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Kuniaki Otsuka,1,2 Shougo Murakami,3 Kiyotaka Okajima,4 Koichi Shibata,1 Yutaka Kubo,5 Denis G Gubin,6– 8 Larry A Beaty,2 Germaine Cornelissen2 1Tokyo Women’s Medical University, Tokyo, Japan; 2Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA; 3Department of Cardiovascular Medicine, Soseikai General Hospital, Kyoto, Japan; 4Cardiovascular Internal Medicine, Higashi Omiya General Hospital, Saitama, Japan; 5Department of Medicine, Machida Keisen Hospital, Tokyo, Japan; 6Laboratory for Chronobiology and Chronomedicine, Research Institute of Biomedicine and Biomedical Technologies, Medical University, Tyumen, 625023, Russia; 7Department of Biology, Medical University, Tyumen, 625023, Russia; 8Tyumen Cardiology Research Center, Tomsk National Research Medical Center, Russian Academy of Science, Tomsk, RussiaCorrespondence: Germaine Cornelissen, Halberg Chronobiology Center, University of Minnesota, MMC8609, 420 Delaware Street SE, Minneapolis, MN, 55455, USA, Email corne001@umn.edu.an Kuniaki Otsuka, Executive Medical Center, Totsuka Royal Clinic, Tokyo Women’s Medical University, Related Medical Facility, Sinjuku City, Tokyo, Japan, Email frtotk99@ba2.so-net.ne.jpBackground: Blood pressure (BP) variability is involved in the appraisal of threat and safety, and can serve as a potential marker of psychological resilience against stress. The relationship between biological rhythms of BP and resilience was cross-sectionally assessed by 7-day/24-hour chronobiologic screening in a rural Japanese community (Tosa), with focus on the 12-hour component and the “circadian-circasemidian coupling” of systolic (S) BP.Subjects and Methods: Tosa residents (N = 239, 147 women, 23– 74 years), free of anti-hypertensive medication, completed 7-day/24-hour ambulatory BP monitoring. The circadian-circasemidian coupling was determined individually by computing the difference between the circadian phase and the circasemidian morning-phase of SBP. Participants were classified into three groups: those with a short coupling interval of about 4.5 hours (Group A), those with an intermediate coupling interval of about 6.0 hours (Group B), and those with a long coupling interval of about 8.0 hours (Group C).Results: Residents of Group B who showed optimal circadian-circasemidian coordination had less pronounced morning and evening SBP surges, as compared to residents of Group A (10.82 vs 14.29 mmHg, P < 0.0001) and Group C (11.86 vs 15.21 mmHg, P < 0.0001), respectively. The incidence of morning or evening SBP surge was less in Group B than in Group A (P < 0.0001) or Group C (P < 0.0001). Group B residents showed highest measures of wellbeing and psychological resilience, assessed by good relation with friends (P < 0.05), life satisfaction (P < 0.05), and subjective happiness (P < 0.05). A disturbed circadian-circasemidian coupling was associated with elevated BP, dyslipidemia, arteriosclerosis and a depressive mood.Conclusion: The circadian-circasemidian coupling of SBP could serve as a new biomarker in clinical practice to guide precision medicine interventions aimed at achieving properly timed rhythms, and thereby resilience and wellbeing.Keywords: 7-day/24-hour chronobiologic screening, blood pressure, biological 12-hour rhythm, appropriate circadian-circasemidian coupling, circadian acrophase, 12-hour morning acrophase, morning blood pressure surge, evening blood pressure surge, human resilience, wellbeing

