BackgroundIn Japan, some residents develop mental health problems. In previous studies, it was reported that long working hours might be a cause of stress reaction such as depression. There were some reports that compared residents with 80 or more working hours with those with less than 80 working hours. However, many residents are practically detained for extra-long time, designated as 100 h or more per week, for medical practice, training, self-study, etc. There have been few reports on extra-long hours of work. This study evaluated the working environment and the amount of stress experienced by first-year residents, and examined the relationship between long working hours and depression, especially in the group of extra-long working hours.MethodsThe study included 1241 first-year residents employed at 250 training hospitals in 2011. A self-report questionnaire was administered at the beginning of the residency and 3 months later to collect data on demographics, depressive symptoms, and training conditions (e.g., duration of work, sleep, disposable time, and night shift). Depressive symptoms were rated using the Center for Epidemiologic Studies Depression Scale.ResultsThe mean duration of work per week was 79.4 h, with 97 residents (7.8%) working 100 h or more. At 3 months, clinically significant depressive symptoms were reported by 45.5% of residents working 100 or more h per week, which proportion was significantly greater than that for respondents working less than 60 h (P < 0.001). Multivariate logistic regression analysis showed that a working week of 80 to 99.9 h was associated with a 2.83 fold higher risk and 100 h or more was associated with a 6.96-fold higher risk of developing depressive symptoms compared with a working week of less than 60 h.ConclusionWorking excessively long hours was significantly associated with development of depressive symptoms. Proper management of resident physicians’ working hours is critical to maintaining their physical and mental health and to improve the quality of care they provide.

The SOC score was significantly related to future depressive symptoms among medical residents. The SOC Scale might be a useful and easy-to-use predictor of future depression.

Purpose: Cancers of biliary system represent highly malignant diseases of dismal prognosis. We have previously introduced AxdAdB3, an E1A, E1B double-restricted oncolytic adenovirus, which showed excellent oncolytic efficacy for approximately half of the biliary cancer lines with an enhanced safety to normal cells. The purpose of this study was to evaluate whether RGD-fiber modification (AxdAdB3-F/RGD), which enables integrin-dependent infection, can improve the infectivity and efficacy of AxdAdB3 for biliary cancers. Experimental Design: Expressions of adenoviral receptors, coxsackievirus adenovirus receptor (CAR) and integrins (αvβ3 and αvβ5), were compared with the level of infectivity of LacZ-expressing replication-defective adenoviruses with wild-type fibers or RGD-modified fibers in a panel of biliary cancer cell lines in vitro. Viral replication and cytotoxicity in vitro of AxdAdB3-F/RGD, a novel E1A, E1B double-restricted replication-selective adenovirus with RGD-modified fibers, were compared with those of its parent virus, AxdAdB3, in various biliary cancer cells and in normal cells. In vivo antitumor effects of these oncolytic viruses were compared in a xenograft tumor model. Results: Expression of CAR significantly correlated with the adenovirus infectivity, whereas integrin αvβ5 was abundantly expressed in almost all biliary cancer cells. Whereas AxdAdB3 effectively replicated and lysed only the biliary cancer cells with a preserved expression of CAR, AxdAdB3-F/RGD exhibited efficient replication and potent oncolysis in both CAR-positive and CAR-negative biliary cancer cells. AxdAdB3-F/RGD showed attenuated replication and little cytopathy in human normal cells (i.e., hepatocytes, WI-38 cells) as well as AxdAdB3. Furthermore, in nude mice with s.c. xenografts of CAR-deficient human biliary cancer, i.t. AxdAdB3-F/RGD therapy caused a marked inhibition of tumor growth. Conclusions: The RGD-fiber modification strategy enhanced the infectivity, replication, and oncolytic effects of the E1A, E1B double-restricted oncolytic adenovirus for CAR-deficient biliary cancers. In addition, it preserved the merit of excellent safety of the double-restricted virus for normal cells. These results suggest a potential use of this agent for the treatment of biliary cancers.

Combination therapy with replicative oncolytic viruses is a recent topic in innovative cancer therapy, but few studies have examined the efficacy of oncolytic adenovirus plus replication-deficient adenovirus carrying a suicide gene. We aim to evaluate whether an E1A, E1B double-restricted oncolytic adenovirus, AxdAdB-3, can improve the efficacy for gallbladder cancers (GBCs) of the replication-deficient adenovirus-based herpes simplex virus thymidine kinase (HSVtk)/ganciclovir (GCV) therapy directed by the carcinoembryonic antigen (CEA) promoter. Cytopathic effects of AxdAdB-3 plus AxCEAprTK (an adenovirus expressing HSVtk directed by CEA promoter) or AxCAHSVtk (an adenovirus expressing HSVtk directed by a nonspecific CAG promoter) with GCV administration were examined in several GBC lines and normal cells. Efficacy in vivo was tested in severe combined immunodeficiency disease mice with GBC xenografts. Addition of AxdAdB-3 (1 multiplicity of infection, MOI) significantly enhanced the cytopathic effects of AxCEAprTK (10 MOI)/GCV on GBC cells. The augmented effect was attributable to the replication of the AxCEAprTK and also to the enhanced CEA promoter activity, which was presumably transactivated by E1A. In normal cells, AxdAdB-3 (20 MOI) plus AxCEAprTK (200 MOI)/GCV was not cytopathic, whereas AxdAdB-3 (1 MOI) plus AxCAHSVtk (10 MOI)/GCV was significantly toxic. Low-dose AxdAdB-3 (2 Â 10 7 PFU, plaque-forming unit) plus AxCEAprTK (2 Â 10 8 PFU)/GCV significantly suppressed the growth of GBC xenografts as compared with either AxdAdB-3 (2 Â 10 7 PFU)/GCV or AxCEAprTK (2 Â 10 9 PFU)/GCV alone. E1A, E1B double-restricted replicating adenovirus at low dose significantly augmented the efficacy of CEA promoter-directed HSVtk/GCV therapy without obvious toxicity to normal cells, suggesting a potential use of this combination for treating GBC and other CEA-producing malignancies.