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Abstract Background Direct oral anticoagulants (DOACs) are preferred for stroke prevention in nonvalvular atrial fibrillation (NVAF); however, warfarin is still used. This study examined why physicians may choose warfarin over DOACs and the associated safety outcomes in patients with NVAF. Methods We conducted a new‐user, active‐comparator cohort study in newly diagnosed patients with NVAF to assess safety outcomes after the introduction of DOACs in Japan. Results The median observation period was 1120 days; 1428 patients started anticoagulation therapy with warfarin and 1551 with DOACs. Warfarin was chosen for patients with lower creatinine clearance and left ventricular ejection fractions and those using aspirin and verapamil. The unadjusted risk of major bleeding was considerably higher in the warfarin group but was nonsignificant after adjusting for variables associated with the choice of warfarin, in addition to age and sex. The risk of death was higher in the warfarin group, even after adjustments for relevant variables. However, high‐risk subgroups, including those with older ages and multiple comorbidities, such as renal impairment, for whom warfarin was more likely to be selected, had severely compromised prognoses with either anticoagulant. The risk of stroke/systemic embolism was not significantly different between the two groups. Conclusions Warfarin is often chosen for older patients with multiple comorbidities characterized by reduced renal function, which is associated with a higher risk of major bleeding and mortality. These high‐risk patients seem to have a poor prognosis regardless of the type of anticoagulant used. Thus, safe anticoagulant therapy remains a challenge for such patients.

Background/Aims Metabolic dysfunction-associated steatotic liver disease (MASLD) was recently proposed as an alternative disease concept to nonalcoholic fatty liver disease (NAFLD). We aimed to investigate the prognosis of patients with biopsy-confirmed MASLD using data from a multicenter study. Methods This was a sub-analysis of the Clinical Outcome Nonalcoholic Fatty Liver Disease (CLIONE) study that included 1,398 patients with NAFLD. Liver biopsy specimens were pathologically diagnosed and histologically scored using the NASH Clinical Research Network system, the FLIP algorithm, and the SAF score. Patients who met at least one cardiometabolic criterion were diagnosed with MASLD. Results Approximately 99% of cases (n=1,381) were classified as MASLD. Patients with no cardiometabolic risk (n=17) had a significantly lower BMI than patients with MASLD (20.9 kg/m2 vs. 28.0 kg/m2, P

Abstract Aim Fracture‐related femoral neck displacement is more likely in patients with schizophrenia because of delayed diagnosis, as these patients frequently have less severe fracture‐associated subjective symptoms. This study aimed to investigate the association of schizophrenia with the risk of fracture‐related femoral neck displacement in hospitalized patients. Methods We retrospectively analyzed the medical records of patients with femoral neck fractures treated between April 2013 and March 2018 at a single institution. Multivariate logistic regression was used to explore the relationship between schizophrenia and fracture‐related femoral neck displacement after adjusting for risk factors. Results We compared 30 and 194 patients with and without schizophrenia, respectively. The prevalence of fracture‐related displacement was 80.0% in patients with schizophrenia and 62.4% in the controls (p = 0.06). After adjusting for confounding variables, schizophrenia significantly correlated with fracture‐related femoral neck displacement (odds ratio: 4.74, 95% confidence interval: 1.09–20.60, p = 0.0378). Conclusions Schizophrenia is associated with a higher risk of severe femoral neck fracture. To improve outcomes and alleviate the societal burden of femoral neck fractures, early radiographic assessment and surgical intervention for femoral fractures are essential for patients with schizophrenia, even in those without pain symptoms.

Abstract Background Anemia is encountered in patients with nonvalvular atrial fibrillation (NVAF) on oral anticoagulants (OACs) but the prognostic impact was not well scrutinized in real‐world settings. Methods We conducted a historical multicenter registry of patients with NVAF taking OACs at 71 centers in Japan. Those with mechanical heart valves or a history of pulmonary thrombosis or deep venous thrombosis were excluded. Anemic patients were divided into three groups of hemoglobin (Hb) level: moderate/severe (Hb

Background and Aims: Nonalcoholic fatty liver diseases (NAFLD) and nonalcoholic steatohepatitis (NASH) can cause hepatocellular carcinoma (HCC). We examined histological features and reported noninvasive markers/models for stratifying the risk of HCC development in patients with biopsy-proven NAFLD or NASH. Methods: A total of 1389 patients who had a histological diagnosis of NAFLD or NASH based on liver biopsy and underwent regular surveillance for HCC were included. The ability to predict HCC development was compared between histological features including liver fibrosis and NAFLD activity score, and noninvasive markers/models including aMAP (age, male, albumin–bilirubin, and platelet) score, FIB-4 (Fibrosis-4) index, and ALBI (albumin-bilirubin) score calculated at the time of biopsy. Results: The C index of aMAP score was 0.887, which was consistent with the original report, comparable to FIB-4 index (0.878), and higher than those of ALBI score (0.789), histological liver fibrosis (0.723), and NAFLD activity score (0.589). The hazard ratios for HCC development in the aMAP intermediate and high-risk groups were 21.0 (95% confidence interval [CI], 3.6–402.0) and 110.3 (95% CI, 16.3–2251.4), respectively, in comparison to the aMAP score low-risk group. Those in the FIB-4 index moderate- and high-fibrosis groups were 10.3 (95% CI, 1.7–199.8) and 93.1 (95% CI, 16.3–1773.8), respectively, in comparison to the FIB-4 index mild-fibrosis group. No patients in the aMAP score low-risk group developed HCC during the study period. Conclusion: For stratifying the risk of HCC development in patients with biopsy-proven NAFLD or NASH, both aMAP score and FIB-4 index showed high discriminative ability as noninvasive markers, which were superior histological features.

Although cardiovascular mortality in Japan is lower than in other industrialized countries, clinical outcomes in coronary artery disease (CAD) patients with type 2 diabetes mellitus (T2DM) remain poor despite multiple evidence-based drug therapies and interventions. We assumed that part of residual risk in these patients may be attributable to enhanced inflammation, which can be inhibited presumably by colchicine. However, dose-responsiveness of anti-inflammatory effect of colchicine has not been elucidated. Therefore, we designed a multicenter, randomized, double-blinded, parallel-group study to explore the dose-dependent effects of low-dose colchicine on serum high-sensitivity C-reactive protein (hs-CRP) concentration and safety in CAD patients with T2DM and enhanced inflammatory response as a phase 2 study. Enhanced inflammatory response was defined as peripheral white-blood cell count ≥7,000/μL. Patients (N = 63) will be randomly assigned to two doses of colchicine 0.25 mg/day, 0.5 mg/day, or placebo in a 1:1:1 ratio once daily for 12 weeks. Changes in serum hs-CRP levels will be evaluated as the primary endpoint, and changes in flow-mediated vasodilation and plasma myeloperoxidase levels will be evaluated as secondary endpoints. The results of this study will contribute to the development of a protocol for a planned future phase 3 trial to estimate the reduction in CAD. The present study describes the rationale, design, and methods of the trial.

