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Background: Clinical leadership competencies for effective teamwork differ between Western cultures, where an independent self-construal prevails, and Japanese society, where the self-construal is rooted in interdependence. Although 27 out of 82 Japanese medical schools have 'leadership' as an educational outcome, specific competencies are poorly described, hindering the development of contextually-relevant leadership education. This study aimed to identify clinical leadership competencies and articulate the attributes and skills fundamental to leadership as perceived by Japanese physicians., Methods: The 80 items of the UK clinical leadership competency framework (CLCF) formed the stimulus in a modified Delphi. Participants, comprising 26 Japanese physicians, rated the importance of each item using a 5-point Likert scale with free-text comments regarding the modification of competencies and suggestions for new items. Items were eliminated if the Likert mean was less than 4.0 and if fewer than 70% of participants considered them to be important. Newly described or modified items derived from free-text comments were rated for importance in a second round with reflective thematic analysis of the free-text descriptions., Results: A CLCF of 84 items, reflective of Japanese clinical leadership, was created by eliminating three items describing tasks rarely involving Japanese physician leaders, revising seven items to emphasize understanding of members, and adding seven items to maximize feelings of team comfort. Seven skills and attributes emerged to construct Japanese clinical leadership from thematic analysis. "Humility" was viewed as a fundamental to leadership. Humility-driven "self-discipline" and "attentive listening", "supporting members" and "guiding members" with humility-based compassion, were essential elements to create "psychological safety" for freedom of expression. Achieving "unity" through emotional integration was identified as the overall goal of leadership., Conclusions: The reorganized CLCF has embedded more member-centered behaviors that build rapport and comfort for the members than the original CLCF. Modeling the Confucian virtue of humility and building unity by acting with compassion toward members are characteristics of Japanese clinical leadership that reflect an interdependent social context. These findings are a step toward the development of leadership education aligned with a Japanese context., Competing Interests: Declarations Ethics approval and consent to participate The study was approved by the Fukushima Medical University Ethics committee (#J123). Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background/aim: Nab-paclitaxel is used to treat patients with pancreatic cancer. However, it frequently induces peripheral neuropathy. Notably, pharmacokinetic factors may be associated with neuropathic symptoms as the onset depends on the cumulative dose. Therefore, we prospectively examined the association between the cumulative dose of nab-paclitaxel at the onset of peripheral neuropathy and polymorphisms of hepatic transporter genes., Patients and Methods: Patients with pancreatic cancer receiving nab-paclitaxel (125 mg/m 2 ) and gemcitabine (1,000 mg/m 2 ) were enrolled. Peripheral neuropathy was assessed using the Common Terminology Criteria for Adverse Events (CTCAE), Patient-Reported Outcomes CTCAE (PRO-CTCAE), and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx), every 2-12 weeks, and every 4 weeks thereafter. solute carrier organic anion transporter family member 1B1 (SLCO1B1) 521T>C, 388A>G; SLCO1B3 rs11045585; ATP-binding cassette transporters, subfamily B, member 1 (ABCB1) 1236C>T, 2677G>T/A, 3435C>T; ABCC1 rs2644983; ABCC2 24C>T; and ABCG2 421C>A were analyzed by direct sequencing. Correlations between transporter genotypes and cumulative dose at symptom onset were assessed using Kaplan-Meier and log-rank tests., Results: In total, 25 patients were enrolled. The lowest median cumulative dose for nab-paclitaxel at peripheral neuropathy onset using PRO-CTCAE was 593 mg. By CTCAE it was 800 mg, and by FACT/GOG-Ntx it was 1,090 mg (p<0.0001). At symptom onset, patients with ABCC2 -24C/T genotype had received a significantly lower median cumulative dose by PRO-CTCAE (540 mg) than those with C/C (720 mg) (p=0.0188). However, the other polymorphisms studied were not associated with symptoms., Conclusion: Herein, we found for the first time that ABCC2 -24C/T genotype was significantly associated with the onset of nab-paclitaxel-induced peripheral neuropathy detected with PRO-CTCAE., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background and Objectives: The global shift towards competency-based medical education (CBME) has led to the development of national guidelines for CBME implementation (CBME Guides). The characteristics of CBME Guides from CBME-developed countries were analysed to inform the revision process for the CBME Guide in Japan, a CBME-developing country., Methods: Document analysis of CBME Guides from Canada, Singapore, the Netherlands, the United Kingdom, and the United States was conducted by six Japanese medical education experts. The process of analysing the CBME Guides was also reviewed., Results: While the CBME Guides contain many commonalities in structure and content, there is variation in terminology and forms of expression. The characteristics vary according to national systems, culture, and customs. The content of the Guides may have changed depending on the publication date, in line with changes in medical technology, medical needs, and advances in the understanding of CBME., Conclusions: Analysing CBME Guides from CBME-developed countries may lead to more meaningful revisions to a CBME-developing country's guide, enabling it to be better aligned with the local, social, cultural, and historical context of the country now and in the future.

The objectives of this study were to conduct a survey of failure-of-passive-transfer (FPT) in eastern Hokkaido Japan, to evaluate the association between herd-level FPT and death and culling or treatment, and to test the effectiveness of monitoring using herd-level FPT. A total of 4,411 Holstein and Holstein-Wagyu crossbreds calves born from Holstein dams during the year beginning April 2, 2019 on 39 dairy farms were included in the study to investigate death-and-culling and the treatment rate during the first month of life, as well as rearing management up to 3 weeks of age. A subset of Holsteins (n=381) was included in the study for passive transfer and farms were diagnosed as having FPT if more than 20% of newborn calves had serum IgG levels below 10 g/L at the herd level. The prevalence of FPT (

Objective: The purpose of this study is to compare patient trends in otitis media with effusion (OME) symptoms and diagnoses before and after the COVID-19 pandemic in order to investigate the effects of the coronavirus disease of 2019 (COVID-19)., Methods: A retrospective, multi-center, observational study was carried out between January 2018 and December 2022 at hospitals in the Iwate Prefecture with full-time doctors. All patients were initially separated into two groups, one for the pre-COVID-19 era (from January 2018 to June 2020), and the other for the COVID-19 era (from July 2020 to December 2022)., Results: In the pre-COVID-19 era, 132 patients had tympanostomy tubes (TT) placed, while 64 patients had them placed in the COVID-19 era. Between the pre-COVID-19 and COVID-19 eras, there were no statistically significant differences in terms of age, sex, side, craniofacial deformity, or adenoidectomy. Children in elementary school showed a greater decline than those in preschool (42-11 patients in elementary school (74%) and 49 to 32 patients in preschool school (35%); p = 0.025)., Conclusions: The percentage of TT placements for OME dropped to roughly half during the COVID-19 epidemic. This was particularly obvious in elementary school students., Competing Interests: Declaration of competing interest All authors state no conflict of interest. All authors have seen and approved the final version of the manuscript being submitted. They warrant that the article is the authors' original work, hasn't received prior publication and isn't under consideration for publication elsewhere., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: Andexanet alfa, a specific antidote to factor Xa (FXa) inhibitors, has been approved for clinical use in several countries, including Japan, based on the results from the phase 3 trial ANNEXA-4. We aimed to assess the efficacy and safety of andexanet alfa treatment in FXa inhibitor-related acute major bleeding in patients enrolled for ANNEXA-4 in Japan., Methods: This prespecified analysis included patients enrolled at Japanese sites in the prospective, open-label, single-arm ANNEXA-4 trial. Eligible patients had major bleeding within 18 hours of oral FXa inhibitor administration. The coprimary efficacy endpoints were percent change in anti-FXa activity and proportion of patients achieving excellent or good hemostatic efficacy 12 hours post-treatment., Results: A total of 19 patients were enrolled, all of whom had intracranial hemorrhage; 16 patients were evaluable for efficacy. Median percent reduction in anti-FXa activity from baseline to nadir was 95.4% in patients taking apixaban, 96.1% in patients taking rivaroxaban, and 82.2% in patients taking edoxaban. Overall, 14/16 patients (88%) achieved excellent or good hemostasis (apixaban, 5/5; rivaroxaban, 6/7; edoxaban, 3/4). Within 30 days, treatment-related adverse events (AEs) and serious AEs occurred in 2 and 5 patients, respectively. One patient died during follow-up, and 2 patients experienced thrombotic events., Conclusion: Treatment with andexanet alfa rapidly reduced anti-FXa activity with favorable hemostatic efficacy in Japanese patients with acute major bleeding. Serious AEs of thrombotic events during rapid reversal of anti-FXa activity arose as particular safety concerns in this population as with previous studies.

