchment area to the Danish Working Environment Authority during 11 years. We calculated incidences of work injury for groups of migrant workers compared with native Danes and adjusted incidence rate ratios based on information on the complete working population.

Results: The incidences of work injuries among migrant workers from the new EU countries and from the rest of the world were higher compared with Danish workers and workers from the old EU countries and other Western countries. Especially migrants older than 30 years and in low-risk industries were at higher risk. Workers who had migrated recently were at even higher risk.

Conclusions: We found increased risk of work injuries among migrant workers. Studying migrants in registers is a methodological challenge as some migrants are not registered, for legal or illegal reasons; thus, only a selected group is studied, but this may most likely underestimate the risk.
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http://dx.doi.org/10.1136/oemed-2016-103681DOI Listing
March 2017

Learning and feedback from the Danish patient safety incident reporting system can be improved.

Dan Med J 2016 Jun;63(6)

Introduction: The perceived usefulness of incident reporting systems is an important motivational factor for reporting. The usefulness may be facilitated by well-established feedback mechanisms and by learning processes. The aim of this study was to investigate how feedback mechanisms and learning processes were implemented at four Danish hospital units all located in one of the five Danish regions.

Methods: Based on the concepts of feedback and learning from incident processes, a questionnaire was developed and distributed to 335 patient safety representatives from 200 departments at four Danish hospital units in one of the five Danish regions.

Results: The study showed that external reporters were rarely contacted for dialogue, grouped front-line staff were sparsely involved in the learning process, few evaluated the effectiveness of implemented interventions and personal factors were frequently perceived as a primary contributory factor to these incidents. In contrast, the patient safety representatives perceived their competencies as sufficient for the job, internal reporters were often contacted for dialogue, evaluation was widely used and management supported the work with incident reports.

Conclusions: The results of the study identified several shortcomings in the implementation of learning processes and feedback mechanisms. The apparent existence of a person-focused approach stands out as an element of notice. The insufficient implementation we observed indicates that there is room for improvement in the efforts made to maximise learning from incidents in the investigated population.

Funding: not relevant.

Trial Registration: not relevant.
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June 2016

Psychological Stress Activates the Inflammasome via Release of Adenosine Triphosphate and Stimulation of the Purinergic Type 2X7 Receptor.

Biol Psychiatry 2016 07 8;80(1):12-22. Epub 2015 Dec 8.

Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut. Electronic address:

Background: The mechanisms underlying stress-induced inflammation that contribute to major depressive disorder are unknown. We examine the role of the adenosine triphosphate (ATP)/purinergic type 2X7 receptor (P2X7R) pathway and the NLRP3 (nucleotide-binding, leucine-rich repeat, pyrin domain containing 3) inflammasome in interleukin (IL)-1β and depressive behavioral responses to stress.

Methods: The influence of acute restraint stress on extracellular ATP, glutamate, IL-1β, and tumor necrosis factor alpha in hippocampus was determined by microdialysis, and the influence of acute restraint stress on the NLRP3 inflammasome was determined by western blot analysis. The influence of P2X7R antagonist administration on IL-1β and tumor necrosis factor alpha and on anxiety and depressive behaviors was determined in the chronic unpredictable stress rodent model. The role of the NLRP3 inflammasome was determined by analysis of Nlrp3 null mice.

Results: Acute restraint stress rapidly increased extracellular ATP, an endogenous agonist of P2X7R; the inflammatory cytokine IL-1β; and the active form of the NLRP3 inflammasome in the hippocampus. Administration of a P2X7R antagonist completely blocked the release of IL-1β and tumor necrosis factor alpha, another stress-induced cytokine, and activated NLRP3. Moreover, P2X7R antagonist administration reversed the anhedonic and anxiety behaviors caused by chronic unpredictable stress exposure, and deletion of the Nlrp3 gene rendered mice resistant to development of depressive behaviors caused by chronic unpredictable stress.

Conclusions: These findings demonstrate that psychological "stress" is sensed by the innate immune system in the brain via the ATP/P2X7R-NLRP3 inflammasome cascade, and they identify novel therapeutic targets for the treatment of stress-related mood disorders and comorbid illnesses.
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http://dx.doi.org/10.1016/j.biopsych.2015.11.026DOI Listing
July 2016

High-Fat Diet Induced Anxiety and Anhedonia: Impact on Brain Homeostasis and Inflammation.