Abstract Background Hepatojugular reflux is a cardiac physical examination with a long history of use in heart failure diagnosis across many clinical settings. However, the development of new diagnostic methods has thrown the clinical role of hepatojugular reflux into question. Our meta‐analysis aimed to determine the diagnostic accuracy of hepatojugular reflux and assess its usefulness in diagnosing congestive heart failure among at‐risk patients. Methods This meta‐analysis of studies reporting diagnostic hepatojugular reflux values of patients at risk for congestive heart failure followed PRISMA guidelines. We searched MEDLINE, EMBASE, Web of Science, CENTRAL, and Google Scholar for eligible studies from inception through February 1, 2021. After QUADAS‐2 quality assessment, we conducted data synthesis using the random effects model and a hierarchical summary receiver operating characteristic model. As an additional analysis, we sorted the studies by clinical setting and performed synthesis again. We submitted our protocol to PROSPERO (International Prospective Register of Systematic Reviews; ID No. CRD42020215004). Results The literature search provided 4121 studies for evaluation. Seven studies and their 5195 participants were deemed eligible for synthesis. Clinical diagnosis was the most frequent reference standard. Bivariate random‐effects analysis found hepatojugular reflux sensitivity of 0.12, 95% confidence interval (CI) [0.07–0.19], and specificity of 0.96, 95% CI [0.95–0.97]. The DOR was 29.7, 95% CI [18.4–45.3]. The additional analysis of the emergency settings provided a sensitivity of 0.14, 95% CI [0.12–0.17] and specificity of 0.95, 95% CI [0.93–0.96]. Conclusions Our meta‐analysis suggests that hepatojugular reflux has practical value for diagnosis of congestive heart failure with high specificity.

Abstract 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.

BackgroundWe compared the lowering effects of pemafibrate and omega-3 fatty acid ethyl on fasting apolipoprotein (apo) B-48 (apoB-48), a marker that reflects postprandial hypertriglyceridemia, which is one of the residual risks for atherosclerotic cardiovascular disease (ASCVD) with statin treatment.MethodsThis prospective, multicenter, open-label, randomized, parallel group trial was conducted at 4 medical institutions between April 2020 and May 2022. A total of 126 ambulatory patients with dyslipidemia receiving statin treatment for more than 4 weeks, aged 20–79 years with fasting triglyceride (TG) levels of ≥177 mg/dl were randomly assigned to 16-week pemafibrate 0.4 mg per day treatment group (PEMA, n = 63) or omega-3 fatty acid ethyl 4 g per day treatment group (OMEGA-3, n = 63). The primary endpoint was the percentage change in fasting apoB-48 from baseline to week 16.ResultsThe percentage changes in fasting apoB-48 in PEMA and OMEGA-3 were −50.8% (interquartile range −62.9 to −30.3%) and −17.5% (−38.3 to 15.3%) (P < 0.001), respectively. As the secondary endpoints, the changes in fasting apoB-48 in PEMA and OMEGA-3 were −3.10 μg/ml (−5.63 to −1.87) and −0.90 μg/ml (−2.95 to 0.65) (P < 0.001), respectively. Greater decreases with significant differences in the percentage changes in TG, remnant lipoprotein cholesterol, apoC-III, fasting plasma glucose, alanine aminotransferase, gamma-glutamyl transpeptidase, and alkaline phosphatase were observed in PEMA, compared with OMEGA-3. Greater increases with significant differences in those in high-density lipoprotein (HDL) cholesterol, apoA-I, and apoA-II were observed in PEMA, compared with OMEGA-3. PEMA showed anti-atherosclerotic lipoprotein profiles in gel-permeation high-performance liquid chromatography analyses, compared with OMEGA-3. Although adverse events occurred in 9 of 63 (14.3%) patients in PEMA and 3 of 63 (4.8%) patients in OMEGA-3, no serious adverse events associated with drug were observed in either group.ConclusionsThis is the first randomized trial to compare the lowering effects of pemafibrate and omega-3 fatty acid ethyl on fasting apoB-48. We concluded that pemafibrate was superior to omega-3 fatty acid ethyl in lowering effect of fasting apoB-48. Pemafibrate is expected to reduce the residual risk for ASCVD with statin treatment.Clinical trial registrationhttps://rctportal.niph.go.jp/en, identifier jRCTs071200011.

Abstract Aims White blood cell (WBC) count in healthy people is associated with the risk of coronary artery disease (CAD) and mortality. This study aimed to determine whether WBC count predicts heart failure (HF) requiring hospitalization as well as all‐cause death, acute myocardial infarction (AMI) and stroke in patients with Type 2 diabetes mellitus and established CAD. Methods We conducted this retrospective registry study that enrolled consecutive patients with Type 2 diabetes mellitus and CAD based on coronary arteriography records and medical charts at 70 teaching hospitals in Japan from 2005 to 2015. A total of 7608 participants (28.2% women, mean age 68 ± 10 years) were eligible. In the cohort, the median (interquartile range) and mean follow‐up durations were 39 (16.5–66.1 months) and 44.3 ± 32.7 months, respectively. The primary outcome was HF requiring hospitalization. The secondary outcomes were AMI, stroke, all‐cause death, 3‐point major adverse cardiovascular events (MACE) (AMI/stroke/death) and 4‐point MACE (AMI/stroke/death/HF requiring hospitalization). Outcomes were reported as cumulative incidences (proportion of patients experiencing an event) and incidence rates (events/100 person‐years). The primary and secondary outcomes were assessed using the Kaplan–Meier method and were compared using the log‐rank test stratified by the baseline WBC count. The association between the WBC count at baseline and each MACE was assessed using the Cox proportional hazard model and expressed as the hazard ratio (HR) and 95% confidence interval (CI) after adjusting for other well‐known risk factors for MACE. Results During the follow‐up, 880 patients were hospitalized owing to HF. The WBC Quartile 4 (≥7700 cells/μL) had significantly lower HF event‐free survival rate (log‐rank test, P

Introduction This study will compare the lowering effects of pemafibrate and omega-3 fatty acid ethyl esters on fasting apolipoprotein B-48 (apoB-48), a surrogate marker reflecting postprandial hypertriglyceridaemia, which is a residual risk for atherosclerotic cardiovascular disease with statin treatment.Methods and analysis This is a prospective, multicentre, open-label, randomised, parallel group, comparative trial. Adult Japanese patients with dyslipidaemia receiving statin treatment for more than 4 weeks with a fasting triglyceride level ≥177 mg/dL will be randomly assigned in a 1:1 ratio to receive pemafibrate (0.4 mg orally per day) or omega-3 fatty acid ethyl esters (4 g orally per day) for 16 weeks. The primary endpoint is the percentage change in fasting apoB-48 from baseline to 16 weeks. The key secondary endpoints include the change in fasting apoB-48 from baseline to 16 weeks, the percentage changes in clinical variables from baseline to 16 weeks and the incidence of adverse events. A total sample size of 128 was set by considering the increased drop-out rate due to the COVID-19 pandemic, in addition to estimation based on a two-sided alpha of 0.05 and a power of 0.8 for apoB-48.Ethics and dissemination The study protocol has been approved by the Certified Review Board of the University of the Ryukyus for Clinical Research Ethics (No. CRB7200001) and will be performed in accordance with the Declaration of Helsinki. Written informed consent will be obtained from all participants. The results of the study will be disseminated through publications and conference presentations to participants, healthcare professionals and the public.Trial registration number jRCTs071200011.