Although the causes of neurodevelopmental disorders remain unknown, several environmental risk factors have attracted considerable attention. We conducted a retrospective, longitudinal, population-based cohort study using data from infant health examinations of children born to mothers with pregnancies between April 1, 2014 and March 31, 2016 in Kobe City to identify the perinatal factors associated with neurodevelopmental referrals in 3-year-old children. There were 15,223 and 1283 children in the normal and referral groups, respectively. Neurodevelopmental referrals at the health checkup for 3-year-old children were significantly associated with the lack of social support during pregnancy (adjusted odds ratio [aOR] 1.99, 99% CI 1.14-3.45, p = 0.001), history of psychiatric consultation (aOR 1.56, 99% CI 1.10-2.22, p = 0.001), no social assistance post-delivery (aOR 1.49, 99% CI 1.03-2.16, p = 0.006), Edinburgh Post-natal Depression Scale (EPDS) score ≥ 9 (aOR 1.36, 99% CI 1.01-1.84, p = 0.008), infant gender (male) (aOR 2.51, 99% CI 2.05-3.06, p < 0.001), and cesarean delivery (aOR 1.39, 99% CI 1.11-1.75, p < 0.001). In conclusion, this exploratory study in the general Japanese population identified six perinatal factors associated with neurodevelopmental referrals in 3-year-old children: infant gender (male), cesarean section, maternal history of psychiatric consultation, EPDS score ≥ 9, lack of social support during pregnancy, and no social assistance post-delivery., (© 2024. The Author(s).)

The objective of this study was to analyze death and culling (DC) of calves during the first month of life and associated economic losses on dairy farms in eastern Hokkaido, Japan. The DC in the first month of life of 4411 Holstein and Wagyu crossbred calves born in the year 2019-2020 on 39 dairy farms milking Holsteins was investigated. Based on a target DC rate of 6.75%, farms were classified into two groups, those with high DC rates (HDC, 11.68%, n = 18) and those with low DC rates (LDC, 2.67%, n = 21), and analyzed for DC factors (breed, sex, parity of dams, and housing type of dams) and diseases causing DC, their loss estimates, and replenishment of DC calves (birth rate, purchase of heifers, and housing type of dams). Comparisons between groups were made using the Kaplan-Meier method, the Mann-Whitney U test, and chi-square test. The DC rate of Holsteins was significantly higher (P < 0.001) for HDC farms than for LDC ones. But, the DC rate of Wagyu crossbreds was not different between the groups, which suggested hybrid vigor. The DC rates for digestive diseases were significantly higher (P < 0.01) in the HDC farms, except for congenital diseases and deaths of unknown cause. The overall loss estimates of DC per calf-month for all farms was 8892, JPY/calf-months, 14,726 for HDC farms, and 4065 for LDC farms. The loss estimates of items with significant differences in DC rates were significantly higher (P < 0.05) in the HDC farms, with higher loss estimates for Holsteins and digestive diseases being the most common characteristics of HDC farms. In binomial logistic regression analysis with "HDC farms or not" as the response variable and replenishment of DC calves as the explanatory variable, HDC was significantly more likely (OR: 1.10, P < 0.05) on farms with a higher birth proportion of Holsteins, and HDC farms supplemented the DC calves by increasing the birth proportion of Holsteins., Competing Interests: Declaration of Competing Interest The authors declare that this study is not supported by any special funds., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

In Japan, where vehicles drive on the left side of the road, pedestrian fatal accidents caused by vehicles traveling at speeds of less than or equal to 20 km/h, occur most frequently when a vehicle is turning right. The objective of the present study is to clarify the driving behavior in terms of eye glances and driver speeds when drivers of two different types of vehicles turn right at an intersection on a left-hand traffic road. We experimentally investigated the drivers' gaze, vehicle speed, and distance on the vehicle traveling trajectory from the vehicle to the pedestrian crossing line, using a sedan and a truck with a gross vehicle weight of < 7.5 tons (a light-duty truck) during right-turn maneuver. We considered four different conditions: no pedestrian dummy (No-P), right pedestrian dummy (R-P), left pedestrian dummy (L-P), and right and left pedestrian dummies (RL-P). Regarding the gazing characteristics, there was no significant difference in the average total gaze time at each AOI between the two vehicles under different conditions, which suggests that the total gaze time was not affected by the vehicle type. All participants gazed at the pedestrian dummies in R-P, L-P, and RL-P. However, the average total gaze time at the right pedestrian dummy (0.63-0.72 s) in R-P was significantly shorter than that at the left pedestrian dummy (1.46-1.57 s) in L- P for both vehicles. The average vehicle speed at the entrance line to the intersection (L1) of the light-duty truck (16.8-18.2 km/h) was lower than that of the sedan (18.8-19.7 km/h). The average vehicle speed at the pedestrian crossing line (L0) of the light-duty truck (15.5-16.0 km/h) was lower than that of the sedan (16.0-17.8 km/h). There was no significant difference in the average vehicle speeds at L1 and L0 between them under any two conditions. We investigated the estimated time to collision (TTC), calculated from the distance on the vehicle traveling trajectory from the vehicle to the pedestrian crossing line and the vehicle speed at the moment when the drivers first gazed at the pedestrian dummies. The average TTC of the right pedestrian dummy in R-P for the sedan (3.5 s) was significantly shorter than that for the light-duty truck (4.0 s). Similarly, the average TTC of the left pedestrian dummy in L-P for the sedan (3.7 s) was significantly shorter than that for the light-duty truck (4.8 s). The driving characteristics obtained in this study may contribute to the development of advanced driver support systems, particularly for vehicles turning right at intersections.

Aims: Lipoprotein(a) [Lp(a)] is a plasma lipoprotein consisting of a low-density lipoprotein (LDL)-like particle with apolipoprotein (Apo)(a), attached via a disulfide bond to Apo B100. Previous studies have shown that high Lp(a) levels are associated with an increased risk of cardiovascular disease in patients with familial hypercholesterolemia (FH). To date, limited data are available as to distribution of Lp(a) in FH and associations of Lp(a) with other lipid profiles and cardiovascular disease. Our study aimed to investigate serum Lp(a) levels in relation to other lipid profiles and clinical conditions in the national largest-ever cohort of Japanese FH patients., Methods: This study is a secondary analysis of the Familial Hypercholesterolemia Expert Forum (FAME) Study that includes a Japanese nationwide cohort of FH patients. In 399 patients under treatment for heterozygous FH who had a baseline measurement of serum Lp(a), the present study examined the distribution of Lp(a) levels and associations of Lp(a) with other lipid profiles and clinical conditions including coronary artery disease (CAD)., Results: The distribution of Lp(a) was skewed to the right with a median of 20.8 mg/dL, showing a log-normal distribution. Serum Apo B and Apo E levels were positively associated with Lp(a) levels. Age-adjusted mean of Apo B was 8.77 mg/dL higher and that of Apo E was 0.39 mg/dL higher in the highest category (40+ mg/dL) of Lp(a) than in the lowest category (＜20 mg/dL). LDL-C levels did not show such an association with Lp(a) levels. A tendency towards a positive relationship between Lp(a) and prevalent CAD was observed in men., Conclusion: Our study demonstrated a distribution pattern of Lp(a) in Japanese FH patients and positive relationships of Lp(a) with Apo B and Apo E levels.

Aims: Familial hypercholesterolemia (FH) is characterized by high low-density lipoprotein (LDL) cholesterol levels, xanthomas including Achilles tendon thickening, and premature coronary artery disease (CAD). Carotid intima-media thickness (IMT) is a well-established surrogate marker for CAD in FH and Achilles tendon thickening is a specific physical finding in patients with FH. The objective of the present study was to identify factors associated with carotid IMT and Achilles tendon thickness in FH heterozygotes on lipid-lowering therapy. This study also aimed to examine the follow-up changes in carotid IMT and Achilles tendon thickness among them in the current real-world FH practice., Methods: The current study is a subanalysis of the Familial Hypercholesterolemia Expert Forum (FAME) Study. The severity of carotid atherosclerosis was assessed with the maximal and mean IMT using ultrasonography, and Achilles tendon thickness was measured using X-rays. The present study used 571 patients under medical treatment for heterozygous FH who had baseline measurements for maximal IMT (n=511), mean IMT (n=459), or Achilles tendon thickness (n=486). The IMT was measured annually, and Achilles tendon thickness was evaluated every two years., Results: Higher LDL cholesterol (LDL-C) level and lower HDL cholesterol (HDL-C) level were associated with greater maximal and mean IMT as well as greater Achilles tendon thickness. Achilles tendon thickness tended to be greater in patients who had a smoking history than in never-smokers. Maximal IMT and Achilles tendon thickness were significantly greater in patients with CAD than in those without. Additionally, lower HDL-C level and hypertension were associated with higher values of maximal and mean IMT, suggesting the importance of comprehensive risk management including reduced HDL-C and blood pressure control in FH care. In longitudinal observations, percentage changes in maximal IMT and mean IMT gradually increased during the observation period. In contrast, percentage changes in Achilles tendon thickness became progressively thinner throughout the observation period., Conclusions: We found a positive association between LDL-C levels and severity of carotid atherosclerosis in heterozygous FH patients on treatment. This observation suggests the insufficiency of lipid-lowering therapy and the presence of therapeutic inertia among clinicians in the real-world FH practice.

