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Type 2 diabetes mellitus (T2DM) is a major cause of microvascular dysfunction. However, its effect on blood flow patterns during ischemic demand has not been adequately elucidated. In this study, we investigated the hypothesis that microvascular dysfunction in patients with T2DM manifests as brachial reactive hyperemia (BRH), defined as the ratio of peak blood flow velocities in a brachial artery before and after forearm cuff occlusion. The study enrolled 943 subjects (men, n = 152 [T2DM] and n = 371 [non-T2DM]; women, n = 107 [T2DM] and n = 313 [non-T2DM], respectively) with no history of cardiovascular disease. Semiautomatic measurements were obtained three times at 1.5-year intervals to confirm the reproducibility of factors involved in BRH for each sex. An age-adjusted mixed model demonstrated attenuated BRH in the presence of T2DM in both men (p = 0.022) and women (p = 0.031) throughout the study period. Post hoc analysis showed that the estimated BRH was significantly attenuated in patients with T2DM regardless of sex, except at baseline in women. In multivariate regression analysis, T2DM was a negative predictor of BRH at every measurement in men. For women, BRH was more strongly associated with alcohol consumption. Repeated measurements analysis revealed that T2DM was associated with attenuated postocclusion reactive hyperemia.

There are many studies about negotiation procedures for contract problems in supply chains. Several recent papers have considered a new negotiation procedure for a repurchase contract problem in a supply chain consisting of a manufacturer and a retailer. There, usually, are some wholesalers between a manufacturer and a retailer. Therefore, a supply chain including some wholesalers in addition to a manufacturer and a retailer should be considered. In this study, we call the supply chain in which three or more members are arranged in series the tandem supply chain. We, firstly, address a negotiation problem for a contract about wholesale and repurchase prices in the tandem supply chain in which three members, that is, a manufacturer, a wholesaler and a retailer are arranged in series. The whole contract in the tandem supply chain is composed of two contracts dependent mutually, i.e., the contract between the manufacturer and wholesaler and the contract between the wholesaler and retailer. The collaborative bargaining solution in the tandem supply chain consisting of three members is discussed. This paper, finally, formulates the tandem supply chain including several wholesalers.

Background: Elevated levels of triglyceride (TG) and non-high-density lipoprotein cholesterol (non-HDL-C) are regarded as a residual lipid risk in low-density lipoprotein cholesterol (LDL-C)-lowering therapy. This study investigated the association between lipid risk stratified by TG and non-HDL-C and the prognosis of patients with coronary artery disease (CAD), and the association between stratified lipid risk and flow-mediated dilatation (FMD) index. Methods and Results: The 624 CAD patients enrolled in flow-mediated dilation (FMD)-J study A were divided into 4 groups: low-risk group (n=413) with TG <150 mg/dL and non-HDL-C <170 mg/dL; hyper-TG group (n=180) with TG ≥150 mg/dL and non-HDL-C <170 mg/dL; hyper-non-HDL group (n=12) with TG <150 mg/dL and non-HDL-C ≥170 mg/dL; and high-risk group (n=19) with TG ≥150 mg/dL and non-HDL-C ≥170 mg/dL. Comparison of the groups showed the cumulative incidence of a 3-point major adverse cardiovascular event (MACE) was different and highest in the high-risk group in all the patients (P=0.009), and in patients with a FMD index ≥7.0% (P=0.021), but not in those with a FMD index <7.0%. Multivariable regression analysis showed that high lipid risk (P=0.019) and FMD <7.0% (P=0.040) were independently correlated with the incidence of a 3-point MACE. Conclusions: Novel stratification of lipid risk, simply using TG and non-HDL-C levels, combined with FMD measurement, is useful for predicting cardiovascular outcomes in patients with CAD.

Background: Elevated levels of triglyceride (TG) and non-high-density lipoprotein cholesterol (non-HDL-C) are regarded as a residual lipid risk in low-density lipoprotein cholesterol (LDL-C)-lowering therapy. This study investigated the association between lipid risk stratified by TG and non-HDL-C and the prognosis of patients with coronary artery disease (CAD), and the association between stratified lipid risk and flow-mediated dilatation (FMD) index. Methods and Results: The 624 CAD patients enrolled in flow-mediated dilation (FMD)-J study A were divided into 4 groups: low-risk group (n=413) with TG <150 mg/dL and non-HDL-C <170 mg/dL; hyper-TG group (n=180) with TG ≥150 mg/dL and non-HDL-C <170 mg/dL; hyper-non-HDL group (n=12) with TG <150 mg/dL and non-HDL-C ≥170 mg/dL; and high-risk group (n=19) with TG ≥150 mg/dL and non-HDL-C ≥170 mg/dL. Comparison of the groups showed the cumulative incidence of a 3-point major adverse cardiovascular event (MACE) was different and highest in the high-risk group in all the patients (P=0.009), and in patients with a FMD index ≥7.0% (P=0.021), but not in those with a FMD index <7.0%. Multivariable regression analysis showed that high lipid risk (P=0.019) and FMD <7.0% (P=0.040) were independently correlated with the incidence of a 3-point MACE. Conclusions: Novel stratification of lipid risk, simply using TG and non-HDL-C levels, combined with FMD measurement, is useful for predicting cardiovascular outcomes in patients with CAD.