Abstract Background The number of women with congenital heart disease (CHD) who are of childbearing age is increasing due to advancements in medical management. Nonetheless, data on the outcomes of delivery in women with CHD remain limited. Therefore, we conducted a retrospective cohort study using a nationwide database of deliveries by women with CHD. Methods Deliveries by women with CHD discharged from acute-care hospitals between April 2017 and March 2018 were identified based on the Diagnosis Procedure Combination database which covers almost all acute-care hospitals in Japan. By using this database, we tried to include relatively high-risk deliveries by women with CHD. Subjects were divided into three groups according to the underlying disease complexity: simple, moderate, and great complexity. The clinical characteristics and incidence of peripartum cardiovascular events were compared among the three groups. Results A total of 249 deliveries from 107 hospitals were included. The largest facility had 29 deliveries per year. Given the uncertainty of underlying cardiac anomalies, 48 women were excluded, and the remaining 201 women (median age, 32 years) were analyzed. In-hospital maternal death, use of extracorporeal membrane oxygenation, intra-aortic balloon pump, pacemaker, and direct current cardioversion were not observed. Nine patients (4.5%) required intravenous diuretic administration. However, the difference in the frequency of diuretic use was not significant among the three groups (simple, 1.9%; moderate, 7.2%; great, 6.9%; P = 0.204). One participant required valve replacement surgery at 22 days after a successful cesarean section. As the disease complexity increased, deliveries occurred more frequently at university hospitals (simple, 41.7%; moderate, 52.2%; great, 72.4%; P = 0.013) and the length of hospitalization was significantly longer, with median durations of 9.0 (interquartile range [IQR] 7.0–11.0) days, 10.0 (IQR 8.0–24.0) days, and 11.0 (IQR 8.0–36.0) days in the simple, moderate, and great complexity groups, respectively (P = 0.002). Conclusions Appropriate patient selection and management by specialized tertiary institutions may contribute to positive outcomes in pregnancies in women with CHD.

Abstract Background The most recent treatment guidelines for type 2 diabetes (T2D) recommend sodium-glucose cotransporter 2 (SGLT2) inhibitors should be considered preferentially in patients with T2D with either a high cardiovascular risk or with cardiovascular disease (CVD), regardless of their diabetes status and prior use of conventional metformin therapy. Whether the therapeutic impact of SGLT2 inhibitors on clinical parameters differs according to the use of metformin therapy however remains unclear. Methods The study was a post hoc analysis of the EMBLEM trial (UMIN000024502). All participants (n = 105; women 31.4%; mean age 64.8 years) had both T2D and CVD and were randomized to either 24 weeks of empagliflozin 10 mg daily or placebo. Analysis of the data assessed the effect of empagliflozin on changes from baseline to 24 weeks in glycemic and non-glycemic clinical parameters, according to the baseline use of metformin. Results Overall, 53 (50.5%) patients received baseline metformin. In the 52 patients treated with empagliflozin (48.1% with baseline metformin), the decrease in systolic blood pressure from baseline levels was greater in patients receiving metformin, compared to that observed in metformin-naïve patients (group difference − 8.5 [95% confidence interval (CI) − 17.7 to 0.6 mmHg], p = 0.066). Reduction in body mass index (BMI) was significantly greater in patients receiving baseline metformin, relative to nonusers (− 0.54 [95% CI − 1.07 to − 0.01] kg/m2, p = 0.047). The group ratio (baseline metformin users vs. nonusers) of proportional changes in the geometric mean of high-sensitivity Troponin-I (hs-TnI) was 0.74 (95% CI 0.59 to 0.92, p = 0.009). No obvious differences were observed in glycemic parameters (fasting plasma glucose, glycohemoglobin, and glycoalbumin) between the baseline metformin users and nonusers. Conclusion Our findings suggest 24 weeks of empagliflozin treatment was associated with an improvement in glycemic control, irrespective of the baseline use of metformin therapy. The effects of empagliflozin on reductions in BMI and hs-TnI were more apparent in patients who received baseline metformin therapy, compared to that observed in metformin-naïve patients. Trial registration University Medical Information Network Clinical Trial Registry, number 000024502

Abstract Aim Osteoporosis and bone fractures occur often on psychiatric wards. Although recent studies showed that bone mineral density (BMD) decreases in psychiatric patients, many risk factors remain unknown. This study aimed to explore the risk factors for decreased BMD in long‐term psychiatric inpatients in a closed ward. Methods A cross‐sectional study of psychiatric inpatients hospitalized for over 20 weeks was conducted. Patients were divided into three groups according to BMD: normal, osteopenia, and osteoporosis. Psychiatric symptoms were assessed using the Brief Psychiatric Rating Scale (BPRS). The relevant history of psychiatric diseases was collected, and biomarkers related to osteoporosis were measured. Univariable and multivariable ordinal logistic regression analyses were performed to identify variables significantly associated with BMD category. Additional analyses evaluated the associations between an identified clinical variable and biomarkers and psychiatric symptoms that may be related to osteoporosis. Results Seventy‐one patients (28 normal BMD, 17 osteopenia, and 26 osteoporosis) participated in the study. The multivariable ordinal logistic analysis showed that the duration of untreated psychosis (DUP) was a risk factor (odds ratio = 0.77, 95% confidence interval: 0.63–0.91, p = 0.006), adjusting for the major confounders of sex and age. Additional analysis showed significant differences in BPRS, BPRS Negative Symptom score, and the Cu/Zn ratio between the short‐DUP group (DUP ≤ 1 year) and the long‐DUP group (DUP > 1 year). Conclusion The DUP may affect BMD in long‐term psychiatric inpatients, presumably partly through increased severity of negative symptoms and micronutrient abnormalities. Shortening the untreated period might reduce the risk of osteoporosis.

Purpose: We investigated the association between current smoking and clinical outcomes in patients with atrial fibrillation (AF) prescribed vitamin K antagonist (VKA). Methods: We conducted a retrospective study at 71 centers in Japan. The inclusion criterion was taking a VKA for AF. Exclusion criteria were mechanical heart valves or history of pulmonary thrombosis or deep vein thrombosis. Consecutive patients were registered in February 2013 and followed until February 2017. The primary outcomes included ischemic events and major bleedings. The secondary outcomes were ischemic stroke, hemorrhagic stroke, and all-cause mortality. Results: A total of 7826 patients were included, with a mean age of 73 years; 5274 (67%) were men. The adjusted hazard ratios (HRs; 95% confidence intervals [CIs]) of current smokers relative to non–current smokers for ischemic events and major bleedings were 1.64 (1.05–2.57) and 1.09 (0.72–1.65), respectively. The adjusted HRs (95% CIs) of current smokers relative to non–current smokers for ischemic stroke, hemorrhagic stroke, and all-cause mortality were 1.65 (1.03–2.64), 0.52 (0.12–2.15), and 1.26 (0.83–1.92), respectively. Conclusions: There were significant associations between current smoking and ischemic events or ischemic stroke in patients with AF on VKA.

