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Approximately, 90% of men with advanced prostate cancer will develop bone metastasis. However, there have been few reports about noninvasive biomarker to detect and predict clinical outcome of bone metastasis (BM) in prostate cancer patients.We examined 1127 patients who underwent prostate biopsy from August 2012 to June 2017. We also investigated bone turnover markers such as bone-specific alkaline phosphatase, type I collagen cross-linked N-terminal telopeptide, C-terminal pyridinoline cross-linked telopeptide of type I collagen, and tartrate-resistant acid phosphatase type 5b (TRACP 5b).A total of 282 patients were diagnosed as prostate cancer with complete clinical data, and 34 patients with bone metastasis. Multivariate analysis revealed C-terminal pyridinoline cross-linked telopeptide of type I collagen, tartrate-resistant acid phosphatase type 5b, and prostate-specific antigen (PSA) were independent biomarkers in detection of BM (p 0.05, respectively). Furthermore, we developed predictive model formula based on tartrate-resistant acid phosphatase type 5b and PSA, for which the area under the curve was 0.95. In patients with bone metastasis, multivariate cox proportional hazards analysis revealed that this model was significantly associated with poor clinical outcome of cancer-specific survival (p 0.05). In validation cohort with 137 patients, we also confirmed the utility of this model for diagnosis of BM (the area under the curve = 0.95).Our developed formula of tartrate-resistant acid phosphatase type 5b in accordance with PSA may serve as the useful tool in diagnosis and prediction of clinical outcome for prostate cancer with bone metastasis.

A left common pulmonary vein (LCPV) is the most common anatomical variation in the pulmonary vein (PV) and often influences strategies of PV isolation for atrial fibrillation (AF). Our objective was to elucidate the electrical properties of the specific shape of LCPV and to apply it to an ablation procedure.We investigated consecutive 12 out of 204 paroxysmal AF patients who had the shape of a straight common trunk in LCPV defined by the formation of a single conduit with parallel cranial and caudal walls after the coalescence of superior and inferior PVs on the distal side. The distance between the top of the bifurcation of LPVs and the level coinciding with the middle of the anterior wall of LCPV (left lateral ridge: LLR) was more than 10 mm in all the patients. The activation pattern of the LLR showed longitudinal conduction without outside connections. All the LCPV except one were successfully isolated without ablating the LLR (C-shape ablation). Only one patient had AF recurrence during the follow-up period.The LLR in LCPV with a straight common trunk has longitudinal conduction without outside connections, which permits the isolation of LCPV without ablating LLR.

Trastuzumab-induced cardiomyopathy is a known complication of its use in breast cancer treatment. However, cardiac complications of trastuzumab without left ventricular systolic dysfunction have been rarely reported. These include left bundle branch block, sinus node dysfunction, and ventricular tachycardia. We herein report a case of a 47-year-old female with human epidermal growth factor receptor 2-positive, stage IV breast cancer without a history of cardiovascular disease. During treatment with trastuzumab emtansine (T-DM1), she presented with out-of-hospital cardiac arrest and was resuscitated by automated cardioverter defibrillator (AED). Emergent cardiac catheterization revealed no organic obstruction and coronary vasospasm in her coronary arteries, and no left ventricular systolic dysfunction. Ventricular fibrillation (VF) was documented by an event memory of AED. T-DM1 was withdrawn and implantable cardioverter defibrillator was implanted. Thereafter, VF or life-threatening arrhythmia were not documented for 36 months until her death by breast cancer. We concluded that the etiology of her VF event was T-DM1-induced cardiotoxicity. We believe this is the first report of life-threatening VF event without cardiomyopathy induced by T-DM1.

This study formulates the uncertainty relation accompanying the quantum fluctuation of the life and death drives using the two-state system quantum-mechanical mathematical model. A function hypothesis model of the intervention method with either-or questions is then developed. A drive is treated as a dynamical variable and represented as the operator of the spin components, and the mental state is represented as the quantum-mechanical state vector. The psychological model can be expressed through such a correspondence as a quantum mathematical model. In this way, we can quantitatively discuss the transition probabilities and the uncertainty relations in the psychological model. The either-or questions function to assist the energy processing of the internal drive through the fixation of position enabled by the resonance of position and drive. The assignment of words to particles of the opposite vector enables the formulation of questions probing 50% probability. A processing can therefore be expected through the uncertainty relationships between the life and death drives. This mathematical model benefits the literature by creating a starting point for the differentiation and integration of the two drives in a psychodynamics intervention while maintaining the perspective of economic theory. The actual measurement and examination of linking such psychodynamic interventions of either-or questions are necessary.

