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Reiko Nakao,1 Takeshi Nikawa,2 Katsutaka Oishi1,3,4 1Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, 2Department of Nutritional Physiology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 3Department of Applied Biological Science, Graduate School of Science and Technology, Tokyo University of Science, Noda, 4Department of Computational and Medical Sciences, Graduate School of Frontier Sciences, the University of Tokyo, Kashiwa, Japan Abstract: Skeletal muscle functions in locomotion, postural support, and energy metabolism. The loss of skeletal muscle mass and function leads to diseases such as sarcopenia and metabolic disorders. Inactivity (lack of exercise) and an imbalanced diet (increased fat or decreased protein intake) are thought to be involved in the prevalence of such pathologies. On the other hand, recent epidemiological studies of humans have suggested that circadian disruption caused by shift work, jet lag, and sleep disorders is associated with obesity and metabolic syndrome. Experimental studies of mice deficient in clock genes have also identified skeletal muscle defects, suggesting a molecular link between circadian clock machinery and skeletal muscle physiology. Furthermore, accumulating evidence about chronotherapy, including chronopharmacology, chrononutrition, and chronoexercise, has indicated that timing is important to optimize medical intervention for various diseases. The present review addresses current understanding of the functional roles of the molecular clock with respect to skeletal muscle and the potential of chronotherapy for diseases associated with skeletal muscle. Keywords: biological rhythm, metabolic syndrome, physical activity, neural signal, chronotherapy

In 2017, a new two-step algorithm for the treatment of COPD was proposed. This algorithm was based on the severity of symptoms and phenotypes or treatable traits, and patient-specialised assessment targeting eosinophilic inflammation, chronic bronchitis, and frequent infections is recommended after exacerbation occurs despite maximal bronchodilation therapy. However, recent studies have revealed the clinical characteristics of patients who should have second controllers added, such as ICS. We again realized that treatable traits should be assessed and intervened for as early as possible. Moreover, the treatment algorithm is necessary to be adapted to the situation of clinical practice, taking into account the characteristics of the patients. The time to revise COPD treatment algorithm has come and we propose a new 3-step parallel approach for initial COPD treatment. After the diagnosis of COPD, the first assessment is to divide into two categories based on the usual clinical characteristics for patients with COPD and the specific clinical characteristics for each patient with concomitant disease. In the former, the assessment should be based on the level of dyspnea and the frequency of exacerbations. After the assessment, mono- or dual bronchodilator should be selected. In the latter, the assessment should be based on asthma characteristics, chronic bronchitis, and chronic heart failure. After the assessment, patients with asthmatic characteristics may consider treatment with ICS, while patients with chronic bronchitis may consider treatment with roflumilast and/or macrolide, while patients with chronic heart failure may consider treatment with selective Β1-blocker. The 3-step parallel approach is completed by adding an additional therapy for patients with concomitant disease to essential therapy for patients with COPD. In addition, it is important to review the response around 4 weeks after the initial therapy. This COPD management proposal might be considered as an approach based on patients' clinical characteristics and on personalized therapy.

Outbreaks of hand, foot and mouth disease have been documented in Japan since 1963. This disease is primarily caused by the two closely related serotypes of Enterovirus A71 (EV-A71) and Coxsackievirus A16 (CV-A16). Here, we analyse Japanese virologic and syndromic surveillance time-series data from 1982 to 2015. As in some other countries in the Asia Pacific region, EV-A71 in Japan has a 3 year cyclical component, whereas CV-A16 is predominantly annual. We observe empirical signatures of an inhibitory interaction between the serotypes; virologic lines of evidence suggest they may indeed interact immunologically. We fit the time series to mechanistic epidemiological models: as a first-order effect, we find the data consistent with single-serotype susceptible–infected–recovered dynamics. We then extend the modelling to incorporate an inhibitory interaction between serotypes. Our results suggest the existence of a transient cross-protection and possible asymmetry in its strength such that CV-A16 serves as a stronger forcing on EV-A71. Allowing for asymmetry yields accurate out-of-sample predictions and the directionality of this effect is consistent with the virologic literature. Confirmation of these hypothesized interactions would have important implications for understanding enterovirus epidemiology and informing vaccine development. Our results highlight the general implication that even subtle interactions could have qualitative impacts on epidemic dynamics and predictability.