Objective Adjuvant chemotherapy with trastuzumab improves the postoperative life expectancy of women with early-stage breast cancer. Although trastuzumab is reportedly cardiotoxic, quantification based on real-world evidence is lacking. Therefore, in this study, we aimed to analyse trastuzumab cardiotoxicity using a nationwide claim-based database.Methods In this retrospective study, we used data from a nationwide claims database (Japan Medical Data Center, Tokyo, Japan) under the universal healthcare system. Women with breast cancer who underwent initial surgery were included. Patients with recurrent or advanced-stage breast cancer, with a history of heart failure, receiving neoadjuvant chemotherapy or a preoperative history of less than 6 months were excluded. Propensity score (PS) was calculated using logistic regression based on age, cardiovascular risk factors, radiotherapy and concomitant anthracyclines (AC).Results We identified 12 060 eligible patients (mean age 50.8±8.56 years) between January 2010 and December 2019. After 1:2 PS matching (trastuzumab users, TZ, n=1005; non-users, NT, n=2010), Cox proportional hazards model analysis showed that the rate of heart failure development within 18 months postoperative was significantly higher in the TZ group than in the NT group (adjusted HR 2.28, 95% CI 1.38 to 3.77). Baseline cardiac evaluation in the combined AC/TZ cases was 27.2% preoperative, 66.0% pre-AC and 86.6% pre-TZ, respectively.Conclusion Trastuzumab cardiotoxicity remained relevant in the claim-based analysis adjusted for AC effects. Further collaborative studies in cardio-oncology with real-world data are warranted to improve the rate of baseline cardiovascular risk assessment in patients with cancer scheduled for cardiotoxic cancer treatment.

Abstract Backgrounds/Aim Sodium glucose co-transporter 2 inhibitors promote osmotic/natriuretic diuresis and reduce excess fluid volume, and this improves cardiovascular outcomes, including hospitalization for heart failure. We sought to assess the effect of empagliflozin on estimated fluid volumes in patients with type 2 diabetes and cardiovascular disease (CVD). Methods The study was a post-hoc analysis of the EMBLEM trial (UMIN000024502), an investigator-initiated, multi-center, placebo-controlled, double-blinded, randomized-controlled trial designed primarily to evaluate the effect of 24 weeks of empagliflozin treatment on vascular endothelial function in patients with type 2 diabetes and established CVD. The analysis compared serial changes between empagliflozin (10 mg once daily, n = 52) and placebo (n = 53) in estimated plasma volume (ePV), calculated by the Straus formula and estimated the extracellular volume (eEV), determined by the body surface area, measured at baseline and 4, 12, and 24 weeks after initiation of treatment. Correlations were examined between the changes from baseline to week 24 in each estimated fluid volume parameter and several clinical variables of interest, including N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration. Results In an analysis using mixed-effects models for repeated measures, relative to placebo empagliflozin reduced ePV by − 2.23% (95% CI − 5.72 to 1.25) at week 4, − 8.07% (− 12.76 to − 3.37) at week 12, and − 5.60% (− 9.87 to − 1.32) at week 24; eEV by − 70.3 mL (95% CI − 136.8 to − 3.8) at week 4, − 135.9 mL (− 209.6 to − 62.3) at week 12, and − 144.4 mL (− 226.3 to − 62.4) at week 24. The effect of empagliflozin on these parameters was mostly consistent across various patient clinical characteristics. The change in log-transformed NT-proBNP was positively correlated with change in ePV (r = 0.351, p = 0.015), but not with change in eEV. Conclusions Our data demonstrated that initiation of empagliflozin treatment substantially reduced estimated fluid volume parameters in patients with type 2 diabetes and CVD, and that this effect was maintained for 24 weeks. Given the early beneficial effect of empagliflozin on cardiovascular outcomes seen in similar patient populations, our findings provide an important insight into the key mechanisms underlying the clinical benefit of the drug. Trial registration University Medical Information Network Clinical Trial Registry, number 000024502

Abstract. Maximum aortic computed tomography value (CTV) is difficult to control because of variations in cardiac function and patient physique. Therefore, to improve early-phase aortic enhancement on dynamic computed tomography (CT), we developed an estimated cardiac index fractional dose (eciFD). The eciFD protocol is a novel and original protocol for administering fractional dose (FD), representing the amount of iodine per unit body weight per injection duration, based on cardiac index (cardiac output divided by body surface area) as estimated by age in early-phase dynamic CT. At the time of administration, by selecting FD based on the patient's age and selecting a parameter that can achieve this FD, an aortic CTV ≥300 HU (ACTV≥300) can be obtained. This study aimed to investigate aortic enhancement on CT angiography using the eciFD protocol. This retrospective study investigated 291 consecutive patients who underwent dynamic CT from neck to abdomen after recommendation of the eciFD protocol at our institution. We compared early-phase aortic CTV distributions by scan delay between an eciFD group (eciFD applied, n = 135) and a non-eciFD group (eciFD not applied, n = 80). The effect of eciFD on early-phase ACTV≥300 was evaluated using logistic regression analysis adjusted for several potentially meaningful clinical confounders related to aortic CTV, namely male sex, heart rate ≤80 beats/min, estimated glomerular filtration rate ≤40 mL/min, use of eciFD, bolus tracking (BT), history of myocardial infarction, and order from the emergency center. The eciFD protocol was a significant factor for early-phase ACTV≥300 after adjusting for several confounders (odds ratio 3.03; 95% confidence intervals 1.59–5.77; P = .001). No interaction was seen between BT and eciFD protocol (p for interaction = 0.76). In terms of CTV distribution, with both a fixed scan delay time and BT, the eciFD group showed a high aortic CTV. The combination of eciFD protocol with BT provided a particularly high percentage of patients with ACTV≥300 (86.4%). The eciFD protocol was useful for improving aortic contrast enhancement. These findings need to be validated in a randomized controlled study.