Aims: Familial hypercholesterolemia (FH) is a genetic disorder characterized by high serum levels of low-density lipoprotein (LDL)-cholesterol (LDL-C), tendon and skin xanthomas, and premature coronary artery disease (CAD). In Japan, detailed information on the current status of drug therapies for patients with FH has not been reported so far, and their efficacy and safety have not been clarified. After the introduction of ezetimibe, which can further reduce serum LDL-C levels on top of statins, the changes of management for FH patients with these drugs are of particular interest. The current study aimed to evaluate the clinical status of FH heterozygotes and homozygotes, especially focusing on the real-world lipid-lowering drug therapy, attained serum LDL-C levels, and cardiovascular events at registration and during the follow-up., Methods: The FAME Study enrolled 762 heterozygous (including 17 newly diagnosed cases) and 7 homozygous FH patients from hospitals and clinics nationwide. Diagnosis of FH was based upon the criteria defined in the Study Report in 2008 of the Research Committee on Primary Hyperlipidemia supported by Grants-in-Aid for Scientific Research from the Japanese Ministry of Health, Labor and Welfare. Data analysis was primarily carried on heterozygous FH patients., Results: Xanthoma or thickening of the Achilles tendon was observed in more than 80% of the patients. CAD was recorded in 23% of patients. Patients with parental and sibling CAD accounted for 47% and 24%, respectively. At baseline, patients without CAD who had LDL-C ＜100 mg/dL accounted for 12.3% and those with CAD who had attained the target (LDL-C ＜70 mg/dL) in the secondary prevention accounted for only 1.8%. In the multiple logistic analysis, male sex, age ＞40, heterozygous FH score ＞20, hypertension, and sibling CAD were significantly and positively associated with prevalent CAD, whereas serum HDL-cholesterol levels showed a significant inverse association with CAD. Patients treated with statin alone, statin＋ezetimibe, statin＋resin, or statin＋probucol accounted for 31.1%, 26.3%, 4.0%, and 3.7%, respectively. Patients treated with three-drug combination (statin＋ezetimibe＋resin or statin＋ezetimibe＋probucol) accounted for 7.5%. Statins and ezetimibe were used in 88.0% and 48.0% at the baseline, respectively. Although high-intensity statins were mainly prescribed, statin doses were much lower than those reported in Western countries. The addition of ezetimibe resulted in ~20% reduction in serum LDL-C. CAD was diagnosed in 17 patients with 21 episodes during follow-up. The Cox hazard model analysis demonstrated that male sex, CAD at the baseline, and parental CAD were related to the development of atherosclerotic cardiovascular disease (ASCVD) events. Furthermore, an increase in serum HDL-C was associated with a significant reduction of ASCVD events, while serum LDL-C and triglyceride levels were not related to ASCVD events., Conclusion: The prevalence of CAD in Japanese patients with heterozygous FH is still very high. In most of the cases, the target level of serum LDL-C was not achieved for primary and secondary prevention of CAD, suggesting that a more aggressive LDL-C lowering and appropriate management of residual risks are necessary.

Background: To assess the effects of Epstein-Barr virus (EBV) and human papillomavirus (HPV) infection on the tumor microenvironment, we examined the relationship between viral infection status, macrophage migration inhibitory factor (MIF), and tumor-associated macrophages in nasopharyngeal carcinoma (NPC)., Methods: A tissue microarray containing 150 cores from 90 patients with NPC and six with chronic inflammation was used. EBV and HPV status were detected using in situ hybridization with commercial EBER1 and HPV16/18 probes. Immunofluorescence double staining of MIF, pan-macrophage marker CD68, M1 macrophage marker CD11c, and M2 macrophage marker CD163 were analyzed using the same tissue microarray. The levels of these markers between NPC and inflammation cases and between tumor nests and stroma were compared. Correlations among these markers were analyzed., Results: We found EBER1(+) cases in 90% of NPC patients, including 10% EBV/HPV co-infection. M1 macrophages mainly infiltrated the tumor nest, while M2 macrophages infiltrated the tumor stroma. We found a significant positive correlation between EBER1 levels and MIF levels in tumor nests and a significant positive correlation between HPV16/18 and CD11c(+) cell levels in NPC tissues., Conclusions: It is suggested that MIF is associated with EBV, and M1 macrophage infiltration is affected by HPV status in NPC., (© 2021. The Author(s).)

The incidence of traffic accidents in Japan has been decreasing annually. Nineteen percent of all accidents involve bicycles, with 51 % of these accidents being at road crossing intersections. Therefore, to reduce the number of accidents, this study analyses driving and cycling characteristics and proposes suitable collisions prevention methods. First, the study measured traffic environment variables using video cameras at a target non-signalized intersection and analyzed the speed and time to intersection of bicycles and motor vehicles. Thus, 47 dangerous situations were observed via the video analysis, and most of these situations occurred when the vehicle's time to intersection ranged from 0.50 to 0.75 s and the bicycle's speed ranged from 2.0-3.0 m/s. Second, using the results of video camera analysis as experimental parameters (e.g., the speed and timing of the presence of the bicycle), this study conducted an experiment with a driving simulator to investigate the effect of warning drivers about the risk of collision. A driver support system was then utilized to provide acoustic and optical warnings to drivers. The experiments revealed that the motor vehicle time to the anticipated collision point (V-TTC) increased with the use of a driver support system. Significant differences between experiments with and without driver support systems were observed when the calculated time between the bicycle and the motor vehicle was 0.25 and 0.50 s. Therefore, when the calculated time was 0.25 and 0.50 s, a driver support system, indicating the presence of a bicycle, was effective in preventing an intersection collision., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The 238 Pu, 239+240 Pu, 241 Am, 242 Cm, 243+244 Cm and 90 Sr concentrations in seafloor surface sediments collected at three sampling stations off the Fukushima Daiichi Nuclear Power Plant (FDNPP) site during the period from 2012 to 2019 were determined to elucidate the impacts of the FDNPP accident onto their concentrations in coastal sediments and to discuss the sources of the measured radionuclides. The 239+240 Pu, 241 Pu and 241 Am concentrations and 240 Pu/ 239 Pu atom ratios in a sediment core were also determined to allow comparison of their inventories between this study and previously reported values and to identify the Pu sources. The 238 Pu, 239+240 Pu, 241 Am and 90 Sr concentrations showed no remarkable temporal variations; no significant increases in concentrations after the FDNPP accident were observed; these concentrations were comfortably within the previously reported concentration range; and no detectable 242 Cm and 243+244 Cm amounts were observed in surface sediments. The observed 238 Pu/ 239+240 Pu activity ratios were approximately two orders of magnitudes lower than those for the damaged FDNPP reactor core inventories and the observed values in terrestrial samples after the accident. The 239+240 Pu, 241 Pu and 241 Am inventories in the sediment core were 389 ± 5, 503 ± 33 and 214 ± 3 Bq m -2 , respectively. The 239+240 Pu inventory was about an order of magnitude greater than the expected cumulative deposition density of global fallout from atmospheric nuclear weapons testing due to an enhanced scavenging effect. The 240 Pu/ 239 Pu atom ratios in the sediment core ranged from 0.239 to 0.246 with a mean value of 0.242 ± 0.002; these ratios were clearly greater than the mean global fallout ratio of 0.18. The results for 238 Pu/ 239+240 Pu activity ratios and 240 Pu/ 239 Pu atom ratios reflected a mixture of global fallout and Pacific Proving Grounds (PPG) close-in fallout Pu rather than Fukushima accident-derived Pu. The sediment column inventory for 239+240 Pu originating from the PPG close-in fallout was calculated as 166 Bq m -2 , which corresponded to 43% of the total inventory. A significant amount of the PPG-derived Pu has been transported by ocean currents and then preferentially scavenged in the coastal waters of Japan., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Concentrations of 129 I and 127 I in kelps (Saccharina) collected from coastal waters off northern Japan were monitored from 2007 to 2019. During the 2007-2008 test operation of the Rokkasho nuclear fuel reprocessing plant, 129 I discharge from the plant increased, and the 129 I concentration and 129 I/ 127 I atom ratio in the kelps reached maxima of 42 μBq/g-dry and 264 × 10 -11 , respectively. By 2009, both had decreased by one order of magnitude. After the Fukushima Dai-ichi Nuclear Power Plant accident in 2011, the 129 I concentration and 129 I/ 127 I atom ratio in the kelps increased to 2.24 μBq/g-dry and 11.6 × 10 -11 , respectively. After 2012, the ratio in kelps decreased to (2.1-8.9) × 10 -11 , which is almost the same as the seawater value off Aomori Prefecture before the test operation. The 129 I/ 127 I atom ratio in kelps thus represents the ambient seawater ratio during the growth period of the kelps., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Nitrogen (N) resorption from senescing leaves enables plants to reuse N, thereby making them less dependent on current N uptake from the environment. Therefore, N resorption is important for survival and fitness, particularly for plants growing under low N supply. We studied N resorption from senescing leaves of 25 legumes and 25 nonlegumes in a temperate region of Japan to test the hypothesis that high N resorption has not evolved in legumes that fix atmospheric N 2 . The extent of N resorption was quantified by N resorption proficiency that is measured as the level to which leaf N concentration was reduced during senescence, i.e., the lower the senesced leaf N concentration, the lower the N loss through leaf fall and higher the N resorption proficiency. In support of the hypothesis, senesced leaf N concentration was higher in legumes than in nonlegumes, but there was considerable overlap between the groups. The higher senesced leaf N concentration of legumes was associated with a lower proportion of leaf N resorbed during senescence, particularly in species with higher leaf N concentrations. According to a hierarchical partitioning analysis, there was a large contribution of species to the total variance in the senesced leaf N concentration as opposed to a minor contribution of functional group (legume/nonlegume). This study reveals that legumes are not proficient at resorbing N from senescing leaves but that N 2 -fixation might not be the single most important determinant of N resorption.

