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Background: Elevated resting heart rate (RHR) is a predictor of incident type 2 diabetes (T2D). Insulin resistance is thought to play a role in this association; however, the extent to which insulin resistance mediates this association is unclear., Methods: 1309 Japanese individuals without diabetes were recruited during 2009-2012 and followed for 5 years, of whom 78 developed T2D, as diagnosed by the 75 g oral glucose tolerance test. Supine RHR was measured by electrocardiography. Using logistic regression analysis, we examined the association between RHR and incident T2D, and interaction with the homeostasis model assessment of insulin resistance (HOMA-IR) index. Causal mediation analysis was applied to decompose the effect of RHR on the outcome and estimate the proportion mediated by the HOMA-IR index., Results: The sex- and age-adjusted cumulative incidence rate of T2D increased with increasing RHR. After adjustment for sex, age, waist circumference, current smoking status, alcohol use, habitual exercise, and cardiovascular disease medications, individuals with a RHR ≥80 bpm, compared with <60 bpm, showed an increased risk of incident T2D [odds ratio (OR), 2.89; 95 % confidence interval (CI), 1.07 to 7.80]. Multivariate adjusted OR for the total effect per 1 SD increase in RHR on incident T2D was 1.37 (95 % CI, 1.01 to 1.74) in the mediation analysis, and the proportion of the total indirect effect mediated by the HOMA-IR index was 27.5 % (95 % CI, 1.5 to 53.5)., Conclusions: Approximately 30 % of the effect of RHR on incident T2D was explained by the indirect effect of insulin resistance., Competing Interests: Declaration of competing interest We hereby certify that all authors have read and approved submission of the manuscript and the manuscript has not been published and is not being considered for publication elsewhere in whole or part in any language except as an abstract. Also, there is no conflict of interest regarding this study., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Salivary glands act as virus reservoirs in various infectious diseases and have been reported to be targeted by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the mechanisms underlying infection and replication in salivary glands are still enigmatic due to the lack of proper in vitro models. Here, we show that human induced salivary glands (hiSGs) generated from human induced pluripotent stem cells can be infected with SARS-CoV-2. The hiSGs exhibit properties similar to those of embryonic salivary glands and are a valuable tool for the functional analysis of genes during development. Orthotopically transplanted hiSGs can be engrafted at a recipient site in mice and show a mature phenotype. In addition, we confirm SARS-CoV-2 infection and replication in hiSGs. SARS-CoV-2 derived from saliva in asymptomatic individuals may participate in the spread of the virus. hiSGs may be a promising model for investigating the role of salivary glands as a virus reservoir., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Rab GTPases, the largest group of small monomeric GTPases, have been shown to participate in membrane trafficking involving many cellular processes. However, their roles during osteoblastic differentiation remain to be elucidated. In this study, we investigated Rab GTPase involvement in osteoblastic differentiation. Protein levels of a series of Rabs (Rab4, Rab5, Rab7, Rab9a, Rab11a/b, and Rab27) were increased during osteoblastic differentiation of MC3T3-E1 cells, and the Rab11a/b levels were particularly pronounced in the presence of Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor, an activator of osteoblastogenesis. We subsequently investigated the functional contribution of Rab11a and Rab11b during osteoblastic differentiation. The alkaline phosphatase (ALP) levels were reduced by Rab11b depletion but not by Rab11a depletion. Because our result suggested that Rab11a and Rab11b could be regulated downstream of Runx2 (Runt-related transcription factor 2), a key transcription factor for osteoblastic differentiation, we investigated the effects of the double knockdown of Runx2 and Rab11a or Rab11b on osteoblastic phenotypes. The double knockdown significantly reduced ALP activity as well as collagen deposition compared with single Runx2 knockdown. Furthermore, the Rab11a and Rab11b response to mechanical stress in vivo was investigated using a mouse orthodontic tooth movement model. Rab11a and Rab11b expression was enhanced in the periodontal ligament, where bone formation is activated by tensile stress. This study shows that Rab11a and Rab11b are regulated downstream of Runx2 in osteoblastic differentiation, and their expressions are also controlled by tensile stress., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