Abstract Aims/Introduction Recent clinical trials on sodium–glucose cotransporter 2 inhibitors showed improved outcomes in patients with type 2 diabetes at a high risk of cardiovascular events. However, the underlying effects on endothelial function remain unclear. Materials and Methods The effect of empagliflozin on endothelial function in cardiovascular high risk diabetes mellitus: Multi‐center placebo‐controlled double‐blind randomized (EMBLEM) trial in patients with type 2 diabetes and cardiovascular disease showed empagliflozin treatment for 24 weeks had no effect on peripheral endothelial function measured by reactive hyperemia peripheral arterial tonometry. This post‐hoc analysis of the EMBLEM trial included a detailed evaluation of the effects of empagliflozin on peripheral endothelial function in order to elucidate the clinical characteristics of responders or non‐responders to treatment. Results Of the 47 patients randomized into the empagliflozin group, 21 (44.7%) showed an increase in the reactive hyperemia index (RHI) after 24 weeks of intervention, with no apparent difference in the clinical characteristics between patients whose RHI either increased (at least >0) or did not increase. There was also no obvious difference between the treatment groups in the proportion of patients who had a clinically meaningful change (≥15%) in log‐transformed RHI. No correlation was found between changes in RHI and clinical variables, such as vital signs and laboratory parameters. Conclusions Treatment with empagliflozin for 24 weeks in patients with type 2 diabetes and cardiovascular disease did not affect peripheral endothelial function, and was not related to changes in clinical variables, including glycemic parameters. These findings suggest that the actions of sodium–glucose cotransporter 2 inhibitors other than direct improvement in peripheral endothelial function were responsible, at least in the early phase, for the clinical benefits found in recent cardiovascular outcome trials.

Abstract Aims Little is known about the impact of sodium glucose co‐transporter 2 (SGLT2) inhibitors on cardiac biomarkers, such as natriuretic peptides, in type 2 diabetes (T2D) patients with concomitant chronic heart failure (CHF). We compared the effect of canagliflozin with glimepiride, based on changes in N‐terminal pro‐brain natriuretic peptide (NT‐proBNP), in that patient population. Methods and results Patients with T2D and stable CHF, randomized to receive canagliflozin 100 mg or glimepiride (starting‐dose: 0.5 mg), were examined using the primary endpoint of non‐inferiority of canagliflozin vs. glimepiride, defined as a margin of 1.1 in the upper limit of the two‐sided 95% confidence interval (CI) for the group ratio of percentage change in NT‐proBNP at 24 weeks. Data analysis of 233 patients showed mean left ventricular ejection fraction (LVEF) at randomization was 57.6 ± 14.6%, with 71% of patients having a preserved LVEF (≥50%). Ratio of NT‐proBNP percentage change was 0.48 (95% CI, −0.13 to 1.59, P = 0.226) and therefore did not meet the prespecified non‐inferiority margin. However, NT‐proBNP levels did show a non‐significant trend lower in the canagliflozin group [adjusted group difference; −74.7 pg/mL (95% CI, −159.3 to 10.9), P = 0.087] and also in the subgroup with preserved LVEF [−58.3 (95% CI, −127.6 to 11.0, P = 0.098]). Conclusions This study did not meet the predefined primary endpoint of changes in NT‐proBNP levels, with 24 weeks of treatment with canagliflozin vs. glimepiride. Further research is warranted to determine whether patients with heart failure with preserved ejection fraction, regardless of diabetes status, could potentially benefit from treatment with SGLT2 inhibitors.

Abstract Background Fatty acid-binding protein 4 (FABP4) acts as a novel adipokine, and elevated FABP4 concentration is associated with obesity, insulin resistance and atherosclerosis. Dipeptidyl peptidase-4 (DPP-4) inhibitors, a class of antidiabetic drugs, have distinct structures among the drugs, possibly leading to a drug class effect and each drug effect. Sitagliptin, a DPP-4 inhibitor, has been reported to decrease FABP4 concentration in drug-naïve and sulfonylurea-treated patients with type 2 diabetes mellitus. Anagliptin, another DPP-4 inhibitor, was shown to decrease low-density lipoprotein cholesterol (LDL-C) level to a greater extent than that by sitagliptin in the Randomized Evaluation of Anagliptin vs. Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. Aim and methods As a sub-analysis study using data obtained from the REASON trial, we investigated the effects of treatment with anagliptin (n = 148, male/female: 89/59) and treatment with sitagliptin (n = 159, male/female: 93/66) for 52 weeks on FABP4 concentration in patients with type 2 diabetes mellitus at a high risk for cardiovascular events who were receiving statin therapy. Results The DPP-4 inhibitor had been administered in 82% of the patients in the anagliptin group and 81% of the patients in sitagliptin group prior to randomization. Serum FABP4 level was significantly decreased by 7.9% by treatment with anagliptin (P = 0.049) and was not significantly decreased by treatment with sitagliptin (P = 0.660). Change in FABP4 level was independently associated with basal FABP4 level and changes in waist circumference and creatinine after adjustment of age, sex and the treatment group. Conclusion Anagliptin decreases serum FABP4 concentration independent of change in hemoglobin A1c or LDL-C in patients with type 2 diabetes mellitus and dyslipidemia who are on statin therapy. Trial registration ClinicalTrials.gov number NCT02330406. Registered January 5, 2015, https://clinicaltrials.gov/ct2/show/NCT02330406

Recent reports indicate that respiratory infectious diseases were suppressed during the novel coronavirus disease-2019 (COVID-19) pandemic. COVID-19 led to behavioral changes aimed to control droplet transmission or contact transmission. In this study, we examined the incidence of common infectious diseases in Japan during the COVID-19 pandemic. COVID-19 data were extracted from the national data based on the National Epidemiological Surveillance of Infectious Diseases (NESID). Common infectious diseases were selected from notifiable infectious diseases under the NESID. The epidemic activity of the diseases during 2015–2020 was evaluated based on the Infectious Disease Weekly Reports published by the National Institute of Infectious Diseases. Each disease was then categorized according to the route of transmission. Many Japanese people had adopted hygienic activities, such as wearing masks and hand washing, even before the COVID-19 pandemic. We examined the correlation between the time-series of disease counts of common infectious diseases and COVID-19 over time using cross-correlation analysis. The weekly number of cases of measles, rotavirus, and several infections transmitted by droplet spread, was negatively correlated with the weekly number of cases of COVID-19 for up to 20 weeks in the past. According to the difference-in-differences analysis, the activity of influenza and rubella was significantly lower starting from the second week in 2020 than that in 2015–2019. Only legionellosis was more frequent throughout the year than in 2015–2019. Lower activity was also observed in some contact transmitted, airborne-transmitted, and fecal-oral transmitted diseases. However, carbapenem-resistant Enterobacteriaceae, exanthema subitum, showed the same trend as that over the previous 5 years. In conclusion, our study shows that public health interventions for the COVID-19 pandemic may have effectively prevented the transmission of most droplet-transmitted diseases and those transmitted through other routes.