Background: Evidence regarding the primary prevention of coronary artery disease events by low-density lipoprotein cholesterol (LDL-C) lowering therapy in older individuals, aged ≥75 years, is insufficient. This trial tested whether LDL-C-lowering therapy with ezetimibe is useful for the primary prevention of cardiovascular events in older patients., Methods: This multicenter, prospective, randomized, open-label, blinded end-point evaluation conducted at 363 medical institutions in Japan examined the preventive efficacy of ezetimibe for patients aged ≥75 years, with elevated LDL-C without history of coronary artery disease. Patients, who all received dietary counseling, were randomly assigned (1:1) to receive ezetimibe (10 mg once daily) versus usual care with randomization stratified by site, age, sex, and baseline LDL-C. The primary outcome was a composite of sudden cardiac death, myocardial infarction, coronary revascularization, or stroke., Results: Overall, 3796 patients were enrolled between May 2009 and December 2014, and 1898 each were randomly assigned to ezetimibe versus control. Median follow-up was 4.1 years. After exclusion of 182 ezetimibe patients and 203 control patients because of lack of appropriate informed consent and other protocol violations, 1716 (90.4%) and 1695 (89.3%) patients were included in the primary analysis, respectively. Ezetimibe reduced the incidence of the primary outcome (hazard ratio [HR], 0.66; 95% CI, 0.50-0.86; P =0.002). Regarding the secondary outcomes, the incidences of composite cardiac events (HR, 0.60; 95% CI, 0.37-0.98; P =0.039) and coronary revascularization (HR, 0.38; 95% CI, 0.18-0.79; P =0.007) were lower in the ezetimibe group than in the control group; however, there was no difference in the incidence of stroke, all-cause mortality, or adverse events between trial groups., Conclusions: LDL-C-lowering therapy with ezetimibe prevented cardiovascular events, suggesting the importance of LDL-C lowering for primary prevention in individuals aged ≥75 years with elevated LDL-C. Given the open-label nature of the trial, its premature termination and issues with follow-up, the magnitude of benefit observed should be interpreted with caution. Clinical Registration: URL: https://www.umin.ac.jp. Unique identifier: UMIN000001988.

Peripartum disorders in dairy cows negatively influence their productivity and reproductive performance. However, only a few reports have clearly indicated the influence of such disorders on the productivity and reproductive performance at a local-area or cow-level in Japan. This study aimed to elucidate the influence of diseases occurring within 60 days after calving on subsequent productivity and reproductive performance. Accordingly, a wide-area database on dairy production was used for epidemiological analysis; subsequently, multivariable analysis was performed to investigate the association of such diseases with productivity or reproductive performance in 6,545 cows from 178 farms in Fukuoka. We used 305-day energy-corrected milk (305 ECM) as an index of productivity and conception and culling as indices of reproductive performance. With regard to causality, mixed-effects model was used for analyzing the association between disease and productivity, and Cox proportional hazard model was used for analyzing the association between disease and reproductive performance. Compared to the disease absence group, the disease presence group demonstrated significantly lower 305 ECM [-154 kg; 95% confidence interval (CI), -229 to -79] and risk of pregnancy [hazard ratio (HR), 0.85; 95% CI, 0.80-0.91] and higher risk of culling (HR, 1.36; 95% CI, 1.17-1.59). These results indicate that, in Fukuoka, dairy cows affected by diseases within 60 days after calving exhibit lower productivity and reproductive performance. Therefore, proper dairy cow management during the peripartum period to prevent diseases during early lactation may maintain or improve productivity.

Objective: This study aimed to investigate the situational characteristics of fatal pedestrian accidents involving vehicles traveling at low speeds in Japan. We focused on vehicles with 4 or more wheels. Such characteristics included daytime or nighttime conditions, road type, vehicle behaviors preceding the accident, and vehicle impact locations. Methods: Pedestrian fatality data on vehicle-pedestrian accidents were obtained from the Institute for Traffic Accident Research and Data Analysis of Japan (ITARDA) from 2005 to 2014. Nine vehicle classifications were considered: Trucks with gross vehicle weight (GVW) ≥7.5 tons and <7.5 tons, buses, box vans, minivans, sport utility vehicles (SUVs), sedans, light passenger cars (LPCs), and light cargo vans (LCVs). We compared the situational daytime or nighttime conditions, road type, vehicle behaviors preceding the accident, and vehicle impact locations for accident-involved vehicles traveling at low and higher speeds across all vehicle types. Results: The results indicate that pedestrian fatalities involving vehicles traveling at low speeds occurred more often under daytime conditions across all vehicle types. At signalized intersections, the relative proportions of pedestrian fatalities were significantly higher when vehicles were traveling at low speed, except when the accidents involved box vans or SUVs. Similarly, when vehicles turned right, the relative proportions of pedestrian fatalities were significantly higher when vehicles traveling at low speed were involved across all vehicle types. In terms of the frontal right vehicle impact location, the relative proportions of pedestrian fatalities were significantly higher when trucks with GVW ≥7.5 tons or <7.5 tons, sedans, or LCVs traveling at low speed were involved. Conclusions: The situational characteristics of fatal pedestrian accidents involving vehicles traveling at low speeds identified in this study can guide targeted development of new traffic safety regulations or technologies specific to vehicle-pedestrian interactions at low vehicle travel speeds (i.e., driver alert devices or automated emergency braking systems). Ultimately, these developments can improve pedestrian safety by reducing the frequency or severity of vehicle-pedestrian accidents for vehicles turning right at intersections and/or reducing the number of resultant pedestrian fatalities.

Accident emergency calling systems (AECSs) are signaled by the deployment of airbags, which causes them to automatically emit information providing the location of the accident site to a public service answering party (PSAP). In some realworld accidents, airbags have failed to deploy. This study clarifies the factors that influence the nondeployment of front airbags in vehicle-vehicle collisions, investigating nondeployment of the driver-side front airbags in sedans and light passenger cars (LPCs) from Japanese accident data. The component rates of deployment for front airbags tend to be higher than those of nondeployment at higher values of pseudo-ΔV in vehicle-vehicle frontal impacts. For both sedans and LPCs, the transition zones between nondeployment and deployment of the front airbag occur at pseudo-ΔV values of 30-50 km/h (ΔV ≈ 21-35 km/h). For mutual impact locations where sedans and LPCs impact opponent vehicles at pseudo-ΔV ≥ 40 km/h (ΔV ≈ 28 km/h) in frontal impacts, the component rate of front airbag nondeployment is higher than that of deployment in right-to-right impacts. The results indicate that factors influencing front airbag nondeployment in vehicle-vehicle collisions are ΔV, impact offset configuration, and crossing angle. Considering front airbag nondeployment in real-world accidents, AECSs should have other functions, such as a manual button, to emit information in addition to automatic emission via airbag signaling.

Aims: The identification and appropriate management of commercial motor vehicle (CMV) drivers with unrecognized obstructive sleep apnea (OSA) is a major public health concern and priority; OSA among drivers has not been fully investigated in Japan, and a better understanding of this undiagnosed disease is warranted. Therefore, we evaluated the prevalence of OSA and the factors related to apnea-hypopnea index (AHI) in Japanese CMV drivers., Methods: This retrospective study included 1309 Japanese CMV drivers aged 40-69 years. All the subjects received type Ⅳ portable sleep monitors (PMs) with Epworth Sleepiness Scale (ESS) and a periodic health check including anthropometrical and laboratory measurements, and a questionnaire of medical history, smoking status, and life style, following which variables related to AHI were analyzed., Results: Of all the subjects, 23.9% had moderate to severe OSA (AHI ≥15). Age, body mass index (BMI), Log e HbA1c and diastolic blood pressure (DBP) showed significance with AHI in 1309 subjects. The following factors were found to have significant odds ratio (OR) for AHI of ≥15 in 1309 subjects: age, ESS, DBP, and Log e HbA1c., Conclusion: Notably, drivers with undiagnosed OSA exist. In these subjects, AHI was related to obesity, hypertension, and diabetes. For the early diagnosis and intervention of OSA, BMI, blood pressure, and HbA1c measurements may be helpful, particularly for drivers. Furthermore, when performing an objective assessment of the suspected OSA, evaluating these parameters during routine medical check-ups may be useful and feasible in the detection of drivers with latent OSA.