There are many studies about negotiation procedures for contract problems in supply chains. Several recent papers have considered a new negotiation procedure for a repurchase contract problem in a supply chain consisting of a manufacturer and a retailer. There, usually, are some wholesalers between a manufacturer and a retailer. Therefore, a supply chain including some wholesalers in addition to a manufacturer and a retailer should be considered. In this study, we call the supply chain in which three or more members are arranged in series the tandem supply chain. We, firstly, address a negotiation problem for a contract about wholesale and repurchase prices in the tandem supply chain in which three members, that is, a manufacturer, a wholesaler and a retailer are arranged in series. The whole contract in the tandem supply chain is composed of two contracts dependent mutually, i.e., the contract between the manufacturer and wholesaler and the contract between the wholesaler and retailer. The collaborative bargaining solution in the tandem supply chain consisting of three members is discussed. This paper, finally, formulates the tandem supply chain including several wholesalers.

Background - Diagnostic criteria of flow-mediated vasodilation (FMD), an index of endothelial function, and nitroglycerin-induced vasodilation (NID), an index of vascular smooth muscle function, of the brachial artery have not been established. The purpose of this study was to propose diagnostic criteria of FMD and NID for normal endothelial function and normal vascular smooth muscle function. Methods and Results - We investigated the cutoff values of FMD and NID in subjects with (risk group) and those without cardiovascular risk factors or cardiovascular diseases (no-risk group) in 7277 Japanese subjects (mean age 51.4±10.8 years) from the Flow-Mediated Dilation Japan study and the Flow-Mediated Dilatation Japan Registry study for analysis of the cutoff value of FMD and in 1764 Japanese subjects (62.2±16.1 years) from the registry of Hiroshima University Hospital for analysis of the cutoff value of NID. Receiver-operator characteristic curve analysis of FMD to discriminate subjects in the no-risk group from patients in the risk group showed that the optimal cutoff value of FMD to diagnose subjects in the no-risk group was 7.1%. Receiver-operator characteristic curve analysis of NID to discriminate subjects in the no-risk group from patients in the risk group showed that the optimal cutoff value of NID to diagnose subjects in the no-risk group was 15.6%. Conclusions - We propose that the cutoff value for normal endothelial function assessed by FMD of the brachial artery is 7.1% and that the cutoff value for normal vascular smooth muscle function assessed by NID of the brachial artery is 15.6% in Japanese subjects.

Purpose: Klebsiella pneumoniae bacteremia is a critical clinical presentation that is associated with high mortality. However, extremely few studies have investigated the virulence factors related to mortality of K. pneumoniae bacteremia in patients. The present study elucidated clinical and virulence factors associated with the 30-day mortality of K. pneumoniae bacteremia at a tertiary hospital. / Methods: The medical records of 129 patients with K. pneumoniae bacteremia admitted to Osaka City University Hospital between January 2012 and December 2018 were retrospectively reviewed. Patient background characteristics, antimicrobial regimens, and prognosis were evaluated. Additionally, virulence factors were assessed using multiplex polymerase chain reaction to elucidate their association with K. pneumoniae....

A recent increase in the incidence of hypervirulent Klebsiella pneumoniae (hvKP) infections, especially those caused by a sublineage of the clonal group CG23 (CG23-I), is raising serious health concerns worldwide. The high virulence of hvKP is, at least in part, attributed to the overproduction of capsular polysaccharide (CPS), which is triggered by a positive regulator of capsular polysaccharide synthesis (cps) genes, named RmpA. Although extensive research has been conducted on the mechanisms ofhvKP virulence, no study has focused on the development of anti-virulence therapeutics....