Objectives To explore the awareness and practice of clinical research integrity among Japanese physicians.Design A nationwide cross-sectional study conducted in March 2020.Setting All hospitals in Japan.Participants Physicians aged

Abstract Purpose Left ventricular (LV) wall thickness can be measured at the posterior wall (PW) and the intraventricular septum (IVS) in a parasternal long axis view by transthoracic echocardiography. Thus, there are three methods to calculate relative wall thickness as follows: RWTPW = 2 × PWth/LVDd; RWTIVS + PW = (IVSth + PWth) /LVDd; and RWTIVS = 2 × IVSth/LVDd (IVSth = interventricular septum thickness; LVDd = LV internal dimension at end--diastole; PWth = posterior wall thickness). The aim was to compare the prognostic values of these RWTs in patients with acute decompensated heart failure (ADHF). Method This was a single-center, retrospective, observational study at a Japanese community hospital. A total of 389 hospitalized ADHF patients were divided into two groups based on the three median RWT values. The primary outcome was all-cause death. Survival analysis was performed, and Cox proportional hazard models unadjusted and adjusted by Get With The Guideline score were used. Results High-RWTPW had poor survival (log-rank, P = 0.009) and was a significant risk (unadjusted HR (95%CI), 1.72 (1.14–2.61), P = 0.01; adjusted HR, 1.95 (1.28–2.98), P = 0.02). High-RWTIVS + PW was not associated with poor survival on survival analysis or the unadjusted Cox model. Only the adjusted Cox model showed that High-RWTIVS + PW was associated with a significant risk of the primary outcome (unadjusted HR (95%CI), 1.45 (0.96–2.17), P = 0.07; adjusted HR, 1.53 (1.01–2.32), P = 0.045). High-RWTIVS did not have significant prognostic value. Conclusions When calculating RWT, RWTPW should be recommended for evaluating the mortality risk in ADHF.

Abstract Background Anagliptin, a dipeptidyl peptidase-4 inhibitor, is reported to reduce the level of low-density lipoprotein cholesterol (LDL-C). The underlying mechanism of this effect and effect on lipid metabolism however remains uncertain. Aim and methods We therefore evaluate the effects of anagliptin on lipid metabolism-related markers compared with those of sitagliptin. The study was a secondary analysis using data obtained from the Randomized Evaluation of Anagliptin versus Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. This trial in patients with type 2 diabetes at a high risk of cardiovascular events and on statin therapy showed that anagliptin reduced LDL-C levels to a greater extent than sitagliptin. Cholesterol absorption (campesterol and sitosterol) and synthesis (lathosterol) markers were measured at baseline and 52 weeks in the study cohort (n = 353). Results There was no significant difference in the changes of campesterol or sitosterol between the two treatment groups (p = 0.85 and 0.55, respectively). Lathosterol concentration was increased significantly at 52 weeks with sitagliptin treatment (baseline, 1.2 ± 0.7 μg/mL vs. 52 weeks, 1.4 ± 1.0 μg/mL, p = 0.02), whereas it did not change in the anagliptin group (baseline, 1.3 ± 0.8 μg/mL vs. 52 weeks, 1.3 ± 0.7 μg/mL, p = 0.99). The difference in absolute change between the two groups showed a borderline significance (p = 0.06). Conclusion These findings suggest that anagliptin reduces LDL-C level by suppressing excess cholesterol synthesis, even in combination with statin therapy. Trial registration ClinicalTrials.gov number NCT02330406. https://clinicaltrials.gov/ct2/show/NCT02330406; registered January 5, 2015.

Objective: Among fatty acid-binding proteins (FABPs), secreted forms of FABP4 and FABP5, which are expressed in adipocytes and macrophages, act as bioactive molecules. We investigated concentrations of FABP4 and FABP5 in patients with type 2 diabetes mellitus.Methods: As a sub-analysis study of the Randomized Evaluation of Anagliptin vs. Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial, 256 patients (male/female: 146/110, age: 68 ± 10 years) with type 2 diabetes mellitus and dyslipidemia who were receiving statin therapy were recruited. Patients who had been treated with a thiazolidinedione were excluded.Results: Several drugs which may modulate FABP4 levels including statins, dipeptidyl peptidase-4 inhibitors and angiotensin II receptor blockers had been administered in 100, 81, and 51% of the recruited patients, respectively. The level of FABP4, but not that of FABP5, was significantly higher in females than in males. Multivariable linear regression analysis demonstrated that waist circumference (β = 0.21), estimated glomerular filtration rate (β = −0.31), triglycerides (β = 0.16), and FABP5 (β = 0.39) were independent predictors of FABP4 level after adjusting age and sex. On the other hand, FABP5 level was independently associated with levels of FABP4 (β = 0.57) and high-density lipoprotein (HDL) cholesterol (β = −0.12).Conclusions: Concentrations of FABP4 and FABP5 are independent predictors of each other in patients with type 2 diabetes mellitus. There are distinct independent associations of FABP4 with renal dysfunction, adiposity and hypertriglyceridemia and there is a distinct independent association of FABP5 with a low HDL cholesterol level in type 2 diabetic patients with dyslipidemia at high risks for cardiovascular disease who are receiving statin therapy.

BackgroundAn elevated level of serum uric acid (SUA) is associated with an increased risk of cardiovascular disease. Pharmacological intervention with urate-lowering agents, such as the conventional purine analogue xanthine oxidase (XO) inhibitor, allopurinol, has been used widely for a long period of time in clinical practice to reduce SUA levels. Febuxostat, a novel non-purine selective inhibitor of XO, has higher potency for inhibition of XO activity and greater urate-lowering efficacy than conventional allopurinol. However, clinical evidence regarding the effects of febuxostat on atherosclerosis is lacking. The purpose of the study was to test whether treatment with febuxostat delays carotid intima-media thickness (IMT) progression in patients with asymptomatic hyperuricemia.Methods and findingsThe study was a multicenter, prospective, randomized, open-label, blinded-endpoint clinical trial undertaken at 48 sites throughout Japan between May 2014 and August 2018. Adults with both asymptomatic hyperuricemia (SUA >7.0 mg/dL) and maximum IMT of the common carotid artery (CCA) ≥1.1 mm at screening were allocated equally using a central web system to receive either dose-titrated febuxostat (10-60 mg daily) or as a control-arm, non-pharmacological lifestyle modification for hyperuricemia, such as a healthy diet and exercise therapy. Of the 514 enrolled participants, 31 were excluded from the analysis, with the remaining 483 people (mean age 69.1 years [standard deviation 10.4 years], female 19.7%) included in the primary analysis (febuxostat group, 239; control group, 244), based on a modified intention-to-treat principal. The carotid IMT images were recorded by a single sonographer at each site and read in a treatment-blinded manner by a single analyzer at a central core laboratory. The primary endpoint was the percentage change from baseline to 24 months in mean IMT of the CCA, determined by analysis of covariance using the allocation adjustment factors (age, gender, history of type 2 diabetes, baseline SUA, and baseline maximum IMT of the CCA) as the covariates. Key secondary endpoints included changes in other carotid ultrasonographic parameters and SUA and the incidence of clinical events. The mean values (± standard deviation) of CCA-IMT were 0.825 mm ± 0.173 mm in the febuxostat group and 0.832 mm ± 0.175 mm in the control group (mean between-group difference [febuxostat - control], -0.007 mm [95% confidence interval (CI) -0.039 mm to 0.024 mm; P = 0.65]) at baseline; 0.832 mm ± 0.182 mm in the febuxostat group and 0.848 mm ± 0.176 mm in the control group (mean between-group difference, -0.016 mm [95% CI -0.051 mm to 0.019 mm; P = 0.37]) at 24 months. Compared with the control group, febuxostat had no significant effect on the primary endpoint (mean percentage change 1.2% [95% CI -0.6% to 3.0%] in the febuxostat group (n = 207) versus 1.4% [95% CI -0.5% to 3.3%] in the control group (n = 193); mean between-group difference, -0.2% [95% CI -2.3% to 1.9%; P = 0.83]). Febuxostat also had no effect on the other carotid ultrasonographic parameters. The mean baseline values of SUA were comparable between the two groups (febuxostat, 7.76 mg/dL ± 0.98 mg/dL versus control, 7.73 mg/dL ± 1.04 mg/dL; mean between-group difference, 0.03 mg/dL [95% CI -0.15 mg/dL to 0.21 mg/dL; P = 0.75]). The mean value of SUA at 24 months was significantly lower in the febuxostat group than in the control group (febuxostat, 4.66 mg/dL ± 1.27 mg/dL versus control, 7.28 mg/dL ± 1.27 mg/dL; mean between-group difference, -2.62 mg/dL [95% CI -2.86 mg/dL to -2.38 mg/dL; P < 0.001]). Episodes of gout arthritis occurred only in the control group (4 patients [1.6%]). There were three deaths in the febuxostat group and seven in the control group during follow-up. A limitation of the study was the study design, as it was not a placebo-controlled trial, had a relatively small sample size and a short intervention period, and only enrolled Japanese patients with asymptomatic hyperuricemia.ConclusionsIn Japanese patients with asymptomatic hyperuricemia, 24 months of febuxostat treatment did not delay carotid atherosclerosis progression, compared with non-pharmacological care. These findings do not support the use of febuxostat for delaying carotid atherosclerosis in this population.Trial registrationUniversity Hospital Medical Information Network Clinical Trial Registry UMIN000012911.