Background and Purpose: The effect of aspirin in primary prevention of stroke is controversial among clinical trials conducted in Western countries, and no data are available for Asian populations with a high risk of intracranial hemorrhage. The objective of this study was to evaluate the effect of aspirin on the risk of stroke and intracranial hemorrhage in the Japanese Primary Prevention Project (JPPP)., Methods: A total of 14 464 patients (age, 60-85 years) with hypertension, dyslipidemia, and diabetes mellitus participated and were randomized into 2 treatment groups: 100 mg of aspirin or no aspirin. The median follow-up period was 5.02 years., Results: The cumulative rate of fatal or nonfatal stroke was similar for the aspirin (2.068%; 95% confidence interval [CI], 1.750-2.443) and no aspirin (2.299%; 95% CI, 1.963-2.692) groups at 5 years; the estimated hazard ratio was 0.927 (95% CI, 0.741-1.160; P=0.509). Aspirin nonsignificantly reduced the risk of ischemic stroke or transient ischemic attack (hazard ratio, 0.783; 95% CI, 0.606-1.012; P=0.061) and nonsignificantly increased the risk of intracranial hemorrhage (hazard ratio, 1.463; 95% CI; 0.956-2.237; P=0.078). A Cox regression adjusted by the risk factors for all stroke, which were age >70 years, smoking, and diabetes mellitus, supported the above result., Conclusions: Aspirin did not show any net benefit for the primary prevention of stroke in elderly Japanese patients with risk factors for stroke, whereas age >70 years, smoking, and diabetes mellitus were risk factors for stroke regardless of aspirin treatment., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00225849., (© 2016 American Heart Association, Inc.)

A radioactivity measurement survey was carried out from 24 April 2008 to 3 June 2011 to determine the levels of plutonium isotopes and (240)Pu/(239)Pu atom ratios in the marine environments off the sites of commercial nuclear power stations around the Japanese islands; the sampling period extended to two months after the Fukushima Dai-ichi Nuclear Power Station accident. In our previous study (Oikawa et al., 2015), data on Pu isotopes and (241)Am in sediments have already been reported. In this study, we report those on Pu isotopes in seawater as well as sediments, and the characteristics of sediments in addition (e.g., ignition loss and biogenic opals). Concentrations of (239+240)Pu in seawater and bottom sediments remained nearly constant at all sampling locations during the survey period. In addition, no regional differences were observed in the (239+240)Pu concentrations in surface waters. Higher (239+240)Pu concentrations were found in bottom waters at deeper sampling locations, but the (240)Pu/(239)Pu atom ratios were nearly constant regardless of the water depth. Higher (239+240)Pu concentrations were also found in bottom sediments at deeper sampling locations, but vice versa for (240)Pu/(239)Pu atom ratios as reported in the previous report. The sediments samples from deeper locations showed the higher percentage of ignition loss as well as the higher content of biogenic opal. There was likely to be some driving force participating in the transfer of Pu isotopes associated with biogenic substances to the deeper seabed. The present survey showed that the accident at the Fukushima Dai-ichi Nuclear Power Station did not contribute much to the inventory of Pu isotopes in the adjacent sea area., (Copyright © 2015. Published by Elsevier Ltd.)

Importance: Prevention of atherosclerotic cardiovascular diseases is an important public health priority in Japan due to an aging population., Objective: To determine whether daily, low-dose aspirin reduces the incidence of cardiovascular events in older Japanese patients with multiple atherosclerotic risk factors., Design, Setting, and Participants: The Japanese Primary Prevention Project (JPPP) was a multicenter, open-label, randomized, parallel-group trial. Patients (N = 14,464) were aged 60 to 85 years, presenting with hypertension, dyslipidemia, or diabetes mellitus recruited by primary care physicians at 1007 clinics in Japan between March 2005 and June 2007, and were followed up for up to 6.5 years, with last follow-up in May 2012. A multidisciplinary expert panel (blinded to treatment assignments) adjudicated study outcomes., Interventions: Patients were randomized 1:1 to enteric-coated aspirin 100 mg/d or no aspirin in addition to ongoing medications., Main Outcomes and Measures: Composite primary outcome was death from cardiovascular causes (myocardial infarction, stroke, and other cardiovascular causes), nonfatal stroke (ischemic or hemorrhagic, including undefined cerebrovascular events), and nonfatal myocardial infarction. Secondary outcomes included individual end points., Results: The study was terminated early by the data monitoring committee after a median follow-up of 5.02 years (interquartile range, 4.55-5.33) based on likely futility. In both the aspirin and no aspirin groups, 56 fatal events occurred. Patients with an occurrence of nonfatal stroke totaled 114 in the aspirin group and 108 in the no aspirin group; of nonfatal myocardial infarction, 20 in the aspirin group and 38 in the no aspirin group; of undefined cerebrovascular events, 3 in the aspirin group and 5 in the no aspirin group. The 5-year cumulative primary outcome event rate was not significantly different between the groups (2.77% [95% CI, 2.40%-3.20%] for aspirin vs 2.96% [95% CI, 2.58%-3.40%] for no aspirin; hazard ratio [HR], 0.94 [95% CI, 0.77-1.15]; P = .54). Aspirin significantly reduced incidence of nonfatal myocardial infarction (0.30 [95% CI, 0.19-0.47] for aspirin vs 0.58 [95% CI, 0.42-0.81] for no aspirin; HR, 0.53 [95% CI, 0.31-0.91]; P = .02) and transient ischemic attack (0.26 [95% CI, 0.16-0.42] for aspirin vs 0.49 [95% CI, 0.35-0.69] for no aspirin; HR, 0.57 [95% CI, 0.32-0.99]; P = .04), and significantly increased the risk of extracranial hemorrhage requiring transfusion or hospitalization (0.86 [95% CI, 0.67-1.11] for aspirin vs 0.51 [95% CI, 0.37-0.72] for no aspirin; HR, 1.85 [95% CI, 1.22-2.81]; P = .004)., Conclusions and Relevance: Once-daily, low-dose aspirin did not significantly reduce the risk of the composite outcome of cardiovascular death, nonfatal stroke, and nonfatal myocardial infarction among Japanese patients 60 years or older with atherosclerotic risk factors., Trial Registration: clinicaltrials.gov Identifier: NCT00225849.

Species niches are expected to differ between different functional groups and between species with different functional traits. However, it is still unclear how functional traits contribute to niche separation between species coexisting in a community and between sites along environmental gradients. We studied seasonal changes in light partitioning among coexisting species belonging to different functional groups in moorland plant communities at different altitudes. We estimated the lifetime light absorption per unit invested leaf biomass (ΦLleafmass) as a measure of the benefit/cost ratio of light acquisition. Evergreen species absorbed more light in spring, whereas deciduous species absorbed more light in summer. A similar tradeoff was also found between short and tall species within each functional group. As a result, evergreen and shorter species had comparable ΦLleafmass values to those of deciduous and taller species. Evergreen species had higher ΦLleafmass at higher altitudes relative to deciduous species, suggesting that evergreen habit is more advantageous for the lifetime light interception at higher altitudes. Our results demonstrate that phenological tradeoffs for light partitioning can contribute to the coexistence of species with different functional traits. Our results also reveal that the most advantageous traits differ depending on environment., (© 2014 The Authors. New Phytologist © 2014 New Phytologist Trust.)

This study aimed to identify the diagnostic characteristics associated with poor prognosis and mortality in dairy cows with acute clinical Escherichia coli mastitis. On 17 dairy farms, 24 dairy cows with acute E. coli mastitis that had received therapeutic treatment were categorized into 2 groups by outcome: 17 cows that recovered (survivors) and 7 cows that died or were euthanized (non-survivors). Two days after onset of acute E. coli mastitis, dysstasia was observed in non-survivors, but not in survivors. Compared with survivors, significantly increased hematocrit (HCT) values and non-esterified fatty acid (NEFA) concentrations, and significantly decreased antithrombin activity and platelet counts were found in non-survivors on days 2 and 3 after therapy. Dysstasia, associated with decreased antithrombin activity and platelet counts, and with increased HCT and NEFA concentrations, was considered to be the major prognostic indicator associated with high mortality after therapeutic treatment in acute E. coli mastitis.

To assess the migration patterns of radiocesium emitted from the Fukushima Dai-ichi Nuclear Power Plant (FDNPP), we analyzed (228)Ra/(226)Ra ratios and (7)Be concentrations and compared them with (134)Cs and (137)Cs concentrations in seawater samples collected within the Sea of Japan before and after the FDNPP accident (i.e., during the period 2007-2012) using low-background γ-spectrometry. The (228)Ra/(226)Ra ratios in surface waters exhibited lateral and seasonal variations, reflecting the flow patterns of surface water. This indicates the transport patterns of the FDNPP-derived radiocesium by surface water. Cosmogenic (7)Be (half-life: 53.3 d) exhibited markedly high concentrations (5-10 mBq/L) at depths shallower than 50 m, with concentrations decreasing steeply (0.2-2 mBq/L) at depths of 50-250 m. The distribution of (7)Be concentrations suggests that the downward delivery of the FDNPP-derived radiocesium to below 50 m depth was negligible for a few months prior to its removal from the Sea of Japan., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The first purpose of this study is to clarify the relation between the car impact velocity and pedestrian injury severity or mortality risk. We investigated the frequency of serious injuries and fatalities of pedestrians using vehicle-pedestrian accident data from the database of the Institute for Traffic Accident Research and Data Analysis (ITARDA) in Japan. The vehicle types considered are sedans, minivans, and box vans (ordinary automobiles) and light passenger cars and light cargo vans (light automobiles). The results revealed that a 10-km/h reduction in impact velocity could mitigate severe pedestrian injuries in cases involving impact velocities of 40 km/h or more for the five vehicle types analyzed. Specifically, if the impact velocity was 30 km/h or less, the frequency of serious injuries was less than 27% and the frequency of fatalities was less than 5% for the five vehicle types. Therefore, if the collision damage mitigation braking system (CDMBS) that uses a sensor to detect pedestrians can effectively reduce the impact velocity for various vehicle types, pedestrian injuries will be greatly mitigated. The second purpose of this study is to identify the factors that affect injury risk. Impact experiments were conducted in which a sedan impacted against a pedestrian full-scale dummy at 40 km/h and a pedestrian headform impactor was impacted against a road surface. The results indicated that the risk of pedestrian serious injury was significantly affected by multiple impact conditions, such as the pedestrian height, car impact velocity, car frontal shape, and car stiffness in cases where the car impacted the pedestrian's head, the degrees of influence of which were driven by the vehicle impact velocity.