This study aimed to examine the association between interindividual variability in strength changes and in training volume. A total of 26 untrained men completed 4-weeks of isometric knee extension (KE group, n = 12) and hip flexion (HF group, n = 14) training. Each training session comprised four sets of ten isometric contractions, 3-s contractions every 20 s. Training volume, which was defined as impulse during contractions, and maximal voluntary contraction (MVC) torque during KE and HF were evaluated. Based on the magnitude of MVC torque changes, the participants were divided into the high and low responders ( n = 13; KE = 6 and HF = 7 per responders). The MVC torque changes (KE, 20.8%; HF, 22.4%) and total training volume did not significantly differ between the two groups. A higher training volume was demonstrated in the low responders than the high responders. The total training volume was positively associated with the MVC torque changes in low responders (r = 0.869%, 95% confidence interval [0.610, 0.960], p < 0.001), but not in high responders [r = 0.229, 95% confidence interval (-0.368, 0.693), p = 0.451], KE or HF group. Results showed that training volume was an important factor in determining the magnitude of strength gains in low responders, and MVC torque could improve by approximately 20% with the use of the study protocol regardless of joint actions involved during training., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ema, Saito and Akagi.)

Circadian misalignments have been linked to adverse cardiometabolic outcomes. However, the association between irregular daily routine and the risk of cardiovascular disease (CVD) remains unknown. We examined this association in a prospective study in Japan. The study included 78,115 Japanese participants aged 45-74 years. The self-reported daily routine was evaluated using the question, 'Is your daily routine or activity schedule regular?' The response (yes/no) was obtained as a binary variable. Cox proportional hazard regression analysis was used to estimate the hazard ratios and 95% confidence intervals for the association between an irregular daily routine and CVD incidence risk. Among the participants, 23.7% reported an irregular daily routine. During the mean follow-up period of 13.3 years, we observed 4641 CVD events. An irregular daily routine was significantly associated with increased risks of CVD and total stroke in women, but not in men. This positive association between an irregular daily routine and the risk of CVD was weak in the high vegetable and fruit consuming population. An irregular daily routine is positively associated with the risk of incident CVD, especially in women. These associations may be weak in populations that consume a diet rich in vegetables and fruits., (© 2022. The Author(s).)

Objective: To identify factors affecting condylar bone changes following surgical-orthodontic treatment., Methods: A total of 200 patients with dentofacial deformities were classified into skeletal Classes I, II, and skeletal Class III groups consisting of 61 and 139 subjects, respectively. Temporomandibular joints (TMJs) were evaluated using clinical findings and computed tomography images before treatment, immediately before surgery, and 6 months after surgery., Results: Condylar bone changes occurred at a significantly higher rate after surgery in both groups. Factors related to condylar bone changes following surgical-orthodontic treatment included skeletal Class I or II, disc displacement, and condylar bone changes before treatment. There were three cases with condylar bone changes after surgery that were diagnosed with condylar resorption and skeletal Class II and anterior disc displacement before surgery., Conclusion: Condylar resorption could occur when the load on the condyle increases after orthognathic surgery and exceeds the permissible limit.