Thus far, no curved linear array endoscopic ultrasound (CLAEUS) findings were established as predictors of difficult selective bile duct cannulation (SBDC). This study aimed to identify CLAEUS findings to predict endoscopic retrograde cholangiopancreatography (ERCP) cases with difficult SBDC. This single-center, retrospective cohort study was conducted between July 2014 and June 2017. This study included all consecutive patients who underwent CLAEUS prior to naïve ERCP. A CLAEUS finding of the simultaneous depiction of bile and pancreatic ducts at the second portion of the duodenum (D2) (simultaneous depiction) was selected as a possible predictor of difficult SBDC, and the κ values in the evaluation of inter- and intra-observer variabilities for "simultaneous depiction" were 0.65 and 0.77, respectively, with substantial correlation. Among the 986 patients who underwent ERCP, 80 patients were relevant for evaluation. Logistic regression analysis revealed strong association between "simultaneous depiction" and difficult SBDC (odds ratio 15.4, 95% confidence interval 4.2-56.0; p

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. Clinical Trial Registration www.umin.ac.jp Unique identifiers: UMIN000012950, UMIN000012951, UMIN000012952, and UMIN000003409

Abstract Background Type 2 diabetes mellitus (T2DM) is characterized by systemic metabolic abnormalities and the development of micro- and macrovascular complications, resulting in a shortened life expectancy. A recent cardiovascular (CV) safety trial, the EMPA-REG OUTCOME trial, showed that empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, markedly reduced CV death and all-cause mortality and hospitalization for heart failure in patients with T2DM and established CV disease (CVD). SGLT2 inhibitors are known to not only decrease plasma glucose levels, but also favorably modulate a wide range of metabolic and hemodynamic disorders related to CV pathways. Although some experimental studies revealed a beneficial effect of SGLT2 inhibitors on atherosclerosis, there is a paucity of clinical data showing that they can slow the progression of atherosclerosis in patients with T2DM. Therefore, the EMBLEM trial was designed to investigate whether empagliflozin treatment can improve endothelial function, which plays a pivotal role in the pathogenesis of atherosclerosis, in patients with T2DM and established CVD. Methods The EMBLEM trial is an ongoing, prospective, multicenter, placebo-controlled double-blind randomized, investigator-initiated clinical trial in Japan. A total of 110 participants with T2DM (HbA1c range 6.0–10.0%) and with established CVD will be randomized (1:1) to receive either empagliflozin 10 mg once daily or a placebo. The primary endpoint of the trial is change in the reactive hyperemia (RH)-peripheral arterial tonometry-derived RH index at 24 weeks from baseline. For comparison of treatment effects between the treatment groups, the baseline-adjusted means and their 95% confidence intervals will be estimated by analysis of covariance adjusted for the following allocation factors: HbA1c (

Background The difference in the predictive ability of the brachial‐ankle pulse wave velocity (baPWV) and its stiffness index β‐transformed value (β‐baPWV, ie, baPWV adjusted for the pulse pressure) for the development of pathophysiological abnormalities related to cardiovascular disease or future occurrence of cardiovascular disease was examined. Methods and Results In study 1, a 7‐year prospective observational study in cohorts of 3274 men and 3490 men, the area under the curve in the receiver operator characteristic curve analysis was higher for baPWV than for β‐baPWV for predicting the development of hypertension (0.73, 95% CI=0.70 to 0.75 versus 0.59, 95% CI=0.56 to 0.62; P

BackgroundThe quick sequential organ failure assessment (qSOFA) score has recently been introduced to the emergency department (ED) and wards, and it predicted a higher number of deaths among patients with sepsis compared with baseline risk. However, studies about the application of the qSOFA score are limited in prehospital settings. Thus, this study aimed to assess the performance of prehospital qSOFA score in predicting the risk of mortality among patients with infection.MethodsThis single center, retrospective cohort study was conducted in a Japanese tertiary care teaching hospital between April 2016 and March 2017. We enrolled all consecutive adult patients transported to the hospital by ambulance and admitted to the ED due to a suspected infection. We calculated the prehospital qSOFA score using the first vital sign obtained at the scene by emergency medical service (EMS) providers. The primary outcome was in-hospital mortality. The Cox proportional hazards model was used to assess the association between prehospital qSOFA positivity and in-hospital mortality.ResultsAmong the 925 patients admitted to the ED due to a suspected infection, 51.1% (473/925) were prehospital qSOFA-positive and 48.9% (452/925) were prehospital qSOFA-negative. The in-hospital mortality rates were 14.0% (66/473) in prehospital qSOFA-positive patients and 6.0% (27/452) in prehospital qSOFA-negative patients. The Cox proportional hazard regression model revealed a strong association between prehospital qSOFA score and in-hospital mortality (adjusted hazard ratio: 2.41, 95% confidence interval: 1.51-3.98; p ConclusionsAmong the patients with suspected infection who were admitted at the ED, a strong association was observed between the prehospital qSOFA score and in-hospital mortality. In order to use this score in clinical practice, future study is necessary to evaluate how infection is suspected in the prehospital arena.