Purpose: The incidence of infections caused by extended spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) has been recently increasing worldwide. ESBL-PE bacteremia has been associated with high mortality and has thus become a clinically critical issue. Accordingly, ESBL-PE strains with low susceptibility to piperacillin/tazobactam (PTZ) are a concern in clinical practice. This study aimed to assess the prognostic factors of patients with bacteremia due to ESBL-PE as well as the antimicrobial susceptibility, particularly to PTZ, among ESBL-PE strains. / Methods: A total of 65 patients with ESBL-PE bacteremia who were admitted to Osaka City University Hospital between January 2011 and April 2017 were enrolled and divided into the survivor group (n=52) and nonsurvivor group (n=13). The medical records of these patients were retrospectively reviewed....

A recent increase in the incidence of hypervirulent Klebsiella pneumoniae (hvKP) infections, especially those caused by a sublineage of the clonal group CG23 (CG23-I), is raising serious health concerns worldwide. The high virulence of hvKP is, at least in part, attributed to the overproduction of capsular polysaccharide (CPS), which is triggered by a positive regulator of capsular polysaccharide synthesis (cps) genes, named RmpA. Although extensive research has been conducted on the mechanisms ofhvKP virulence, no study has focused on the development of anti-virulence therapeutics....

Purpose: Klebsiella pneumoniae bacteremia is a critical clinical presentation that is associated with high mortality. However, extremely few studies have investigated the virulence factors related to mortality of K. pneumoniae bacteremia in patients. The present study elucidated clinical and virulence factors associated with the 30-day mortality of K. pneumoniae bacteremia at a tertiary hospital. / Methods: The medical records of 129 patients with K. pneumoniae bacteremia admitted to Osaka City University Hospital between January 2012 and December 2018 were retrospectively reviewed. Patient background characteristics, antimicrobial regimens, and prognosis were evaluated. Additionally, virulence factors were assessed using multiplex polymerase chain reaction to elucidate their association with K. pneumoniae....

Purpose: The incidence of infections caused by extended spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) has been recently increasing worldwide. ESBL-PE bacteremia has been associated with high mortality and has thus become a clinically critical issue. Accordingly, ESBL-PE strains with low susceptibility to piperacillin/tazobactam (PTZ) are a concern in clinical practice. This study aimed to assess the prognostic factors of patients with bacteremia due to ESBL-PE as well as the antimicrobial susceptibility, particularly to PTZ, among ESBL-PE strains. / Methods: A total of 65 patients with ESBL-PE bacteremia who were admitted to Osaka City University Hospital between January 2011 and April 2017 were enrolled and divided into the survivor group (n=52) and nonsurvivor group (n=13). The medical records of these patients were retrospectively reviewed....

Background: Circulating triglyceride (TG) levels are a current focus as a residual risk for cardiovascular (CV) events. We evaluated the relationship between circulating TG levels and future CV events in patients with coronary artery disease (CAD) who were treated with conventional therapy. Methods and Results: We analyzed data for 652 patients who were enrolled in the FMD-J Study A. We investigated the associations between serum TG levels and first major CV events (death from CV cause, nonfatal acute coronary syndrome (ACS), nonfatal stroke, and CAD) for a 3-year follow-up period. Patients were divided into 4 groups based on serum TG level: low-normal (<100 mg/dL), high-normal (100–149 mg/dL), borderline hypertriglyceridemia (150–199 mg/dL), and moderate hypertriglyceridemia (≥200 mg/dL). During a median follow-up period of 46.6 months, 14 patients died (9 from CV causes), 16 had nonfatal ACS, 6 had nonfatal stroke, and 54 had CAD. The Kaplan-Meier curves for first major CV event among the 4 groups were significantly different (P=0.04). After adjustment for various confounders, serum TG level ≥100 mg/dL were significantly associated with an increased risk of first major CV events compared with serum TG level <100 mg/dL. Conclusions: Serum TG level may be a surrogate marker for predicting CV events in patients with CAD.

Background The usefulness of vascular function tests for management of patients with a history of coronary artery disease is not fully known. Methods and Results We measured flow‐mediated vasodilation (FMD) and brachial–ankle pulse wave velocity (baPWV) in 462 patients with coronary artery disease for assessment of the predictive value of FMD and baPWV for future cardiovascular events in a prospective multicenter observational study. The first primary outcome was coronary events, and the second primary outcome was a composite of coronary events, stroke, heart failure, and sudden death. During a median follow‐up period of 49.2 months, the first primary outcome occurred in 56 patients and the second primary outcome occurred in 66 patients. FMD above the cutoff value of 7.1%, derived from receiver‐operator curve analyses for the first and second primary outcomes, was significantly associated with lower risk of the first (hazard ratio, 0.27; 95% confidence interval, 0.06–0.74; P=0.008) and second (hazard ratio, 0.32; 95% confidence interval, 0.09–0.79; P=0.01) primary outcomes. baPWV above the cutoff value of 1731 cm/s was significantly associated with higher risk of the first (hazard ratio, 1.86; 95% confidence interval, 1.01–3.44; P=0.04) and second (hazard ratio, 2.19; 95% confidence interval, 1.23–3.90; P=0.008) primary outcomes. Among 4 groups stratified according to the combination of cutoff values of FMD and baPWV, stepwise increases in the calculated risk ratio for the first and second primary outcomes were observed. Conclusions In patients with coronary artery disease, both FMD and baPWV were significant predictors of cardiovascular events. The combination of FMD and baPWV provided further cardiovascular risk stratification.