Our method based on low background γ-spectrometry enabled the measurement of low radiocesium concentrations in only 20 L of seawater. In May 2011 after deposition of radiocesium, (134)Cs concentration in surface water within the Sea of Japan was confirmed to be significantly small (<0.1-1 mBq/L) by the method. The concentration was not detected (<0.1 mBq/L) below 50 m depth. The Fukushima-derived radiocesium migrated from the surface water of the Sea of Japan without advection to below the thermocline., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The historic spatiotemporal distribution of 137Cs in the seawaters and sea-floor sediments adjacent to nuclear power plants in Japan are summarized, using data obtained over a period of time more than 20 years prior to the disaster at the Fukushima Daiichi Nuclear Power Plant in 2011. Relatively uniform distributions of 137Cs were observed both in the surface seawaters (1 m in depth) and in deeper seawaters (10 to 30 m above the seabed and ranging from tens to hundreds of meters in depth) independent of the geographical position, although lower concentrations were observed in significantly deeper bottom seawaters. Conversely, there were wide variations in 137Cs levels between sediments, such that higher 137Cs concentrations were observed in the deeper sampling locations. A mathematical model describing the successive transfer of 137Cs from surface waters through deeper waters to sediments suggested that the transfer rate of 137Cs from deep water to the sediments, and the loss rate from bottom sediments, were both greater than the transfer rate from surface water to deeper water. It was found that the calculated regression lines for 137Cs depletion rates over time for surface waters, deeper waters, and sediments were approximately parallel when plotted on a semi-logarithmic coordinate system, regardless of the sampling location. A radionuclide depletion half-life was calculated to be 4 months to 16 years with the geometric mean of 2.22 y for the sediments in the Fukushima region, suggesting that nuclear contamination will be remediated over time through sediment redistribution processes such as remobilization, bioturbation, and migration due to sea currents., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Aim: Visceral fat accumulation plays an integral role in morbidity and mortality rates by increasing the risk of developing metabolic disorders such as type 2 diabetes, dyslipidemia, and hypertension. New genetic loci associated with fat distribution, measured by waist-hip ratios and computed tomography (CT), have recently been identified by genome-wide association studies in European-descent populations. This study used CT to investigate whether single nucleotide polymorphisms (SNPs) that confer susceptibility to fat distribution are associated with visceral fat area (VFA) and subcutaneous fat area (SFA) in the Japanese population., Methods: We measured the VFAs and SFAs of 1424 obese Japanese subjects (BMI≥25 kg/m(2), 635 men and 789 women) that were genotyped at 15 SNPs, namely, TBX15 rs984222, DNM3 rs1011731, LYPLAL1 rs4846567, GRB14 rs10195252, NISCH rs6784615, ADAMTS9 rs6795735, CPEB4 rs6861681, LY86 rs1294421, VEGFA rs6905288, RSPO3 rs9491696, NFE2L3 rs1055144, ITPR2 rs718314, HOXC13 rs1443512, ZNRF3 rs4823006 and THNSL2 rs1659258., Results: The G-allele of LYPLAL1 rs4846567 was borderline associated with an increased ratio of VFA to SFA (V/S ratio; p= 0.0020). LYPLAL1 rs4846567 had a stronger effect on the V/S ratio in women (p= 0.0078) than in men (p= 0.12); however, neither result was significant after Bonferroni correction for multiple comparisons. NISCH rs6784615 was nominally associated with increased VFA (p=0.040) and V/S ratio (p= 0.020). The other SNPs analyzed were not significantly associated with body mass index (BMI), VFA, or SFA., Conclusion: Our results suggest that LYPLAL1 rs4846567 and NISCH rs6784615 may influence fat distribution in the Japanese population.

Objective: The objective of this study is to evaluate the severe conditions between car-to-pedestrian near-miss situations using pedestrian time-to-vehicle (pedestrian TTV) which is the time when the pedestrian would reach the forward moving car line., Methods: Since the information available from the real-world accidents was limited, the authors focused on the near-miss situations captured by driving recorders installed in passenger cars. In their previous study, the authors found there were some similarities between accidents and near-miss incidents. It was made clear that the situations in pedestrians' accidents could be estimated from the near-miss incident data which included motion pictures capturing pedestrian behaviors. In their previous study, the vehicle time-to-collision (vehicle TTC) was investigated from the near-miss incident data. The authors analyzed data for 101 near-miss car-to-pedestrian incident events in which pedestrians were crossing the roads in front of a forward-moving car at an intersection or on a straight road. Using a video of near-miss car-to-pedestrian incidents captured by drive recorders and collected by the Society of Automotive Engineers of Japan (J-SAE) from 2005 to 2009, the pedestrian TTV was calculated. Based on the calculated pedestrian TTV, one of the severe conditions between car-to-pedestrian near-miss situations was evaluated for pedestrians who emerged from behind an obstruction such as a building, a parked vehicle and a moving vehicle., Results: Focusing on the cases of the pedestrians who emerged from behind an obstruction, the averages of the vehicle TTC and pedestrian TTV were 1.31 and 1.05 seconds, respectively, and did not demonstrate a significant difference. Since the averages of the vehicle TTC and pedestrian TTV were similar, there would be a higher possibility of the contact between a car and pedestrian if the driver and pedestrian were not paying any attention., Conclusions: The authors propose that a moving speed of a pedestrian surrogate "dummy" should be determined considering the near-miss incident situations for the evaluation of a CDMBS for pedestrian detection. The authors also propose that the time-to-collision of the dummy to the tested car during the evaluation of the performance of the CDMBS for pedestrian detection should be determined considering the time such as the vehicle TTC in this study. Additionally or alternatively, the pedestrian TTV should be considered, in which the worst situation was assumed for a car that was moving toward a pedestrian without braking due to the car driver's inattentiveness and the pedestrian not slowing down their walking speed or stopping.

Objective: Recently, TMEM127 was shown to be a new pheochromocytoma susceptibility gene; this is consistent with its function as a tumour suppressor gene (Journal of Clinical Endocrinology and Metabolism, 2009, 94, 2817). Most pheochromocytomas arise from the adrenal medulla, and in approximately half of the cases, the tumours are bilateral (Journal of Clinical Endocrinology and Metabolism, 2009, 94, 2817; Journal of the American Medical Association, 2004, 292, 943; Human Mutation, 2010, 31, 41; Science, 2009, 325, 1139). The aim of the present study was to determine whether TMEM127 mutations are involved in the pathogenesis of pheochromocytomas/paragangliomas in Japanese subjects., Patients and Methods: For this study, 74 unrelated patients with pheochromocytoma/paraganglioma who tested negative for mutations and deletions in RET, VHL, SDHB and SDHD were recruited through a multi-institutional collaborative effort in Japan. The TMEM127 gene sequence was determined in their germline DNA, and tumour DNA was analysed for the loss of heterozygosity. In addition, their TMEM127 gene sequences were compared with sequences from 114 normal healthy, ethnically matched controls., Results: Among the 74 eligible patients, two unrelated patients (2·7%) with bilateral adrenal pheochromocytoma were found to have an identical germline TMEM127 mutation (c.116&#95;119delTGTC, p.Ile41ArgfsX39) associated with 2q deletion loss of heterozygosity, which was also previously described in a Brazilian case (Journal of the American Medical Association, 2004, 292, 943). We also determined that none of the 114 normal healthy controls had this deletion mutation., Conclusion: This is the first report showing that TMEM127 mutation plays a pathological role in pheochromocytoma in an Asian population. Although our surveillance is limited, the prevalence and the phenotype of this gene mutation appear to be similar to those reported in previous studies., (© 2012 Blackwell Publishing Ltd.)