Fish and omega-3 fatty acid consumption is known to be beneficial for cardiometabolic health. However, the related evidence for individuals with a relatively higher intake of fish or omega-3 unsaturated fatty acids, e.g., Japanese individuals, is scarce. Therefore, this study aimed to examine the association of fish and omega-3 fatty acid intakes with the carotid intima-media thickness (C-IMT) in the Japanese population. In total, 1803 Japanese men and women aged 30-84 years without a history of myocardial infarction or angina pectoris were included in the study. The fish and omega-3 fatty acid intakes were estimated using food frequency questionnaires. The C-IMT was measured using ultrasound imaging, and the participants were classified into three groups: normal, moderate (1.1 to 1.4 mm of maximum C-IMT), and severely increased C-IMT (≥1.5 mm). Multinomial logistic regression models were used to calculate the odds ratio (OR) and 95% confidence intervals (95% CI) of the presence of moderately and severely increased C-IMT. The omega-3 fatty acid intake was shown to be associated with lower odds of severely increased C-IMT. The multivariable-adjusted OR (95%CI) was 0.55 (0.31-0.97; p for trend = 0.04). We also found a borderline significant negative association between fish intake and the presence of severely increased C-IMT. In conclusion, omega-3 fatty acid intake might protect against the development of atherosclerosis in the Japanese population.

The prospective association between secondhand smoke (SHS) and the risk of incident cardiovascular disease (CVD) remains unclear. This study was the first to examine the association between SHS and risks of ischemic heart disease (IHD), stroke, and total CVD in a large cohort in Asia. The study followed 24,232 never-smoking women aged 40-59 from around Japan (Akita, Iwate, Nagano, Niigata, Ibaraki, Kochi, Nagasaki, and Okinawa prefectures). Their husbands were classified into never, former, and current smokers. After adjustment for age, body mass index, alcohol consumption, histories of hypertension and diabetes mellitus, medication use for hyperlipidemia, menopausal status, and public health center areas, the hazard ratios (HRs) of CVD according to husbands' smoking status were estimated by Cox proportional hazards models. During the 440,360 person-years follow-up, 846 women had total CVDs (103 IHDs, 744 strokes). The proportional hazard assumption was not assured during the total follow-up from 1990 to 2012, but so was then the follow-up of < and ≥ 10 person-years were examined separately. The multivariable HRs (95% confidence intervals) associated with husbands' current versus non-current smoking was 2.02 (1.19-3.45) for IHD, 1.18 (0.98-1.42) for stroke, and 1.25 (1.05-1.49) for total CVD in the follow-up of ≥10 person-years. The SHS from husbands may raise the risk of IHD among middle-aged never-smoking women., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Recurrence in oral squamous cell carcinoma (OSCC) is not rare. Due to lack of studies assessing characteristics of recurrent OSCC, including time to recurrence and outcomes, we sought to investigate its characteristics, time to recurrence, and outcomes in Japanese OSCC patients., Methods: This study was a nonrandomized retrospective cohort study in a tertiary referral centre. It included 208 (117 men and 91 women) patients with recurrent oral cancer who underwent major curative surgery in the Department of Oral and Maxillofacial Surgery at Kobe University Hospital between January 1999 and April 2017. The outcomes were disease-specific survival (DSS) and overall survival (OS)., Results: In multivariable Cox proportional hazards analysis, the time to recurrence (hazard ratio [HR] 3.55, 95% confidence interval [CI] 1.69-6.63; P  = 0.001), extranodal extension (ENE, HR 2.72, 95% CI 1.51-4.89; P  = 0.001), and high T stage (HR 2.00, 95% CI 1.01-3.97; P  = 0.046) were independent predictors of DSS. The time to recurrence (HR 3.29, 95% CI 1.82-5.96; P  < 0.001) and ENE (HR 2.64, 95% CI 1.52-4.56; P  = 0.001) were independent predictors of OS., Conclusion: Time to recurrence, extranodal extension, and higher T stage were independent prognosis predictors in OSCC., Competing Interests: Conflict of interestTakumi Hasegawa, Erina Kobayashi, Rika Amano, Izumi Saito, Daisuke Takeda, Yasumasa Kakei, Akira Kimoto, Akiko Sakakibara, Masaya Akashi declare that they have no conflict of interest., (© The Association of Oral and Maxillofacial Surgeons of India 2021.)

Competing Interests: The authors declare that they have no conflict of interest.