Background : Variations in assessments of medical students by faculty staff and standardized patients (SPs) have not been clarified by previous studies. We examined the concurrences and differences between and among these evaluators for medical students sitting the Post-Clinical Clerkship Objective Structured Clinical Examination (Post-CC OSCE). / Methods : The participants were 94 sixth-year Osaka City University Medical School students who were taking the Post-CC OSCE. They were each examined by three faculty staff and one or two SPs using a global assessment and six classified assessments. We analysed the average global/classified assessment scores for all 94 students, the average classified assessment scores for the students for whom differences exceeding 2 points between the average global assessment scores by the faculty staff and those by the SPs were not found, and those for the students for whom such differences were found using the Mann-Whitney U test....

Background : Variations in assessments of medical students by faculty staff and standardized patients (SPs) have not been clarified by previous studies. We examined the concurrences and differences between and among these evaluators for medical students sitting the Post-Clinical Clerkship Objective Structured Clinical Examination (Post-CC OSCE). / Methods : The participants were 94 sixth-year Osaka City University Medical School students who were taking the Post-CC OSCE. They were each examined by three faculty staff and one or two SPs using a global assessment and six classified assessments. We analysed the average global/classified assessment scores for all 94 students, the average classified assessment scores for the students for whom differences exceeding 2 points between the average global assessment scores by the faculty staff and those by the SPs were not found, and those for the students for whom such differences were found using the Mann-Whitney U test....

Objectives: To examine the longitudinal mutual association between endothelial dysfunction and arterial stiffness, and also to determine which of the two variables was more closely associated with the progression of subclinical organ damage. Methods: The brachial-ankle pulse wave velocity (baPWV), carotid intima-media thickness (CIMT), estimated glomerular filtration rate, microalbuminuria and flow-mediated vasodilatation of the brachial artery (FMD) were measured three times at 1.5-year intervals in 674 Japanese patients receiving antihypertensive treatment. Results: The change of the baPWV during the study period was larger in the subjects with baseline FMD values in the lowest tertile as compared to those with baseline FMD values in the highest tertile. The change of the CIMT was smaller in the subjects with baseline baPWV values in the lowest tertile than in those with baseline baPWV values in the highest tertile. After the adjustment, the FMD value at the baseline was inversely associated with the baPWV at the end of the study period (beta = − 0.07, p = 0.01), although, the reverse association was not significant. The baPWV, but not the FMD value, at the baseline was associated with the CIMT (beta = 0.06, p = 0.04) measured at the end of the study period. Conclusions: In hypertension, endothelial dysfunction was associated with the progression of arterial stiffness, although the reverse association was not confirmed. The increased arterial stiffness rather than endothelial dysfunction may be more closely associated with the progression of atherosclerotic vascular damage, and the endothelial dysfunction-arterial stiffness-atherosclerosis continuum may be important in hypertension.

Aims: For the standardization of flow-mediated vasodilatation (FMD) assessment as a clinical tool, validation of its reliability across multiple institutions and the establishment of normal/reference values based on reliable data from multiple institutions are needed. Methods and results: In Study 1, assessment of FMD (scan recording and analysis) using an ultrasonographic semi-automatic measuring system (sFMD) was conducted at 18 participating institutions (sFMD-INST) (n = 981). All of the brachial arterial scans were also analyzed at a core laboratory (sFMD-COLB). After 111 subjects with inadequate sFMD recordings were excluded (n = 880), the correlation between the sFMD-INST and sFMD-COLB improved from R = 0.725 to R = 0.838 (p < 0.001). In Study 2, based on good-quality sFMD data obtained from 6660 subjects without cardiovascular disease (CVD) and 729 subjects with CVD from 27 institutions, reference values of sFMD are proposed by the Framingham risk score (FRS)-based risk categories and according to gender and age. The receiver-operating characteristic curve analysis revealed a significant power of sFMD values in reference ranges to discriminate between subjects with and without CVD (e.g., area under curve = 0.64 in the FRS-low risk group). Conclusions: When the analysis was limited to cases with clear sFMD recordings, the reliability of the sFMD assessment (scan and its analysis) conducted in individual institutions appeared to be acceptable. Reference sFMD values (lower cuff occlusion) for the Japanese population are proposed based on reliable data derived from multiple institutions, and the reference values may identify patients without advanced vascular damage.