66 Background: In the PREVAIL study, enzalutamide was demonstrated to be effective in men with chemo-naïve metastatic castration-resistant prostate cancer (CRPC). In Japan, enzalutamide was introduced in 2014. Real-world evidence is needed for the long-term safety and efficacy of enzalutamide. The aim of this study was to evaluate the efficacy, safety and prognostic factors in CRPC treated with enzalutamide. Methods: This multicenter, prospective, observational study enrolled 163 Japanese CRPC patients between January 2016 and March 2019. Eligibility criteria were men with chemo-naïve CRPC, no prior treatment with novel androgen receptor signaling inhibitors, and an ECOG- Performance Status ≤ 2. The switching of bicalutamide and flutamide was eligible. Written consent for participation has been obtained from the patient. Enzalutamide 160 mg/day was administered once daily according to usual practice. Data were collected from medical records at baseline and every 3 months until march 2021. The primary endpoint was overall survival (OS), and factors associated with OS were examined. Cox proportional hazards model was used for statistics. The secondary endpoints were PSA response and safety. Results: At a median follow-up of 26.0 months, the median OS was 42.1 months and 24-month OS rate was 69%. Univariate analysis showed that time to CRPC, pretreatment serum PSA, baseline NSE, and baseline interleukin-6 (IL-6) levels were associated with OS. Multivariate analysis revealed that pretreatment serum PSA (hazard ratio [HR] 2.30, 95% confidence interval [CI] 1.30-4.10), baseline NSE (HR 2.97, 95%CI 1.24-7.11), and baseline IL-6 (HR 2.32 95%CI 1.32-4.09) were independent risk factors for OS. PSA decline more than 50% was 74% (n=120). Fatigue (30%, n=49), constipation (20%, n=32) and appetite loss (18%, n=29) were the most common adverse events (AEs). Dose reduction/drug discontinuation rates were 20% (n=33) due to AEs and 18% (n=29) due to patient request. Conclusions: The efficacy and safety of enzalutamide in Japanese real clinical practice were comparable to those reported in PREVAIL study. The present analysis also suggests that serum PSA, NSE and IL-6 levels are independent prognostic factors in CRPC patients. Clinical trial information: UMIN000019855 . [Table: see text]

In this article, Bayes factors (BFs) are used for selecting and weighting the ground motion prediction equations (GMPEs). BFs are defined as the posterior probability of a model being the best model describing data. The Bayesian framework allows for merging information gathered from available seismic data and the experts’ opinion thus allowing for a bridge between data-driven and non-data-driven methods. A multi-dimensional likelihood function is used to account for earthquake-to-earthquake and record-to-record variability. A study is performed to identify the effects of model uncertainty and dataset variations on Bayesian weights by using simulated data. It was found that for a given median prediction, by increasing standard deviation the relative weights increase until it reaches a maximum and then start to decrease. The standard deviation corresponding to the maximum weights corresponds to the scatter of data used for calculating the weights. The method was applied to a local region with nine preselected local and regional GMPEs. The ranking, selection, and weighting are performed using a local dataset and the results are compared with four available ranking methods. While various methods may yield similar or different ranking results, the proposed method is the only one that provides scientific means of selecting appropriate models from a set of initially selected GMPEs.

Aims Asymptomatic patients with structural heart diseases are classified as a population at high risk for heart failure (HF) in Stage B. However, limited data are available regarding incidence and related factors of de-novo HF (DNHF) considering competing risk in this population. Methods and results In 3362 Stage B patients (mean age 68 yrs, male 76%) from the CHART-2 Study (N = 10,219), we examined incidence of death and DNHF, defined as the first episode of either HF hospitalization or HF death, and factors related to DNHF. Results During the median 6.0-year follow-up, 627 deaths (31/1000 person-years) and 293 DNHF (15/1000 person-years) occurred. Among the 627 deaths, 212 (34%) and 325 (52%) were specified as cardiovascular and non-cardiovascular deaths, respectively. During the follow-up of 271 DNHF hospitalizations, we observed 124 deaths, including 65 (52%) cardiovascular and 47 (40%) non-cardiovascular deaths. The competing risk model showed that age, diabetes mellitus, stroke, atrial fibrillation, diastolic blood pressure, hemoglobin levels, estimated glomerular filtration ratio and left ventricular ejection fraction was significantly associated with DNHF. Bayesian structural equation modeling showed that many of these cardiac and non-cardiac variables contribute to DNHF by affecting each other, while diabetes mellitus was independently associated with DNHF. Conclusions Stage B patients had a high incidence of DNHF as well as that of death due to both cardiovascular and non-cardiovascular causes. Thus, management of Stage B patients should include multidisciplinary approaches considering both cardiac and non-cardiac factors, in order to prevent DNHF as well as non-HF death as a competing risk. Trial registration: clinicaltrials.gov identifier: NCT00418041 .