Neuropsychopharmacology 2016 06 14;41(7):1874-87. Epub 2015 Dec 14.

Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.

Depression and type 2 diabetes (T2D) are highly comorbid disorders that carry a large public health burden. However, there is a clear lack of knowledge of the neural pathological pathways underlying these illnesses. The present study aims to elucidate the molecular mechanisms by which a diet rich in fat can cause multiple complications in the brain, thereby affecting intracellular signaling and gene expression that underlie anxiety and depressive behaviors. The results show that a high-fat diet (HFD; ~16 weeks) causes anxiety and anhedonic behaviors. Importantly, the results also show that 4 months of HFD causes disruption of intracellular cascades involved in synaptic plasticity and insulin signaling/glucose homeostasis (ie, Akt, extracellular signal-regulated kinase (ERK), P70S6K), as well as increased corticosterone levels and activation of the innate immune system, including elevation of inflammatory cytokines (ie, IL-6, IL-1β, TNFα). Interestingly, the rapid acting antidepressant ketamine reverses the behavioral deficits caused by HFD and activates ERK and P70S6 kinase signaling in the prefrontal cortex. In addition, we found that pharmacological blockade of the innate immune inflammasome system by repeated administration of an inhibitor of the purinergic P2X7 receptor blocks the anxiety caused by HFD. Together these studies further elucidate the signaling pathways that underlie chronic HFD exposure on anxiety and depressive behaviors, and identify novel therapeutic targets for patients with metabolic disorder or T2D who suffer from anxiety and depression.
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http://dx.doi.org/10.1038/npp.2015.357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4869056PMC
June 2016

Work environment influences adverse events in an emergency department.

Dan Med J 2014 May;61(5):A4812

Arbejdsmedicinsk Klinik, Hospitals-enheden Vest, Regionshospitalet Herning, Gl. Landevej 61, 7400 Herning, -Denmark.

Introduction: The psychosocial work environment has been recognised as a factor that contributes to the occurrence of errors and adverse events at hospitals. There has been a strong focus on stress factors at intensive care units and emergency departments. The purpose of this study was to investigate the occurrence of adverse events and to examine the relationship between work-related stressors, safety culture and adverse events at an emergency department.

Material And Methods: A total of 98 nurses and 26 doctors working in an emergency department at a Danish regional hospital filled out a questionnaire on the occurrence and pattern of adverse events, psychosocial work environment factors, safety climate and learning culture.

Results: The participants had experienced 742 adverse events during the previous month. The most frequent event types were lack of documents, referrals not performed, blood tests not available and lack of documentation. Problems related to reporting and learning and insufficient follow-up and feedback after serious events were the most frequent complaints. A poor patient safety climate and increased cognitive demands were significantly correlated to adverse events.

Conclusion: This study supports previous findings of severe underreporting to the mandatory national reporting system. The issue of reporting bias related to self-reported data should be born in mind. Among work environment issues, the patient safety climate and stress factors related to cognitive demands had the highest impact on the occurrence of adverse events.

Funding: The project was funded by Trygfonden (grant no 7-10-0949).

Trial Registration: not relevant.
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May 2014

Patterns of work injuries: cases admitted to emergency room treatment compared to cases reported to the Danish Working Environment Authority during 2003-2010.

Occup Environ Med 2014 Feb 24;71(2):97-103. Epub 2013 Oct 24.

Department of Occupational Medicine, Danish Ramazzini Centre, Herning Regional Hospital, Herning, Denmark.

Objective: To compare work injuries treated in an emergency department (ED) and injuries reported to the Danish Working Environment Authority (DWEA).

Methods: Work injuries of the ED, Odense University Hospital, and injuries from the geographical catchment area reported to the DWEA between 2003 and 2010 were included. The injuries included in both datasets were identified by merging the ED file and the DWEA file using the civil registry number and injury date information as key.

Results: Approximately 50 000 work injuries occurred in the catchment area of the ED. The intersection between the two injury registration systems was 16%. A major discordance concerned the type of injuries, as some injuries were seen frequently in the ED but not reported to the DWEA to any significant extent, for example 'eye injuries' and 'superficial lacerations or wounds'. On the other hand, some injuries are rarely seen in the ED, but often reported to the DWEA, for example 'low back pain'. Additionally, younger workers visit the ED more often than older workers, and injuries in the high risk sectors have the lowest reporting proportion.