Objective: To investigate the relation between body mass index (BMI) and dry eye disease (DED)., Methods: We conducted a cross-sectional questionnaire-based survey in 85,264 Japanese men and women aged 40 to 74 years who participated in the Japan Public Health Center-based Prospective Study for the Next Generation (JPHC-NEXT Study). Dry eye disease was defined as the presence of severe symptoms or clinical diagnosis. A multivariable logistic regression model was used to estimate the odds ratios (ORs) of DED associated with BMI and their two-sided 95% confidence intervals (CIs). We adjusted for age, cohort area, visual display terminal time, smoking status, alcohol intake, education status, income status, as well as history of hormone replacement therapy for women., Results: Prevalence of DED was 23.4% (n = 19,985; 6,289 men, 13,696 women). Higher BMI was correlated with a lower prevalence of DED in a dose-response fashion, with an adjusted OR of DED (95% CI) per 1 kg/m2 increment of BMI of 0.98 (95% CI: 0.97-0.99) for men and 0.97 (95% CI: 0.97-0.98) for women., Conclusions: This large population-based study showed an inverse relationship between BMI and prevalence of DED in a Japanese population. Underestimation of DED is warned, especially for participants with high BMI., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2021 Contact Lens Association of Ophthalmologists.)

The Japanese hypertension guidelines report that essential hypertension is detected in 1-3% of upper elementary and high school students during blood pressure (BP) screenings. Hypertension in these age groups is an emerging public health concern mainly attributed to the rising rate of pediatric obesity. Considering the existence of BP tracking phenomenon, early preventive education and instruction are necessary, especially for male students with moderately elevated BP showing a tendency toward obesity, despite the low prevalence of hypertension in high school students. Students with a positive family history of hypertension and those born with low birth weight need the same measures. Lifestyle habits, such as increased alcohol intake, dramatically change once students begin university; thus, early education and instruction regarding the factors influencing BP are necessary. In particular, for male students with higher BP during high school, caution regarding increased body weight is required irrespective of their level of obesity. Young adults aged <40 years should be educated about the association between body weight and hypertension. Particular caution surrounding lifestyle habits, including drinking and smoking, is warranted in male hypertensive subjects because hypertension at a young age is strongly associated with obesity. BP monitoring and the management of obesity should be considered efficient approaches to the detection and treatment of hypertension. For the lifetime prevention of hypertension, it is essential to be aware of one's health status and learn about healthy lifestyles beginning in childhood. BP measurement may be an appropriate means to achieve this goal.

Sleep-disordered breathing (SDB) is linked with brachial blood pressure. Although central systolic blood pressure (cSBP) is a better predictor of cardiovascular diseases than is brachial blood pressure, the association between SDB and cSBP is not fully understood. This cross-sectional study included 1484 participants without cardiovascular diseases who were enrolled in the Toon Health Study between 2009 and 2012. The respiratory disturbance index (RDI) was estimated with a one-night sleep test using an airflow monitor. Participants were grouped into three categories according to RDI level: mild (<10 events/h), moderate (10 to <20 events/h), and severe (≥20 events/h). The cSBP was measured using a noninvasive automated tonometer. Multivariable-adjusted cSBP means for the mild, moderate, and severe RDI categories were, respectively, 116.0, 118.0, and 120.7 mm Hg (p for trend = 0.02) for men and 111.8, 113.7, and 111.7 mm Hg (p for trend = 0.59) for women. The association for men was no longer significant after adjusting for BMI. When stratified by BMI (<22 or ≥22 kg/m 2 ), the RDI was associated with cSBP among men with BMI ≥ 22 kg/m 2 , and this association was of borderline significance. Augmentation index, pulse pressure amplification, and brachial blood pressure were not significantly associated with the RDI. Higher RDI values were associated with increased multivariable-adjusted cSBP means among men. This association was more evident among those with BMI ≥ 22 kg/m 2 . In conclusion, we found that the RDI was associated with cSBP among men, and this association was independent of confounding variables among individuals above the ideal weight.