After the 2011 Fukushima accident, the seismic regulations for nuclear power plants (NPP) in Japan have been strengthened to include countermeasures far beyond design-basis accidents. The importance of seismic probabilistic risk assessments, therefore, have been the focus of deserved attention. Generally, an uncertainty quantification has been a very important undertaking to assess for fragility in NPP buildings. Therefore, this study focuses on the reduction in epistemic uncertainty by aiming to clarify the seismic-response effects on NPP buildings based on different modeling methods. As a first step in this study, the authors compared the seismic-response effects using two modeling methods of analysis. To evaluate the seismic response, an analysis was performed on two building model types; these being the three-dimensional (3D) finite-element model and the sway-rocking model with a conventional lumped mass system. To input a ground motion, the authors adopted 200 types of simulated seismic ground motions, generated by fault-rupture models, using stochastic seismic source characteristics. For the uncertainty quantification, we conducted a statistical analysis of the seismic responses acquired from the two modeling methods based on the building response each ground-motion input, and quantitatively evaluated the uncertainty response by considering the different modeling methods. We found a clear difference in the modeling methods near the floor and wall openings. We also imparted our knowledge on these 3D effects for the seismic-response analysis.

Objective: Oncostatin M (OSM) is an inflammatory cytokine of the interleukin-6 family which plays a crucial role in the pathogenesis of atherosclerosis. Therefore, we tested our hypothesis that serum OSM levels are increased in patients with coronary artery diseases (CAD). Methods and results: Serum OSM level was measured by sandwich technique immunoassay in 315 consecutive patients and who underwent coronary angiography at the International University of Health and Welfare Hospital from April 2019 to March 2021. A diagnosis of CAD was made in 169 patients. Serum OSM levels were significantly higher in patients with significant coronary stenosis compared to those without it. [123.0 ± 46.7 pg/mL (n = 169) vs. 98.3 ± 47.9 pg/mL (n = 146), p

BACKGROUND There is no robust evidence of pharmacological interventions to improve mortality in heart failure (HF) patients with preserved left ventricular ejection fraction (LVEF) (HFpEF). In this subanalysis study of the SUPPORT Trial, we addressed the influence of LVEF on the effects of olmesartan in HF. METHODS AND RESULTS Among 1,147 patients enrolled in the SUPPORT Trial, we examined 429 patients with reduced LVEF (HFrEF, LVEF

Conventional seismic probabilistic risk assessments (PRAs) of nuclear power plants consist of probabilistic seismic hazard and fragility curves. Even when earthquake ground-motion time histories are required, they are generated to fit specified response spectra, such as uniform hazard spectra at a specified exceedance probability. These ground motions, however, are not directly linked with seismic-source characteristics. In this context, the authors propose a method based on Monte Carlo simulations to generate a set of input ground-motion time histories to develop an advanced PRA scheme that can explain exceedance probability and the sequence of safety-functional loss in a nuclear power plant. These generated ground motions are consistent with seismic hazard at a reference site, and their seismic-source characteristics can be identified in detail. Ground-motion generation is conducted for a reference site, Oarai in Japan, the location of a hypothetical nuclear power plant. A total of 200 ground motions are generated, ranging from 700 to 1100 cm/s 2 peak acceleration, which corresponds to a 10 −4 to 10 −5 annual exceedance frequency. In the ground-motion generation, seismic sources are selected according to their hazard contribution at the site, and Monte Carlo simulations with stochastic parameters for the seismic-source characteristics are then conducted until ground motions with the target peak acceleration are obtained. These ground motions are selected so that they are consistent with the hazard. Approximately 110,000 simulations were required to generate 200 ground motions with these peak accelerations. Deviations of peak ground motion acceleration generated for 1000–1100 cm/s 2 range from 1.5 to 3.0, where the deviation is evaluated with peak ground motion accelerations generated from the same seismic source. Deviations of 1.0 to 3.0 for stress drops, one of the stochastic parameters of seismic-source characteristics, are required to obtain these acceleration deviations. A similar tendency can be found for some other seismic-source characteristics, meaning that ground motions obtained in this study cannot be generated by simulations of deterministic fault-rupture models with averaged seismic-source characteristics. Generated ground motions incorporate differences between each seismic-source characteristic, and they are effectively available for PRAs of structures.

