"Multivariate analysis of the impact of sleep and working hours on medical errors: a MICE approach".

BACKGROUND: The main objective of this study was to describe the relationship between working conditions, sleep and psycho-affective variables and medical errors. METHODS: This was an observational, analytical and cross-sectional study in which 661 medical residents answered questionnaires about working conditions, sleep and psycho-affective variables. Actigraphic sleep parameters and peripheral temperature circadian rhythm were measured in a subgroup of 38 subjects. Bivariate and multivariate predictors of medical errors were assessed. RESULTS: Medical residents reported working 66.2 ± 21.9 weekly hours. The longest continuous shift was of 28.4 ± 10.9 h. They reported sleeping 6.1 ± 1.6 h per day, with a sleep debt of 94 ± 129 min in workdays. A high percentage of them reported symptoms related to psycho-affective disorders. The longest continuous shift duration (OR = 1.03 [95% CI, 1.00-1.05], p = 0.01), working more than six monthly on-call shifts (OR = 1.87 [95% CI, 1.16-3.02], p = 0.01) and sleeping less than six hours per working day (OR = 1.66 [95% CI, 1.10-2.51], p = 0.02) were independently associated with self-reported medical errors. The report of medical errors was associated with an increase in the percentage of diurnal sleep (2.2% [95% CI, 0.1-4.3] vs 14.5% [95% CI, 5.9-23.0]; p = 0.01) in the actigraphic recording. CONCLUSIONS: Medical residents have a high working hour load that affect their sleep opportunities, circadian rhythms and psycho-affective health, which are also related to the report of medical errors. These results highlight the importance of implementing multidimensional strategies to improve medical trainees' sleep and wellbeing, increasing in turn their own and patients' safety.

Circadian disruption induced by tumor development in a murine model of melanoma.

The circadian system induces oscillations in most physiological variables, with periods close to 24 hours. Dysfunctions in clock-controlled body functions, such as sleep disorders, as well as deregulation of clock gene expression or glucocorticoid levels have been observed in cancer patients. Moreover, these disorders have been associated with a poor prognosis or worse response to treatment. This work explored the circadian rhythms at behavioral and molecular levels in a murine melanoma model induced by subcutaneous inoculation of B16 tumoral cells. We observed that the presence of the tumors induced a decrease in the robustness of the locomotor activity rhythms and in the amount of nighttime activity, together with a delay in the acrophase and in the activity onset. Moreover, these differences were more marked when the tumor size was larger than in the initial stages of the tumorigenesis protocol. In addition, serum glucocorticoids, which exhibit strong clock-controlled rhythms, lost their circadian patterns. Similarly, the rhythmic expression of the clock genes Bmal1 and Cry1 in the hypothalamic Suprachiasmatic Nuclei (SCN) were also deregulated in mice carrying tumors. Altogether, these results suggest that tumor-secreted molecules could modulate the function of the central circadian pacemaker (SCN). This could account for the worsening of the peripheral biological rhythms such as locomotor activity or serum glucocorticoids. Since disruption of the circadian rhythms might accelerate tumorigenesis, monitoring circadian patterns in cancer patients could offer a new tool to get a better prognosis for this disease.

Circadian Rhythms in Bacterial Sepsis Pathology: What We Know and What We Should Know.

Sepsis is a syndrome caused by a deregulated host response to infection, representing the primary cause of death from infection. In animal models, the mortality rate is strongly dependent on the time of sepsis induction, suggesting a main role of the circadian system. In patients undergoing sepsis, deregulated circadian rhythms have also been reported. Here we review data related to the timing of sepsis induction to further understand the different outcomes observed both in patients and in animal models. The magnitude of immune activation as well as the hypothermic response correlated with the time of the worst prognosis. The different outcomes seem to be dependent on the expression of the clock gene Bmal1 in the liver and in myeloid immune cells. The understanding of the role of the circadian system in sepsis pathology could be an important tool to improve patient therapies.

Differential Thermoregulatory and Inflammatory Patterns in the Circadian Response to LPS-Induced Septic Shock.

Sepsis is caused by a dysregulated host response to infection, and characterized by uncontrolled inflammation together with immunosuppression, impaired innate immune functions of phagocytes and complement activation. Septic patients develop fever or hypothermia, being the last one characteristic of severe cases. Both lipopolysaccharide (LPS) and Tumor Necrosis Factor (TNF)-α- induced septic shock in mice is dependent on the time of administration. In this study, we aimed to further characterize the circadian response to high doses of LPS. First, we found that mice injected with LPS at ZT11 developed a higher hypothermia than those inoculated at ZT19. This response was accompanied by higher neuronal activation of the preoptic, suprachiasmatic, and paraventricular nuclei of the hypothalamus. However, LPS-induced Tnf-α and Tnf-α type 1 receptor (TNFR1) expression in the preoptic area was time-independent. We also analyzed peritoneal and spleen macrophages, and observed an exacerbated response after ZT11 stimulation. The serum of mice inoculated with LPS at ZT11 induced deeper hypothermia in naïve animals than the one coming from ZT19-inoculated mice, related to higher TNF-α serum levels during the day. We also analyzed the response in TNFR1-deficient mice, and found that both the daily difference in the mortality rate, the hypothermic response and neuronal activation were lost. Moreover, mice subjected to circadian desynchronization showed no differences in the mortality rate throughout the day, and developed lower minimum temperatures than mice under light-dark conditions. Also, those injected at ZT11 showed increased levels of TNF-α in serum compared to standard light conditions. These results suggest a circadian dependency of the central thermoregulatory and peripheral inflammatory response to septic-shock, with TNF-α playing a central role in this circadian response.