Conclusions: Neither the ED nor DWEA injury files alone give a complete picture of work injuries. But merged, they represent a significant number of injuries, taking into account differences in data sources, for example concerning uneven distribution of age, sex, type of injury and type of industry. Obviously, not all serious work related ED injuries resulting in lost work time are reported to the DWEA.
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http://dx.doi.org/10.1136/oemed-2013-101559DOI Listing
February 2014

Can negative life events and coping style help explain socioeconomic differences in perceived stress among adolescents? A cross-sectional study based on the West Jutland cohort study.

BMC Public Health 2013 Jun 2;13:532. Epub 2013 Jun 2.

Danish Ramazzini Centre, Department of Occupational Medicine, Regional Hospital Herning, Herning, Denmark.

Background: Previous research suggests that perceived stress in adolescence is socially patterned, but that this relationship may depend on the measure of socioeconomic status (SES) used. This study examines if social gradients in perceived stress, negative life events, and coping exist amongst Danish adolescents, and, if life events and coping strategies can partly account for an association between SES and perceived stress. These relationships are studied separately for two different measures of SES.

Methods: Questionnaire data were collected from 3054 14-15 year old youths (83% response rate) during baseline measurement in the West Jutland birth cohort study. Parents were identified via the Central Office of Civil Registration in which the respondents are linked to their parents or guardians via their CPR-number, a personal identification number given to everyone in Denmark. The study employs data from two independent sources, adolescent self-report data (stress, life events and coping) and national registers (parental educational level, household income and confounder variables). Ordinary Least Squares regression estimated the effects of parental SES, negative life events and coping on perceived stress. Analyses were stratified by gender.

Results: Girls reported more perceived stress than boys. SES accounted for a small but significant amount of the variance in perceived stress. Lower parental education and lower household income were associated with higher stress levels irrespective of gender, but the social gradient was strongest amongst girls when parents' education was used to measure SES, and strongest for boys when income was used. Life events and coping were also found to be associated with SES and both mediated part of the SES-perceived stress relationship. In general, the social gradient in perceived stress was accounted for by the study variables to a higher degree among girls than among boys.

Conclusions: Lower parental education and household income are associated with higher levels of perceived stress amongst Danish adolescents. Furthermore, both life events and coping appear to mediate this relation. Gender differences in the ways SES and stress are related may exist.
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http://dx.doi.org/10.1186/1471-2458-13-532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3679909PMC
June 2013

Work-related stressors and occurrence of adverse events in an ED.

Am J Emerg Med 2013 Mar 21;31(3):504-8. Epub 2013 Jan 21.

Danish Ramazzini Centre, Department of Occupational Medicine, Herning Regional Hospital, 7400 Herning, Denmark.

Objective: The purpose of this study was to investigate the relationship between 12 work-related stressors and the occurrence of adverse events in an emergency department (ED).

Methods: Nurses and physicians, working in an ED at a Danish regional hospital, filled out a questionnaire on occurrence and emotional impact of 12 work-related stressors after each shift during a 4-week period. The questionnaire also instructed the participants to describe any adverse events that they were involved in during the shift.

Results: Two hundred fourteen adverse events were reported during the 979 studied shifts. During the same period, only 27 adverse events were reported to the mandatory national reporting system, and only 10 of these were duplicates. A high variability of stressors and emotional impact among the different groups of participants was found. Linear regression analysis showed an association between involvement in adverse events and the occurrence and emotional impact of stressors across groups, whereas no significant association was found for age, seniority, shift type, or length.

Conclusion: The study showed an association between the occurrence and impact of 12 work-related stressors and involvement in adverse events across the groups of participants. Furthermore, the study showed that most adverse events were not reported to the mandatory national reporting system.
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http://dx.doi.org/10.1016/j.ajem.2012.10.002DOI Listing
March 2013

Return to work after percutaneous coronary intervention: the predictive value of self-reported health compared to clinical measures.

PLoS One 2012 16;7(11):e49268. Epub 2012 Nov 16.

Department of Occupational Medicine, Regional Hospital West Jutland, Herning, Denmark.

