MRX protects fork integrity at protein-DNA barriers, and its absence causes checkpoint activation dependent on chromatin context.

To address how eukaryotic replication forks respond to fork stalling caused by strong non-covalent protein-DNA barriers, we engineered the controllable Fob-block system in Saccharomyces cerevisiae. This system allows us to strongly induce and control replication fork barriers (RFB) at their natural location within the rDNA. We discover a pivotal role for the MRX (Mre11, Rad50, Xrs2) complex for fork integrity at RFBs, which differs from its acknowledged function in double-strand break processing. Consequently, in the absence of the MRX complex, single-stranded DNA (ssDNA) accumulates at the rDNA. Based on this, we propose a model where the MRX complex specifically protects stalled forks at protein-DNA barriers, and its absence leads to processing resulting in ssDNA. To our surprise, this ssDNA does not trigger a checkpoint response. Intriguingly, however, placing RFBs ectopically on chromosome VI provokes a strong Rad53 checkpoint activation in the absence of Mre11. We demonstrate that proper checkpoint signalling within the rDNA is restored on deletion of SIR2. This suggests the surprising and novel concept that chromatin is an important player in checkpoint signalling.

Short time between shifts and risk of injury among Danish hospital workers: a register-based cohort study.

Objectives Short time between consecutive work shifts (quick returns, ie, ≤11 hours between shifts) is associated with sleepiness and fatigue, both of which have been linked to risk of injury. This paper aims to study quick returns between work shifts and risk of injury among Danish hospital workers. Method The study population included 69 200 employees, primarily working at hospitals, corresponding to 167 726 person years at risk between 2008-2015. Information on working hours was obtained from payroll data in the Danish Working Hour Database and linked, at an individual level, with data on 11 834 injury records identified in the National Patient Register and the Danish Register of Causes of Death. Multivariate Poisson regression models were used to calculate incidence rate ratios (IRR) with 95% confidence intervals (CI). Results Results showed the shorter the time between shifts, the higher the risk of injury. Thus, an elevated risk of injury was observed after quick returns compared with the standard 15-17 hours between shifts (IRR 1.39, 95% CI 1.23-1.58). Furthermore, when assessing the number of days since a quick return, the risk of injury was especially high within the first two days (day 1: IRR 1.39, 95% CI 1.23-1.58; day 2: IRR 1.39, 95% CI 1.21-1.58) following a quick return. Conclusions Our results suggest that quick returns increased the risk of injury, in particular within the first two days following a quick return. These findings point towards avoiding or reducing the number of quick returns in order to lower employees' risk of injury.

Risk of injury after evening and night work - findings from the Danish Working Hour Database.

Objectives Evening and night work have been associated with higher risk of injury than day work. However, previous findings may be affected by recall bias and unmeasured confounding from differences between day, evening and night workers. This study investigates whether evening and night work during the past week increases risk of injury when reducing recall bias and unmeasured confounding. Methods We linked daily working hours at the individual level of 69 200 employees (167 726 person years from 2008-2015), primarily working at hospitals to registry information on 11 834 injuries leading to emergency room visits or death. Analyses were conducted with Poisson regression models in the full population including permanent day, evening and night workers, and in two sub-populations of evening and night workers, with both day and evening or night work, respectively. Thus, the exchangeability between exposure and reference group was improved in the two sub-populations. Results Risk of injury was higher after a week with evening work [incidence rate ratio (IRR) 1.32, 95% confidence interval (CI) 1.26-1.37] and night work (IRR 1.33, 95% CI 1.25-1.41) compared with only day work. Similar, although attenuated, estimates were found for evening work among evening workers (IRR 1.18, 95% CI 1.12-1.25), and for night work among night workers (IRR 1.10, 95% CI 1.01-1.20). Conclusion There is an overall increased risk of injury after a week that has included evening or night work compared with only day work. Though attenuated, the higher risk remains after reducing unmeasured confounding.

Type 1 diabetes, quality of life, occupational status and education level - A comparative population-based study.

AIM: Type 1 diabetes requires extensive self-management to avoid complications and may have negative effects on the everyday life of people with the disease. The aim of this study was to compare adults with type 1 diabetes to the general population in terms of health-related quality of life, occupational status (level of employment, working hours and sick leave) and education level. METHODS: 2415 adults (aged 18-98years) with type 1 diabetes were compared to 48,511 adults (aged 18-103years) from the general population. Data were obtained from two cross-sectional surveys conducted in 2010 and 2011 of adults living or treated in the Capital Region in Denmark. Differences between adults with type 1 diabetes and the general population were standardised for age and sex and analyzed using linear probability models and negative binomial regression. Differences were further analyzed in subgroups. RESULTS: Compared to the general population, adults with type 1 diabetes experienced lower health-related quality of life, were more frequently unemployed, had more sick leave per year and were slightly better educated. Differences in health-related quality of life and employment increased with age and were larger among women, as compared to men. No significant differences were found with regard to working hours. CONCLUSION: Our findings suggest that type 1 diabetes is associated with lower health-related quality of life, higher unemployment and additional sick leave. The negative association with type 1 diabetes is more pronounced in women and older adults.