Kiyoji Tanaka,1,2 Hiroyuki Sasai,3 Kyohsuke Wakaba,4 Shin Murakami,4,5 Miyuki Ueda,5 Fumio Yamagata,6 Masao Sawada,6 Kazuhiro Takekoshi7 1Faculty of Health and Sport Sciences, University of Tsukuba, Tsukuba, Japan; 2THF Co., Ltd, Tsukuba, Japan; 3Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan; 4Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan; 5Life Science Department, FiNC Inc., Tokyo, Japan; 6Genki Plaza Medical Center for Health Care, Tokyo, Japan; 7Faculty of Medicine, University of Tsukuba, Tsukuba, Japan Purpose: To test the effectiveness of professional dietary coaching via group chat using a smartphone application (app) for weight loss.Methods: This study was a 12-week, assessor-blind, parallel-group, waitlist-controlled randomized trial that included a 4-week follow-up period (trial registration, UMIN000025340). Data were collected between October 2016 and May 2017 and were analyzed between July 2017 and January 2018. Participants were 112 overweight, obese, or abdominally obese Japanese adults, aged 20 to 64 years, with at least one cardiometabolic risk factor. Participants were randomized to the coaching group (n=75) or control group (n=37), with a ratio of 2:1. The coaching group received a commercial weight loss program characterizing dietary coaching by a certified nutrition professional via group chat delivered on a smartphone app. Participants posted photos of every meal into the group chat, and the certified professional gave immediate direct feedback and encouragement. The primary outcome was an 8-week weight change. Secondary outcomes included 8-week changes in cardiometabolic risk factors. The frequency of meal photo uploads was recorded as a measure of adherence.Results: Of the 112 randomized participants, 93 (83.0%) and 81 (72.3%) completed 8-week and 12-week visits, respectively. Intention-to-treat analysis demonstrated significantly larger 8-week weight loss in the coaching group (−1.4 kg; 95% confidence interval [CI]: −2.0, −0.8 kg) than that in the control group (−0.1 kg; 95% CI: −0.6, 0.4 kg). Significantly larger improvements in triglyceride and glycated hemoglobin A1c levels were also obtained in the coaching group. These benefits, except for the triglyceride level, were maintained until week 12. The frequent upload of meal photos was associated with a larger 8-week weight loss in a dose–response fashion (P-value for trend

Nobuyuki Kajiwara,1 Kazuyuki Hayashi,1 Masahiro Misago,2 Shinichiro Murakami,2 Takato Ueoka2 1Department of Nephrology, Ikeda City Hospital, 2Department of General Medicine, Ikeda City Hospital, Johnan, Osaka, Japan Purpose: We sought to profile first-time patients without a referral who sought medical care at the Department of Internal Medicine at a medium-sized acute care hospital in Japan. We anticipated that the analysis would highlight the demand for medical care needs from acute care hospitals and help confirm one of the problems associated with primary care in Japan. Patients and methods: The study population comprised 765 patients who sought outpatient consultation without a referral at “the Department of General Internal Medicine” at the Ikeda City Hospital on Fridays over 4 years. Data on the following variables were collected: age, sex, examination date, reason for encounter (RFE), diagnosis, as well as history of consultation with or without antibiotic treatment at another medical institution for the same RFE. We used the International Classicication of Primary Care, Revised Second edition (ICPC-2-R) codes for RFEs and diagnoses. Results: The main RFE fields were digestive (ICPC-2-R Chapter D), general and unspecified (A), and respiratory (R). The main diagnosis fields were digestive (D), respiratory (R), general and unspecified (A), and musculoskeletal (L). In total, 27.6% of patients had sought consultation at another medical institution for the same RFE. Of these, 64.7% of patients for whom the RFE was cough (ICPC-2-R code, R05), and 72.0% for whom the RFE was fever (A03) were prescribed antibiotics. In total, 62.4% of patients underwent emergency investigations and waited for the results; 4.3% were hospitalized on the same day; and 60.5% were medicated at the initial examination. In 11.5%, the main underlying problem appeared to be psychosomatic. Conclusion: We used the ICPC-2-R to analyze the state of first-visit patients without a referral visiting the Department of Internal Medicine at a medium-sized acute care hospital in Japan. Common RFEs were abdominal pain, cough, and fever. A tendency toward overprescription of antibiotics was observed among primary care physicians. Keywords: medium-sized hospital, general internal medicine, general practice, reason for encounter, International Classification of Primary Care, antibiotic overuse

Periodontitis is a multifactorial disease that progresses via dynamic interaction between bacterial and host-derived genetic factors. The recent trend of omics analyses has discovered many periodontitis-related risk factors. However, how much the individual factor affects the pathogenesis of periodontitis is still unknown. This article aims to identify multiple key factors related to the pathogenesis of periodontitis and quantitatively predict the influence of each factor on alveolar bone resorption by omics analysis and mathematical modeling. First, we induced periodontitis in mice (n = 3 or 4 at each time point) by tooth ligation. Next, we assessed alveolar bone resorption by micro–computed tomography, alterations in the gene expression by RNA sequencing, and the microbiome of the gingivae by 16S ribosomal RNA sequencing during disease pathogenesis. Omics data analysis identified key players (bacteria and molecules) involved in the pathogenesis of periodontitis. We then constructed a mathematical model of the pathogenesis of periodontitis by employing ordinary differential equations that described the dynamic regulatory interplay between the key players and predicted the alveolar bone integrity as output. Finally, we estimated the model parameters using our dynamic experimental data and validated the model prediction of influence on alveolar bone resorption by in vivo experiments. The model predictions and experimental results revealed that monocyte recruitment induced by bacteria-mediated Toll-like receptor activation was the principal reaction regulating alveolar bone resorption in a periodontitis condition. On the other hand, osteoblast-mediated osteoclast differentiation had less impact on bone integrity in a periodontitis condition. [ABSTRACT FROM AUTHOR]