Aims: Coronary heart disease is prevalent in the working-age population. Traditional outcome measures like mortality and readmission are of importance to evaluate the prognosis but are hardly sufficient. Ability to work is an additional outcome of clinical and societal significance. We describe trends and predictors of Return To Work (RTW) after PCI and describe a possible benefit using patient-reported measures in risk stratification of RTW.

Methods: A total of 1585 patients aged less than 67 years treated with PCI in 2006-2008 at the Aarhus University Hospital were enrolled. Clinical information was provided through the West Denmark Heart Registry, and 4 weeks after PCI we mailed a questionnaire regarding self-rated health (response rate 83.5%). RTW was defined at weekly basis using extensive register data on transfer payments. Predictors of RTW were analysed as time to event. ROC curves constructed by logistic regression of predicting variables were evaluated by the c-statistic.

Results: Four weeks before PCI 50% of the patients were working; the corresponding figures were 25% after 4 weeks, 36% after 12 weeks, and 43% after one year. The patients' self-rated health one month after the procedure was a significant better predictor of RTW compared to other variables including LVEF, both at short (12 weeks) and long (one year) term.

Conclusions: The patient's self-rated health four weeks after the procedure was a stronger predictor than left ventricular ejection fraction (LVEF), and consequently useful when patients seek medical advice with respect to RWT.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0049268PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3500279PMC
March 2013

Physical and psychosocial work environment factors and their association with health outcomes in Danish ambulance personnel - a cross-sectional study.

BMC Public Health 2012 Jul 23;12:534. Epub 2012 Jul 23.

Department of Sociology and Social Work, Aalborg University, Aalborg University, Kroghstræde 5, DK 9220, Aalborg Ø, Denmark.

Background: Reviews of the literature on the health and work environment of ambulance personnel have indicated an increased risk of work-related health problems in this occupation. The aim of this study was to compare health status and exposure to different work environmental factors among ambulance personnel and the core work force in Denmark. In addition, to examine the association between physical and psychosocial work environment factors and different measures of health among ambulance personnel.

Methods: Data were taken from a nationwide sample of ambulance personnel and fire fighters (n = 1,691) and was compared to reference samples of the Danish work force. The questionnaire contained measures of physical and psychosocial work environment as well as measures of musculoskeletal pain, mental health, self-rated health and sleep quality.

Results: Ambulance personnel have half the prevalence of poor self-rated health compared to the core work force (5% vs. 10%). Levels of mental health were the same across the two samples whereas a substantially higher proportion of the ambulance personnel reported musculoskeletal pain (42% vs. 29%). The ambulance personnel had higher levels of emotional demands and meaningfulness of and commitment to work, and substantially lower levels of quantitative demands and influence at work. Only one out of ten aspects of physical work environment was consistently associated with higher levels of musculoskeletal pain. Emotional demands was the only psychosocial work factor that was associated with both poorer mental health and worse sleep quality.

Conclusions: Ambulance personnel have similar levels of mental health but substantially higher levels of musculoskeletal pain than the work force in general. They are more exposed to emotional demands and these demands are associated with higher levels of poor mental health and poor sleep quality. To improve work environment, attention should be paid to musculoskeletal problems and the presence of positive organizational support mechanisms that can prevent negative effects from the high levels of emotional demands.
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http://dx.doi.org/10.1186/1471-2458-12-534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3439275PMC
July 2012

Typical and atypical antipsychotic drugs increase extracellular histamine levels in the rat medial prefrontal cortex: contribution of histamine h(1) receptor blockade.

Front Psychiatry 2012 17;3:49. Epub 2012 May 17.

Psychiatric Disorders, Neuroscience Discovery Research, Eli Lilly and Company Indianapolis, IN, USA.