Aims: For the standardization of flow-mediated vasodilatation (FMD) assessment as a clinical tool, validation of its reliability across multiple institutions and the establishment of normal/reference values based on reliable data from multiple institutions are needed. Methods and results: In Study 1, assessment of FMD (scan recording and analysis) using an ultrasonographic semi-automatic measuring system (sFMD) was conducted at 18 participating institutions (sFMD-INST) (n = 981). All of the brachial arterial scans were also analyzed at a core laboratory (sFMD-COLB). After 111 subjects with inadequate sFMD recordings were excluded (n = 880), the correlation between the sFMD-INST and sFMD-COLB improved from R = 0.725 to R = 0.838 (p < 0.001). In Study 2, based on good-quality sFMD data obtained from 6660 subjects without cardiovascular disease (CVD) and 729 subjects with CVD from 27 institutions, reference values of sFMD are proposed by the Framingham risk score (FRS)-based risk categories and according to gender and age. The receiver-operating characteristic curve analysis revealed a significant power of sFMD values in reference ranges to discriminate between subjects with and without CVD (e.g., area under curve = 0.64 in the FRS-low risk group). Conclusions: When the analysis was limited to cases with clear sFMD recordings, the reliability of the sFMD assessment (scan and its analysis) conducted in individual institutions appeared to be acceptable. Reference sFMD values (lower cuff occlusion) for the Japanese population are proposed based on reliable data derived from multiple institutions, and the reference values may identify patients without advanced vascular damage., Atherosclerosis, 242(2), pp.433-442; 2015

Background : High-dose pergolide has been reported to induce valvular heart disease. It has not been fully determined whether valvular heart disease is elicited by low-dose pergolide, similar to high-dose pergolide in Japanese patients. / Methods : Fifty-two consecutive patients (20 males, mean age 70±7 years) with Parkinson's disease were enrolled in our study. Twenty-three patients had been treated with low-dose pergolide (less than 1.5 mg/day) before enrollment. Of these 23 patients, 8 had been treated with pergolide and L-dopa without other ergot-derived dopamine receptor agonists (OE) and defined as the pergolide group without OE (P without OE). Fifteen patients had been treated with pergolide, L-dopa, and OE and defined as the pergolide group with OE (P with OE). The other 29 patients had not been treated with pergolide. Of these 29 patients, ...

Background : High-dose pergolide has been reported to induce valvular heart disease. It has not been fully determined whether valvular heart disease is elicited by low-dose pergolide, similar to high-dose pergolide in Japanese patients. / Methods : Fifty-two consecutive patients (20 males, mean age 70±7 years) with Parkinson's disease were enrolled in our study. Twenty-three patients had been treated with low-dose pergolide (less than 1.5 mg/day) before enrollment. Of these 23 patients, 8 had been treated with pergolide and L-dopa without other ergot-derived dopamine receptor agonists (OE) and defined as the pergolide group without OE (P without OE). Fifteen patients had been treated with pergolide, L-dopa, and OE and defined as the pergolide group with OE (P with OE). The other 29 patients had not been treated with pergolide. Of these 29 patients, ...

Background : Abnormal left ventricular (LV) diastolic relaxation is an early sign of hypertensive heart disease. Whether diastolic dysfunction differs between LV geometric patterns remains controversial. / Methods and Results : We examined 220 hypertensive patients by echocardiography to assess the relationship between diastolic function and LV geometric pattern. We identified four LV geometric patterns: normal geometry, concentric remodeling, concentric hypertrophy, and eccentric hypertrophy. Diastolic function was evaluated by the E/A ratio, E wave deceleration time (Dct), and isovolumic relaxation time (IRT)....

Background : Abnormal left ventricular (LV) diastolic relaxation is an early sign of hypertensive heart disease. Whether diastolic dysfunction differs between LV geometric patterns remains controversial. / Methods and Results : We examined 220 hypertensive patients by echocardiography to assess the relationship between diastolic function and LV geometric pattern. We identified four LV geometric patterns: normal geometry, concentric remodeling, concentric hypertrophy, and eccentric hypertrophy. Diastolic function was evaluated by the E/A ratio, E wave deceleration time (Dct), and isovolumic relaxation time (IRT)....