Brachytherapy is often used to treat oral cancer, as it generally yields a good outcome with little oral function loss. In particular, mold brachytherapy is ideally suited for superficial oral cases, such as cancers developing on the gingiva, palate, or buccal mucosa, with little to no bone involvement and thin tissue thickness. Mold brachytherapy including that at a high-dose-rate (HDR) is used to treat gingival cancer, though hospitalization is the typical treatment setting. Reported here are details of HDR mold brachytherapy performed in an outpatient setting for a mandibular gingival case of squamous cell carcinoma (SCC). Mandibular gingival SCC in a 71-year-old man was treated as an outpatient using HDR mold brachytherapy (54 Gy in 9 fractions, 5 days). After receiving mold treatment for thirty months, there was no sign of recurrence or metastasis. To our knowledge, this is the first report of HDR mold brachytherapy in an outpatient setting for treating mandibular gingival cancer. [ABSTRACT FROM AUTHOR]

The influence of Coulomb collisions between energetic particles in a neutral beam injection (NBI)-heated plasma is numerically investigated utilizing the improved collision operator for the orbit-following type of Monte Carlo codes. This nonlinear collision operator enables the collisional effect by non-Maxwellian plasmas including energetic particles to be taken into account. We have implemented it into GNET, one of the orbit-following Monte Carlo codes solving drift kinetic equation in the 5D phase-space, and performed simulations for tangentially injected NBI cases (beam energy: 180 keV), taking account of beam–beam Coulomb collisions. It is found that the beam–beam collisions cause energetic particle orbits to transition from passing to trapped and enhance the collisional transport, which results in the deterioration of the energetic particle confinement. [ABSTRACT FROM AUTHOR]

Al-Zn-Mg alloy has been known as one of the aluminum alloys with the good age-hardening ability and the high strength among commercial aluminum alloys. The mechanical property of the limited ductility, however, is required to further improvement. In this work, three alloys, which were added Cu or Ag into the Al-Zn-Mg alloy, were prepared to compare the effect of the additional elements on the aging behavior. The content of Ag and Cu were 0.2at.% and the same as, respectively. Ag or Cu added alloy showed higher maximum hardness than base alloy. The particle shape and rod shape precipitates were observed in all alloys peak-aged at 423K. According to addition of Ag or Cu, the number density of the precipitates increased higher than that of base alloy.

Periodontal disease is caused by dysbiosis of the dental biofilm and the host inflammatory response. Various pathogenic factors, such as proteases and lipopolysaccharides (LPSs) produced by bacteria, are involved in disease progression. Endotoxin tolerance is a function of myeloid cells, which sustain inflammation and promote tissue regeneration upon prolonged stimulation by endotoxins such as LPS. The role of endotoxin tolerance is gaining attention in various chronic inflammatory diseases, but its role in periodontal disease remains elusive. Oxidative stress, one of the major risk factors for periodontal disease, promotes disease progression through various mechanisms, of which only some are known. The effect of oxidative stress on endotoxin tolerance has not yet been studied, and we postulated that endotoxin tolerance regulation may be an additional mechanism through which oxidative stress influences periodontal disease. This study aimed to reveal the effect of oxidative stress on endotoxin tolerance and that of endotoxin tolerance on periodontitis progression. The effect of oxidative stress on endotoxin tolerance was analyzed in vitro using peritoneal macrophages of mice and hydrogen peroxide (H2O2). The results showed that oxidative stress inhibits endotoxin tolerance induced by Porphyromonas gingivalis LPS in macrophages, at least partially, by downregulating LPS-elicited negative regulators of Toll-like receptor (TLR) signaling. A novel oxidative stress mouse model was established using SMP30KO mice incapable of ascorbate biosynthesis. Using this model, we revealed that oxidative stress impairs endotoxin tolerance potential in macrophages in vivo. Furthermore, gingival expression of endotoxin tolerance-related genes and TLR signaling negative regulators was decreased, and symptoms of ligature-induced periodontitis were aggravated in the oxidative stress mouse model. Our findings suggest that oxidative stress may contribute to periodontitis progression through endotoxin tolerance inhibition. [ABSTRACT FROM AUTHOR]