Atypical antipsychotics such as clozapine and olanzapine have been shown to enhance histamine turnover and this effect has been hypothesized to contribute to their improved therapeutic profile compared to typical antipsychotics. In the present study, we examined the effects of antipsychotic drugs on histamine (HA) efflux in the mPFC of the rat by means of in vivo microdialysis and sought to differentiate the receptor mechanisms which underlie such effects. Olanzapine and clozapine increased mPFC HA efflux in a dose related manner. Increased HA efflux was also observed after quetiapine, chlorpromazine, and perphenazine treatment. We found no effect of the selective 5-HT(2A) antagonist MDL100907, 5-HT(2c) antagonist SB242084, or the 5-HT(6) antagonist Ro 04-6790 on mPFC HA efflux. HA efflux was increased following treatment with selective H(1) receptor antagonists pyrilamine, diphenhydramine, and triprolidine, the H(3) receptor antagonist ciproxifan and the mixed 5-HT(2A)/H(1) receptor antagonist ketanserin. The potential novel antipsychotic drug FMPD, which has a lower affinity at H(1) receptors than olanzapine, did not affect HA efflux. Similarly, other antipsychotics with lower H(1) receptor affinity (risperidone, aripiprazole, and haloperidol) were also without effect on HA efflux. Finally, HA efflux after antipsychotic treatment was significantly correlated with affinity at H(1) receptors whereas nine other receptors, including 5-HT(2A), were not. These results demonstrate that both typical and atypical antipsychotics increase mPFC histamine efflux and this effect may be mediated via antagonism of histamine H(1) receptors.
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http://dx.doi.org/10.3389/fpsyt.2012.00049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3354526PMC
October 2012

Social inequalities in childhood are predictors of unemployment in early adulthood.

Dan Med J 2012 Mar;59(3):A4394

Occupational Medicine, Herning Regional Hospital.

Introduction: The aim of the present study was to establish if social inequalities in early childhood, particularly living in a socially and economically deprived neighbourhood, are predictive of later unemployment.

Material And Methods: A cohort was established in 1987. It consists of 8-9 year-old children living in a socially deprived suburb who were followed in national registers for all categories of welfare benefits. The follow-up covered the period when participants were 21-27 years of age. A control group with the same age and gender distribution who were living in a neighbouring, relatively privileged middle class district were also followed for the purpose of comparison.

Results: The annual unemployment rate during the seven years of follow-up was significantly higher in the deprived neighbourhood group than in the middle class neighbourhood group, whereas long-term unemployment lasting more than two years did not differ significantly between the groups. Childhood background including a mother receiving social benefit was an independent factor associated with increased risk of later unemployment, whereas gender and single parenthood were not.

Conclusion: The present findings suggest that socioeconomic disadvantage during childhood substantially increases the risk of unemployment in early adulthood, even during a follow-up period in the first decade of the 21st century when employment opportunities in Denmark were excellent.

Funding: not relevant.

Trial Registration: not relevant.
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March 2012

Incidence of work injuries amongst Danish adolescents and their association with work environment factors.

Am J Ind Med 2011 Feb 8;54(2):143-52. Epub 2010 Nov 8.

Department of Occupational Medicine, Danish Ramazzini Centre, Regional Hospital Herning, Denmark.

Background: The objective was to examine the incidence of work accidents that required medical attention among Danish adolescents and to identify possible work environment factors associated with such accidents.

Methods: We collected information in two questionnaire rounds (2004 and 2007) from a birth cohort comprising all adolescents born in 1989 (n = 3,687) living in Ringkjøbing County, Denmark. The questionnaire contained items on self-reported number of accidents and number of working hours in both rounds and on work environment factors in the second round.

Results: Approximately 5% of the adolescents who held a job, experienced a work injury at the age of 17. This equals an incidence of 65 accidents per million working hours. Most adolescents had decent working conditions, although nearly half reported that their work was heavy, monotonous or psychologically demanding. Heavy work, high psychological demands and low social support increased the risk of experiencing work injuries after adjustment for a number of factors.

Conclusions: The incidence of work injuries among adolescents appears to be higher than the incidence among their older colleagues. Lack of social support from management significantly raised adolescents' risk of experiencing a work injury. This suggests that more direct supervision may be a good way of preventing accidents in this age group.
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http://dx.doi.org/10.1002/ajim.20911DOI Listing
February 2011

N-(4-((2-(trifluoromethyl)-3-hydroxy-4-(isobutyryl)phenoxy)methyl)benzyl)-1-methyl-1H-imidazole-4-carboxamide (THIIC), a novel metabotropic glutamate 2 potentiator with potential anxiolytic/antidepressant properties: in vivo profiling suggests a link between behavioral and central nervous system neurochemical changes.

J Pharmacol Exp Ther 2011 Jan 14;336(1):165-77. Epub 2010 Oct 14.

Neuroscience Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, DC0510, Indianapolis, IN 46285, USA.