Aim: The Japan EPA Lipid Intervention Study (JELIS) reported a 19% reduction of the risk for coronary artery disease after long-term use of pure eicosapentaenoic acid (EPA) in Japanese patients with hypercholesterolemia. The variation in plasma fatty acid composition influenced the risk of coronary events. The aim of this study was to examine in JELIS participants the possible correlation of changes in plasma fatty acids with those of serum lipids., Methods: The coefficient for the correlation between the absolute change in plasma fatty acid concentrations and the changes in serum lipids was calculated in 13,901 JELIS participants., Results: Low-density lipoprotein (LDL) cholesterol exhibited a positive correlation with docosahexaenoic acid (DHA; r=0.117 in control group, r=0.155 in EPA group) and linoleic acid (r=0.139 in control group, r=0.177 in EPA group), but the correlation coefficients with EPA (r=0.097 in control group, r=-0.032 in EPA group) were less than 0.1. We distributed the patients into 9 groups according to tertiles of the change in EPA and DHA. The average absolute decrease of LDL cholesterol and L/H ratio in each group was significantly smaller (p<0.001) in the DHA-high tertile, but not in any EPA tertile., Conclusion: The changes in DHA, but not in EPA, showed a positive correlation with the changes in LDL-cholesterol.

Aim: The present study examined the importance of reducing non-high-density lipoprotein cholesterol (non-HDL-C) for the primary prevention of the occurrence of coronary artery disease (CAD) in the JELIS, and the effects of EPA., Methods: The patients were distributed into 4 subgroups using the lipid management goal for LDL-C recommended by the Japan Atherosclerosis Society guideline (2007) and the goal for non-HDL-C defined as 30 mg/dL higher than LDL-C: A) achieved both goals; B) achieved the LDL-C but not non-HDL-C goal; C) achieved the non-HDL-C but not LDL-C goal; and D) did not attain either goal. The incidences of CAD in the 4 subgroups were compared, and the effects of eicosapentaenoic acid (EPA) on the risk of CAD in these subgroups were examined., Results: In the non-EPA group, the incidence of CAD in patients who did not achieve the goals for LDL-C or non-HDL-C was higher than in patients who achieved those goals. Patients in subgroups B, C, and D were at higher risk for CAD than those in subgroup A (B, HR 2.31; C, HR 1.90; D, HR 2.47). EPA reduced the risk of CAD by 38% in subgroups B, C, and D (p= 0.007)., Conclusion: We reconfirmed non-HDL-C as a predictor of the risk for CAD and a residual risk marker of CAD after LDL-C-lowering therapy. EPA was useful to reduce the occurrence of CAD in patients who did not achieve the goals for LDL-C and/or non-HDL-C.

Familial hypercholesterolemia (FH) is a highly prevalent autosomal dominant hereditary disease, generally characterized by three major signs, hyper-low-density-lipoprotein (LDL) cholesterolemia, tendon/skin xanthomas and premature coronary artery disease (CAD). Because the risk of CAD is very high in these patients, they should be identified at an early stage of their lives and started on intensive treatment to control LDL-cholesterol. We here introduce a new guideline for the management of FH patients in Japan intending to achieve better control to prevent CAD. Diagnostic criteria for heterozygous FH are 2 or more of 1) LDL-cholesterol ≥180 mg/dL, 2) tendon/skin xanthoma(s), and 3) family history of FH or premature CAD within second degree relatives, for adults; and to have both 1) LDL-cholesterol ≥140 mg/dL and 2) family history of FH or premature CAD within second degree relatives, for children. For the treatment of adult heterozygous FH, intensive lipid control with statins and other drugs is necessary. Other risks of CAD, such as smoking, diabetes mellitus, hypertension etc., should also be controlled strictly. Atherosclerosis in coronary, carotid, or peripheral arteries, the aorta and aortic valve should be screened periodically. FH in children, pregnant women, and women who wish to bear a child should be referred to specialists. For homozygotes and severe heterozygotes resistant to drug therapies, LDL apheresis should be performed. The treatment cost of homozygous FH is authorized to be covered under the program of Research on Measures against Intractable Diseases by the Japanese Ministry of Health, Labour, and Welfare.

Visceral fat accumulation has an important role in increasing the morbidity and mortality rates, by increasing the risk of developing several metabolic disorders, such as type 2 diabetes, dyslipidemia and hypertension. New genetic loci that are associated with increased systolic and diastolic blood pressures have been identified by genome-wide association studies in Caucasian populations. This study investigates whether single nucleotide polymorphisms (SNPs) that confer susceptibility to high blood pressure are also associated with visceral fat obesity. We genotyped 1279 Japanese subjects (556 men and 723 women) who underwent computed tomography for measuring the visceral fat area (VFA) and subcutaneous fat area (SFA) at the following SNPs: FGF5 rs16998073, CACNB2 rs11014166, C10orf107 rs1530440, CYP17A1 rs1004467, NT5C2 rs11191548, PLEKHA7 rs381815, ATP2B1 rs2681472 and rs2681492, ARID3B rs6495112, CSK rs1378942, PLCD3 rs12946454, and ZNF652 rs16948048. In an additive model, risk alleles of the CYP17A1 rs1004467 and NT5C2 rs11191548 were found to be significantly associated with reduced SFA (P=0.00011 and 0.0016, respectively). When the analysis was performed separately in men and women, significant associations of rs1004467 (additive model) and rs11191548 (recessive model) with reduced VFA (P=0.0018 and 0.0022, respectively) and SFA (P=0.00039 and 0.00059, respectively) were observed in women, but not in men. Our results suggest that polymorphisms in the CYP17A1 and NT5C2 genes influence a reduction in both visceral and subcutaneous fat mass in Japanese women.

A decrease in high density lipoprotein-cholesterol (HDL-C) is a strong risk factor for atherosclerotic disorders in Japan, probably more important than an increase in low density lipoprotein-cholesterol (LDL-C). While there are rational grounds for the argument that elevation of HDL-C leads to decreased risk, there has as yet been no direct evidence of such an effect. If elevation of HDL-C decreases the risk, this effect is expected throughout the normal range of HDL-C or perhaps even higher than that. Simulation based on epidemiological data indicated that it may eventually reduce the incidence of ischemic heart disease by 60-70% in Japan. In the risk management guideline, "low" HDL-C is presently defined as 40 mg/dL or below. While there is no evidence that strongly urges a change in this definition, the results of epidemiological studies support "The higher the HDL-C level, the lower the risk,"even in the "normal range". Elevation of the HDL-C level may reduce the risk, probably at least up to 70 mg/dL; however, there are no supportive data for this effect still being obtained over 80 mg/dL. Patients with homozygous CETP deficiency should be followed-up while controlling other risk factors, so as not to dismiss the possibility of a risk increase with an extremely elevated HDL-C level.

Aim: Heterozygous patients of familial hypercholesterolemia (FH) are known to have a high risk of coronary artery disease (CAD). Early diagnosis and prompt treatment are necessary to prevent their CAD. In this study we tried to amend the Japanese diagnostic criteria of FH for general practitioners by examining each component of the current criteria., Methods: A multicenter study was performed, which included 1356 dyslipidemic patients at 6 centers. Pretreatment demographic information including LDL-cholesterol (LDL-C), Achilles tendon thickness (ATT), family history of FH and premature CAD and the result of genetic analysis were analyzed., Results: Of 1356 patients, 419 were diagnosed with FH by criteria in 1988, which were used as a golden standard. We tried to define FH according to 3 conventional major items, i.e., 1) LDL-C, 2) ATT and/or cutaneous nodular xanthomas (CX), 3) family history of FH and/or family history of premature CAD. We then determined the cutoff of LDL-C using the new criteria. When we used 180 mg/dL as the cutoff of LDL-C, 94.3% of FH patients and 0.85% of non-FH satisfied 2 or more criteria. When we used 190 mg/dL, 92.1% of FH and 0.85% of non-FH satisfied 2 or more criteria; therefore, we chose 180 mg/dL for the cutoff of LDL-C in the new criteria and proposed that the diagnosis of definite FH can be made if 2 or more criteria are satisfied., Conclusions: We examined each component for the diagnosis of heterozygous FH in a multicenter study in Japan.

Context: Risk factors for cardiovascular complications in Japanese patients with diabetes have not been fully elucidated., Objective: Our objective was to determine incidence of and risk factors for coronary heart disease (CHD) and stroke in Japanese diabetic patients., Design and Settings: We conducted a prospective study at 59 hospitals throughout Japan., Patients: Patients included 940 men and 831 women with type 2 diabetes (mean age, 58.2 yr) without a history of cardiovascular complications who were followed for a median of 7.86 yr., Intervention: This was an observational study., Main Outcome Measures: Incidence of CHD and stroke was evaluated., Results: Incidences of CHD and stroke per 1000 person-years were 9.59 and 7.45, respectively, whereas those of myocardial and brain infarctions were 3.84 and 6.29, respectively. Multivariate Cox analysis revealed that the serum log-transformed triglyceride level was a potent and independent predictor of CHD [hazard ratio (HR) = 1.54; 95% confidence interval (CI) = 1.22-1.94 per 1 sd increase), comparable to low-density lipoprotein (LDL) cholesterol (HR = 1.49; 95% CI = 1.25-1.78 per 1 sd increase). Triglycerides and LDL cholesterol linearly and continuously increased CHD risk, and subjects in the top third for both had markedly high risks of CHD, and their effects were possibly additive. However, serum triglycerides worked independently of blood pressure levels. Systolic blood pressure was the only significant predictor for stroke except for age (HR = 1.31; 95% CI = 1.04-1.65, per 1 sd increase)., Conclusions: In Japanese patients with type 2 diabetes, the serum triglyceride level was a leading predictor of CHD, comparable to LDL cholesterol. Because the serum triglyceride level is not a leading predictor of CHD in diabetic subjects in Western countries, ethnic group-specific strategies for prevention of diabetic macroangiopathy may be indicated.