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. Clinical Trial Registration URL: www.umin.ac.jp. Unique identifier: UMIN000012950.

Recent epidemiological studies have demonstrated that coffee drinking is associated with reduced mortality of cardiovascular disease. However, its precise mechanisms remain to be clarified. In this study, we examined whether single ingestion of caffeine contained in a cup of coffee improves microvascular function in healthy subjects. A double-blind, placebo-controlled, crossover study was performed in 27 healthy volunteers. A cup of either caffeinated or decaffeinated coffee was drunk by the subjects, and reactive hyperemia of finger blood flow was assessed by laser Doppler flowmetry. In an interval of more than 2 days, the same experimental protocol was repeated with another coffee in a crossover manner. Caffeinated coffee intake slightly but significantly elevated blood pressure and decreased finger blood flow as compared with decaffeinated coffee intake. There was no significant difference in heart rate between caffeinated and decaffeinated coffee intake. Importantly, caffeinated coffee intake significantly enhanced post-occlusive reactive hyperemia of finger blood flow, an index of microvascular endothelial function, compared with decaffeinated coffee intake. These results provide the first evidence that caffeine contained in a cup of coffee enhances microvascular function in healthy individuals.

BackgroundExperimental studies have suggested that dipeptidyl peptidase-4 (DPP-4) inhibitors provide cardiovascular protective effects. We performed a randomized study to evaluate the effects of sitagliptin added on to the conventional therapy compared with conventional therapy alone (diet, exercise, and/or drugs, except for incretin-related agents) on the intima-media thickness (IMT) of the carotid artery, a surrogate marker for the evaluation of atherosclerotic cardiovascular disease, in people with type 2 diabetes mellitus (T2DM).Methods and findingsWe used a multicenter PROBE (prospective, randomized, open label, blinded endpoint) design. Individuals aged ≥30 y with T2DM (6.2% ≤ HbA1c < 9.4%) were randomly allocated to receive either sitagliptin (25 to 100 mg/d) or conventional therapy. Carotid ultrasound was performed at participating medical centers, and all parameters were measured in a core laboratory. Of the 463 enrolled participants with T2DM, 442 were included in the primary analysis (sitagliptin group, 222; conventional therapy group, 220). Estimated mean (± standard error) common carotid artery IMT at 24 mo of follow-up in the sitagliptin and conventional therapy groups was 0.827 ± 0.007 mm and 0.837 ± 0.007 mm, respectively, with a mean difference of -0.009 mm (97.2% CI -0.028 to 0.011, p = 0.309). HbA1c level at 24 mo was significantly lower with sitagliptin than with conventional therapy (6.56% ± 0.05% versus 6.72% ± 0.05%, p = 0.008; group mean difference -0.159, 95% CI -0.278 to -0.041). Episodes of serious hypoglycemia were recorded only in the conventional therapy group, and the rate of other adverse events was not different between the two groups. As it was not a placebo-controlled trial and carotid IMT was measured as a surrogate marker of atherosclerosis, there were some limitations of interpretation.ConclusionsIn the PROLOGUE study, there was no evidence that treatment with sitagliptin had an additional effect on the progression of carotid IMT in participants with T2DM beyond that achieved with conventional treatment.Trial registrationUniversity Hospital Medical Information Network Clinical Trials Registry UMIN000004490.

We investigated the association between common type 2 susceptibility variants of CDK5 regulatory subunit associated protein 1-like 1(CDKAL1) and therapeutic responses to anti-diabetic agents among patients with type 2 diabetes. Two SNPs (rs7754840: C>G, rs7756992: A>G) were genotyped via the Taqman PCR method. A total of 798 type 2 diabetic patients were included. HbA1c reduction after use of DPP-4 inhibitors for 3 months was significantly greater in patients with a risk allele for type 2 diabetes (GG -0.4%, CG -0.5%, CC -0.8%, p = 0.02 for rs7754840 and AA -0.4%, AG -0.5%, GG -0.8%, p = 0.01 for rs7756992). Linear regression analysis showed that per allele reductions of hemoglobin A1c (HbA1c) after 3 months were -0.10% for rs7754840 (p = 0.02) and -0.13% for rs7756992 (p = 0.0008) after adjusting for clinically influential covariates such as age, sex, BMI, duration of diabetes, baseline HbA1c and concomitant anti-diabetic agents. The results suggested that common variants of CDKAL1 are associated with therapeutic response to DPP-4 inhibitors.

Recent randomized controlled trials showed that blockade of the renin–angiotensin system (RAS) by angiotensin-converting enzyme (ACE) inhibitors and angiotensin II–receptor blockers (ARBs) reduced cardiovascular and renal events. These drugs are widely used in the management of cardiovascular and renal diseases. Results from Randomized Controlled Trials (RCTs) so far, however, also raise several questions to be addressed. It should be noted that the residual event rate in the treatment arm in outcome studies that have employed ACE inhibitors or ARBs remains high. Such insufficient efficacy of RAS inhibition may result from the fact that neither ACE inhibitors nor ARBs completely suppress activity of RAS. Since then effort has been made to determine whether the dual blockade of RAS could provide further improvement in cardiovascular and renal outcome. This review extracts unsolved questions in the treatment with RAS inhibitors from outcome studies and discusses them from the clinical pharmacological point of view. Keywords:: Randomised Clinical Trial (RCT), angiotensin II–receptor blocker (ARB), angiotensin-converting enzyme (ACE) inhibitor, chronic kidney disease (CKD), heart failure

We investigated the effects of purified eicosapentaenoic acid (EPA) on vascular endothelial function and free fatty acid composition in Japanese hyperlipidemic subjects. In subjects with hyperlipidemia (total cholesterol ≥220 mg/dL and/or triglycerides ≥150 mg/dL), lipid profile and forearm blood flow (FBF) during reactive hyperemia were determined before and 3 months after supplementation with 1800 mg/day EPA. Peak FBF during reactive hyperemia was lower in the hyperlipidemic group than the normolipidemic group. EPA supplementation did not change serum levels of total, HDL, or LDL cholesterol, apolipoproteins, remnant-like particle (RLP) cholesterol, RLP triglycerides, or malondialdehyde-modified LDL cholesterol. EPA supplementation did not change total free fatty acid levels in serum, but changed the fatty acid composition, with increased EPA and decreased linoleic acid, γ-linolenic acid, and dihomo-γ-linolenic acid. EPA supplementation recovered peak FBF after 3 months. Peak FBF recovery was correlated positively with EPA and EPA/arachidonic acid levels and correlated inversely with dihomo-γ-linolenic acid. EPA supplementation restores endothelium-dependent vasodilatation in hyperlipidemic patients despite having no effect on serum cholesterol and triglyceride patterns. These results suggest that EPA supplementation may improve vascular function at least partly via changes in fatty acid composition.