The normalization of excessive glutamatergic neurotransmission through the activation of metabotropic glutamate 2 (mGlu2) receptors may have therapeutic potential in a variety of psychiatric disorders, including anxiety/depression and schizophrenia. Here, we characterize the pharmacological properties of N-(4-((2-(trifluoromethyl)-3-hydroxy-4-(isobutyryl)phenoxy)methyl)benzyl)-1-methyl-1H-imidazole-4-carboxamide (THIIC), a structurally novel, potent, and selective allosteric potentiator of human and rat mGlu2 receptors (EC(50) = 23 and 13 nM, respectively). THIIC produced anxiolytic-like efficacy in the rat stress-induced hyperthermia assay and the mouse stress-induced elevation of cerebellar cGMP and marble-burying assays. THIIC also produced robust activity in three assays that detect antidepressant-like activity, including the mouse forced-swim test, the rat differential reinforcement of low rate 72-s assay, and the rat dominant-submissive test, with a maximal response similar to that of imipramine. Effects of THIIC in the forced-swim test and marble burying were deleted in mGlu2 receptor null mice. Analysis of sleep electroencephalogram (EEG) showed that THIIC had a sleep-promoting profile with increased non-rapid eye movement (REM) and decreased REM sleep. THIIC also decreased the dark phase increase in extracellular histamine in the medial prefrontal cortex and decreased levels of the histamine metabolite tele-methylhistamine (t-MeHA) in rat cerebrospinal fluid. Collectively, these results indicate that the novel mGlu2-positive allosteric modulator THIIC has robust activity in models used to predict anxiolytic/antidepressant efficacy, substantiating, at least with this molecule, differentiation in the biological impact of mGlu2 potentiation versus mGlu2/3 orthosteric agonism. In addition, we provide evidence that sleep EEG and CSF t-MeHA might function as viable biomarker approaches to facilitate the translational development of THIIC and other mGlu2 potentiators.
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http://dx.doi.org/10.1124/jpet.110.172957DOI Listing
January 2011

Preclinical evaluation of melanin-concentrating hormone receptor 1 antagonism for the treatment of obesity and depression.

J Pharmacol Exp Ther 2009 May 30;329(2):429-38. Epub 2009 Jan 30.

Neuroscience and Endocrine Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.

The mammalian neuropeptide, melanin-concentrating hormone, interacts with two G protein-coupled receptors, melanin-concentrating hormone receptor (MCHR) 1 and MCHR2; however, only MCHR1 is expressed in rats and mice. In the present study, we evaluated MCHR1 antagonism in preclinical models believed to be predictive of antiobesity and antidepressant activity. Central activity of the selective MCHR1 antagonist, GW803430 [6-(4-chloro-phenyl)-3-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3H-thieno[3,2-d]pyrimidin-4-one], was evaluated using ex vivo binding with autoradiography. Effective doses of GW803430 (1 and 3 mg/kg p.o.) were correlated with antiobesity activity in a 14-day study of diet-induced obese rats. GW803430 was evaluated subsequently for antidepressant-like effects in mice and rats. Acute and subchronic administration reduced immobility time in the mouse forced-swim test at doses of 3 (acute) and 3 and 10 (chronic) mg/kg p.o., an effect that was absent in MCHR1(-/-) mice. Combined subeffective doses of GW803430 (0.3 and 1 mg/kg p.o.) and imipramine (5 mg/kg) produced a robust antidepressant-like response. The compound was also active in the tail suspension test at a dose of 10 mg/kg p.o. GW803430 (30 mg/kg p.o.) significantly reduced submissive behaviors at weeks 2 and 3, a model of submissive behavior that may predict antidepressant onset. GW803430 decreased marble burying in mice at doses of 3, 10, and 30 mg/kg p.o., an assay that detects anxiolytic-like effects. Thus, GW803430 produces robust antiobesity and antidepressant-like effects in rats and mice at doses that compete for central MCHR1 in vivo. As such, MCHR1 should be considered as a promising target for future drug discovery efforts.
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http://dx.doi.org/10.1124/jpet.108.143362DOI Listing
May 2009

The orexin-1 antagonist SB-334867 blocks antipsychotic treatment emergent catalepsy: implications for the treatment of extrapyramidal symptoms.