Visceral fat accumulation has an important role in increasing morbidity and mortality rate by increasing the risk of developing several metabolic disorders, such as type 2 diabetes, dyslipidemia and hypertension. New genetic loci that contribute to the development of obesity have been identified by genome-wide association studies in Caucasian populations. We genotyped 1279 Japanese subjects (556 men and 723 women), who underwent computed tomography (CT) for measuring visceral fat area (VFA) and subcutaneous fat area (SFA), for the following single-nucleotide polymorphisms (SNPs): NEGR1 rs2815752, SEC16B rs10913469, TMEM18 rs6548238, ETV5 rs7647305, GNPDA2 rs10938397, BDNF rs6265 and rs925946, MTCH2 rs10838738, SH2B1 rs7498665, MAF rs1424233, and KCTD15 rs29941 and rs11084753. In the additive model, none of the SNPs were significantly associated with body mass index (BMI). The SH2B1 rs7498665 risk allele was found to be significantly associated with VFA (P=0.00047) but not with BMI or SFA. When the analysis was performed in men and women separately, no significant associations with VFA were observed (P=0.0099 in men and P=0.022 in women). None of the other SNPs were significantly associated with SFA. Our results suggest that there is a VFA-specific genetic factor and that a polymorphism in the SH2B1 gene influences the risk of visceral fat accumulation.

Aim: The Japan EPA Lipid Intervention Study (JELIS) was the first prospective randomized clinical trial to demonstrate prevention of coronary events by pure eicosapentaenoic acid (EPA). The aim of this study was to examine the relationships between various plasma fatty acid concentrations and the risk of coronary events in JELIS participants., Methods: In 15,534 participants, we calculated the hazard ratio for major coronary events (sudden cardiac death, fatal or nonfatal myocardial infarction, unstable angina pectoris, and angioplasty/stenting or coronary artery bypass grafting) relative to the on-treatment average level of plasma fatty acids with the Cox proportional hazard model., Results: As a result of EPA intervention, the plasma EPA concentration increased, but the docosahexaenoic acid (DHA) concentration did not. The other fatty acids measured decreased slightly. The higher plasma level of EPA (hazard ratio=0.83, p=0.049, in all participants and hazard ratio=0.71, p=0.018, in the EPA intervention group), but not of DHA, was inversely associated with the risk of major coronary events. The associations between other fatty acids and the risk of major coronary events were not significant. In all JELIS participants, the risk of major coronary events was significantly decreased (20%) in the group with high (150 µg/mL or more) on-treatment plasma EPA concentration compared with that in the low (less than 87 µg/mL) group., Conclusion: The risk of coronary artery disease is influenced by variations in plasma fatty acid composition. Among n-3 polyunsaturated fatty acids, EPA and DHA exhibited differences in the correlation with the risk of major coronary events.

Aim: We previously reported that obesity (defined as a body mass index (BMI) >or=25 kg/m(2)) was not an independent risk factor for coronary heart disease (CHD) in hypercholesterolemic patients without a history of CHD from the Japan Lipid Intervention Trial (J-LIT). In this study, the obese J-LIT subgroup was further analyzed to assess CHD risk., Methods: In the J-LIT study, patients received simvastatin treatment (usually at 5 mg/day) for 6 years. A total of 38,385 patients (mean age: 57.7+/-7.9, 12,111 men) without prior CHD and/or stroke were analyzed., Results: In this cohort, 181 CHD (acute myocardial infarction or sudden cardiac death) were observed. Obesity (n=12,929) was not an independent risk factor for CHD (relative risk; 1.18, 95% confidence interval; 0.87?1.59) after adjustment for the major risk known factors, such as age, sex, hypertension, diabetes mellitus (DM), and smoking. However, blood pressure, triglycerides, and fasting plasma glucose all increased, while high-density lipoprotein-cholesterol decreased, with increased BMI. The percentage of patients having two or three risk factors (such as dyslipidemia, hypertension, and DM) also increased with increased BMI., Conclusions: Obesity was not an independent risk factor for CHD in hypercholesterolemic patients on statin therapy; however, it is important to control obesity, a condition in which CHD risks accumulate, in order to improve associated risk factors along with the treatment of each risk factor, thus further reducing the risk of CHD.

Aims/hypothesis: The aim of the study was to clarify whether a therapeutic intervention focused on lifestyle modification affected the incidence of vascular complications in patients with established diabetes., Methods: A total of 2,033 eligible Japanese men and women aged 40-70 years with type 2 diabetes from 59 institutes were randomised to a conventional treatment group (CON), which continued to receive the usual care, and a lifestyle intervention group (INT), which received education on lifestyle modification regarding dietary habits, physical activities and adherence to treatment by telephone counselling and at each outpatient clinic visit, in addition to the usual care. Randomisation and open-label allocation were done by a central computer system. Primary analysis regarding measurements of control status and occurrence of macro- and microvascular complications was based on 1,304 participants followed for an 8 year period., Results: Although status of control of most classic cardiovascular risk factors, including body weight, glycaemia, serum lipids and BP, did not differ between groups during the study period, the incidence of stroke in the INT group (5.48/1,000 patient-years) was significantly lower than in the CON group (9.52/1,000 patient-years) by Kaplan- Meier analysis (p=0.02 by logrank test) and by multivariate Cox analysis (HR 0.62, 95% CI 0.39-0.98, p=0.04). The incidence of CHD, retinopathy and nephropathy did not differ significantly between groups. Lipoprotein(a) was another significant independent risk factor for stroke., Conclusions/interpretation: These findings suggest that lifestyle modification had limited effects on most typical control variables, but did have a significant effect on stroke incidence in patients with established type 2 diabetes., Clinical Trial Registration: UMIN-CTR C000000222, Funding: The Ministry of Health, Labour and Welfare, Japan

There is evidence that the obesity phenotype in the Caucasian populations is associated with variations in several genes, including neuronal growth regulator 1 (NEGR1), SEC16 homolog B (SCE16B), transmembrane protein 18 (TMEM18), ets variant 5 (ETV5), glucosamine-6-phosphate deaminase 2 (GNPDA2), prolactin (PRL), brain-derived neurotrophic factor (BDNF), mitochondrial carrier homolog 2 (MTCH2), Fas apoptotic inhibitory molecule 2 (FAIM2), SH2B adaptor protein 1 (SH2B1), v-maf musculoaponeurotic fibrosarcoma oncogene homolog (MAF), Niemann-Pick disease, type C1 (NPC1), melanocortin 4 receptor (MC4R) and potassium channel tetramerisation domain containing 15 (KCTD15). To investigate the relationship between obesity and these genes in the Japanese population, we genotyped 27 single-nucleotide polymorphisms (SNPs) in 14 genes from obese subjects (n=1129, body mass index (BMI) > or =30 kg m(-2)) and normal-weight control subjects (n=1736, BMI <25 kg m(-2)). The SNP rs10913469 in SEC16B (P=0.000012) and four SNPs (rs2867125, rs6548238, rs4854344 and rs7561317) in the TMEM18 gene (P=0.00015), all of which were in almost absolute linkage disequilibrium, were significantly associated with obesity in the Japanese population. SNPs in GNPDA2, BDNF, FAIM2 and MC4R genes were marginally associated with obesity (P<0.05). Our data suggest that some SNPs identified by genome-wide association studies in the Caucasians also confer susceptibility to obesity in Japanese subjects.

Background: JELIS was a large-scale clinical trial that investigated the effects of eicosapentaenoic acid (EPA) on coronary artery disease (CAD). In this paper, the data of patients registered in JELIS were analysed to compare the incidence of CAD between patients with impaired glucose metabolism (IGM) and normoglycemic (NG) patients. The effect of EPA on the incidence of CAD in patients with IGM was also assessed., Methods: The 18,645 hypercholesterolemic patients registered in JELIS were divided into two groups. One group consisted of patients with IGM (n=4565), which included the patients who had diabetes mellitus and patients who had a fasting plasma glucose of 110mg/dL or higher, either at the time of registration or after 6 months. The other group consisted of NG patients (n=14,080). CAD incidence of the two groups over the average 4.6-year follow-up period was compared, and the effect of EPA was assessed., Results: Compared to NG patients, IGM patients had a significantly higher CAD hazard ratio (1.71 in the non-EPA group and 1.63 in the EPA group). The treatment with EPA resulted in a 22% decrease in the CAD incidence (P=0.048) in IGM patients and an 18% decrease (P=0.062) in NG patients., Conclusions: It was found that the CAD risk in IGM patients is higher than in NG patients, and that highly purified EPA is very effective in decreasing the incidence of CAD among Japanese IGM patients, even though the intake of fish is high.