Schizophr Bull 2007 Nov 28;33(6):1291-7. Epub 2007 Jul 28.

Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.

We have previously shown that the orexin-1 antagonist SB-334867 blocks the electrophysiological effects of haloperidol and olanzapine on the activity of A9 and A10 dopamine neurons. To evaluate if orexin-1 antagonists might block other effects of antipsychotic drugs in animals, we examined the effects of SB-334867 on behavioral, neurochemical, and neuroendocrine effects of antipsychotic drugs. Pretreatment with SB-334867 (0.01-10 mg/kg, intraperitoneal [IP]) significantly decreased the catalepsy produced by the administration of haloperidol (1 mg/kg, subcutaneous [SC]), risperidone (2 mg/kg, SC), and olanzapine (10 mg/kg, SC). Administration of SB-334467 also reversed catalepsy after it had been established in animals pretreated 2 hours earlier with haloperidol. However, pretreatment with SB-334867 (1-10 mg/kg, IP) did not block the decreases in exploratory locomotor activity produced by administration of haloperidol (0.1 mg/kg, SC) or risperidone (0.3 mg/kg, SC). In addition, pretreatment with SB-334867 (1-10 mg/kg, IP) neither blocked the increased levels of dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens or striatum nor the elevation in serum prolactin produced by administration of haloperidol (0.1 mg/kg, SC) and risperidone (1 mg/kg, SC). Administration of SB-334867 alone neither changed locomotor activity and DOPAC or prolactin levels nor produced catalepsy. These results show that orexin-1 antagonists block the catoleptogenic effects of antipsychotics but do not block other locomotor, neurochemical, or neuroendocrine effects of antipsychotics. Because catalepsy is thought to be a good predictor of extrapyramidal symptoms in humans, treatment with orexin-1 antagonists might decrease the occurrence or severity of antipsychotic treatment-emergent extrapyramidal symptoms in humans.
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http://dx.doi.org/10.1093/schbul/sbm087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2779883PMC
November 2007

The prevention of occupational injuries in two industrial plants using an incident reporting scheme.

J Safety Res 2006 22;37(5):479-86. Epub 2006 Nov 22.

Department of Occupational Medicine, Herning Hospital, DK-7400 Herning, Denmark.

Introduction: The aim of this study was to examine whether the introduction of an incident reporting scheme with feedback in two industrial plants had an effect on the number of major incidents.

Method: An intervention design with measurements before the implementation of the incident reporting scheme and two years later was used to examine the relationship between incident rates, safety climate, the willingness to report incidents and perceived management commitment to safety.

Results: The results showed that a successful implementation of an incident reporting scheme was followed by a decline in the incidence of major incidents at a Danish metal plant. A key factor in implementing the scheme was top management commitment, which was lacking at another plant, where the implementation of a similar scheme failed.

Conclusion: Although the study shows some encouraging results concerning the use of incident reporting schemes to prevent occupational accidents, the possibility to draw causal conclusions is limited in the present study, and further studies are needed before the effectiveness of such schemes can be evaluated with certainty.
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http://dx.doi.org/10.1016/j.jsr.2006.06.005DOI Listing
February 2007

The orexin-1 receptor antagonist SB-334867 blocks the effects of antipsychotics on the activity of A9 and A10 dopamine neurons: implications for antipsychotic therapy.

Neuropsychopharmacology 2007 Apr 25;32(4):786-92. Epub 2006 Oct 25.

Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.

Antipsychotic drugs alter the activity of dopamine neurons in the ventral tegmental area (A10) and substantia nigra pars compacta (A9). As there is a dense projection of orexin neurons from the lateral hypothalamus to A10 dopaminergic neurons, and some antipsychotics have been shown to increase the expression of c-fos in orexin-containing cells in the hypothalamus, we hypothesized that stimulation of orexin receptors plays a role in the effects of antipsychotics on the activity of A9 and A10 dopamine cells. Single-unit recordings in anesthetized rats demonstrated the central effects of the selective orexin-1 receptor antagonist SB-334867 (2 mg/kg, intravenous), as it reversed the excitatory effects of orexin-A administration (6 microg, intracerebroventricular) on the activity of locus coeruleus (LC) cells. Recordings from midbrain dopamine neurons showed that acute administration of SB-334867 alone did not alter the number of spontaneously active A9 or A10 cells, but did reverse: (1) the increase in the number of spontaneously active A9 and/or A10 dopamine cells caused by the acute administration of haloperidol (1 mg/kg, subcutaneous) or olanzapine (10 mg/kg, s.c.) and (2) the decrease in the number of spontaneously active A9 and/or A10 dopamine cells caused by the chronic administration of haloperidol (1 mg/kg/day x 21 days, s.c.) or olanzapine (10 mg/kg/day x 21 days, s.c.). However, SB-334867 did not block a different electrophysiological effect of olanzapine, as it did not block the olanzapine-induced activation of LC cells. These results indicate that activation of orexin-1 receptors plays an important role on the effects of antipsychotic drugs on dopamine neuronal activity and may play an important role in the clinical effects of antipsychotic drugs.
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http://dx.doi.org/10.1038/sj.npp.1301239DOI Listing
April 2007

The validity of a questionnaire-based epidemiological study of occupational dermatosis.

Contact Dermatitis 2006 Nov;55(5):295-300

Department of Occupational Medicine, Herning Hospital, DK-7400 Herning, Denmark.

The aim of this study was to evaluate the validity of a questionnaire and medical anamnesis to identify persons with dermatitis in an occupational setting. The design was a clinical epidemiological cross-sectional study. The study was performed between the second and fourth week of January 2001. A questionnaire was followed a week later by a medical occupational interview and a clinical dermatological examination, including a comprehensive patch test with potential workplace chemicals. The anamnesis and the clinical examination were made independently by occupational and dermatological physicians, and the skin examination was performed blinded to anamnestic data. The setting was the mother plants of a Danish-based international company producing wind turbine systems. The study population was a workplace cohort, highly exposed to epoxy resin systems and other chemicals, and totalled 724 production workers at 4 facilities. The rate of participation was 84.7%. Using enquete questions of current skin rash against the clinical presence of dermatitis, we found a sensitivity of 22% and a specificity of 89%, compared to 45% and 87%, respectively, when the anamnestic work history, taken by an occupational physician, was the screening parameter. Using 'workplace periodic prevalence' of dermatitis, we found sensitivities in the range of 63-76% by a questionnaire and 70-83% by medical anamnesis. Questionnaire screening by skin symptoms gave the highest values for redness, a sensitivity of 33% and a specificity of 76%, and decreasing validity parameters as more symptoms were added to the list of screening questions. We found that the use of a questionnaire and medical anamnesis were problematic, when the purpose was screening for contact dermatitis and allergy, in this industrial cohort manufacturing reinforced plastic products. But these instruments might be useful for epidemiological surveillance, when the questionnaire has been validated in the given occupational setting.
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http://dx.doi.org/10.1111/j.1600-0536.2006.00920.xDOI Listing
November 2006

Worker participation in change processes in a Danish industrial setting.

Am J Ind Med 2006 Sep;49(9):767-79

Department of Occupational Medicine, Herning Hospital, Herning, Denmark.

Background: Improving the design, management and organization of work may be an important step in improving occupational health. An intervention, guided by the principles of participatory action research (PAR), is directed at traditional work environment problems in the epoxy plastic industry, that is, eczema and accident-related injuries.

Methods: The study population consisted of employees at two wind turbine- manufacturing plants. A quasi-experimental design was employed with before and after measurements and a comparison group with a 3(1/2) year follow-up period.

Results: The role of employee elected safety representatives was changed from one of controlling and "policing" to that of safety advisors. The attitudes of employees also changed, from an individualistic understanding of safety as the responsibility of the single employee, to a more collective understanding of safety as being everyone's shared responsibility. Structural changes led to a less hierarchical management system. This process led eventually to the establishment of self-governing work groups in which each member had a well-defined area of responsibility. The change process was associated with improvements in the psychosocial work environment and safety climate, a 66% reduction in the incidence of eczema, and a 48.6% reduction in the incidence of occupational accidents. In the comparison population, a twin factory under the same company, similar but delayed and less dramatic changes also occurred.

Conclusions: Implementation of a comprehensive intervention was followed by improved employee perceptions of the company's safety standards and the psychosocial work environment, as well as by substantial reductions in the incidence of eczema and occupational accidents.
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http://dx.doi.org/10.1002/ajim.20350DOI Listing
September 2006
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