本研究では、原子力施設の確率論的地震リスク評価の信頼性向上に資するため、原子炉建屋の地震応答解析結果におけるモデル化手法の違いによる影響を評価し、フラジリティ評価における認識論的不確実さを定量化することを目的としている。入力地震動として、偶然的不確実さを考慮するため、ハザード適合地震波を用いた。現実的な応答を得るため、原子炉建屋の3次元詳細モデルによる地震応答解析を実施し、建屋の壁および床の最大加速度について、中央値と対数標準偏差により統計的評価を行った。本研究により、建屋の上層部や床の開口部周辺において面外変形などの3次元効果が現れることが分かった。

Recent developments in theory and solution algorithms have facilitated the application of Bayesian Probabilistic Networks (BPNs) to probabilistic engineering problems. BPNs’ ability to easily perform backward analysis and parameter updating offers advantage over existing methods. This paper attempts to propose a BPN for reliability assessment of structural systems based on their cut-set representation. A five-layer Bayesian network is proposed which includes random variables, component events, failure paths and failure modes to compute the structural probability of failure. Convenient inclusion of parameter dependency or correlation is an advantage of the proposed method. While in existing methods extensive computation or simplifying assumption are used to account for component and mode dependencies, the proposed method utilizes the inherent ability of BPNs to model the joint probability distributions using factors of independent conditional probabilities. This greatly reduces efforts to include parameter dependencies which may significantly affect the output. Application to a real-world example of 4-storey reinforced concrete structure is presented and optimizations to lower the computation costs are reviewed. Also it is described how disaggregation of structural failure and updated distribution of random variables can be obtained using backward inference without any additional recalculations.

After the 2011 Fukushima accident, engineers of nuclear power plants are looking beyond the basic design requirements and ensuring that countermeasures are built in to avert possible nuclear accidents. In seismic probabilistic risk assessment (SPRA), uncertainties can be classified in two ways as aleatory uncertainties or epistemic uncertainties. To improve the reliability of SPRA, the difference in seismic response due to difference of building modelings related to epistemic uncertainty was focused on. Two modeling methods were used for a seismic response analysis: a three-dimensional finite-element model and a conventional sway-rocking stick model. Simulated input ground motions related to aleatory uncertainty were generated for the input waves. Then, the seismic floor response results of the various input ground motions of the two modeling methods were quantified. For the uncertainty quantification related to the different building modelings, a statistical analysis of the floor response results of the nuclear reactor building were further performed. Finally, for the quantification of the uncertainty in the fragility analysis for SPRA, the way to use of these results were discussed.

This study identified and quantified possible cliff edge effects through a seismic safety evaluation of a nuclear power plant, based on the concepts of risk and defense in depth. Cliff edges of the both physical and knowledge-oriented type were considered in this study. We investigated a seismic isolation effect, etc., for physical cliff edges, and the modeling of the target structure, boundary conditions, etc., for knowledge-oriented cliff edges. Response analysis was performed using a sway-rocking (SR) model and a three-dimensional model of the target building. The seismic isolation effect of the base-isolated building was confirmed by comparison to the results of earthquake-resistant building. In the case of a collision with the retaining wall of the base-isolated building, the level of damage was found to depend on the modeling of the collision condition assumed. On the other hand, the study confirmed the differences between the results from the SR model and the three-dimensional model. And the greater fidelity of the three-dimensional model was also confirmed. This paper presents and discusses these results.

Background It is unclear whether the prognostic impact of diabetes mellitus (DM) in chronic heart failure (CHF) is influenced by ischemic heart disease (IHD) and/or nephropathy. Methods and results We enrolled 4,065 consecutive patients with stage C/D CHF (mean age, 69.0 years; 68.7% male) in the CHART-2 Study (n=10,219). We defined DM as current history of DM treatment or HbA1c ≥6.5% (National Glycohemoglobin Standardization Program [NGSP]), and nephropathy as urine albumin:creatinine ratio ≥30 mg/g or urine dipstick test ≥(±) at enrollment. Impacts of DM and nephropathy on the composite of death, myocardial infarction, stroke, and HF admission were examined. Among the 4,065 patients, 1,448 (35.6%) had DM, while IHD and nephropathy were also noted in 1,644 (40.4%) and in 1,549 (38.1%), respectively. During the median follow-up of 2.88 years, 1,025 (25.2%) reached the composite endpoint. On multivariate Cox regression, DM was significantly associated with the composite endpoint in all patients (HR, 1.17; P=0.02), and in those with IHD (HR, 1.38; P=0.004), but not in those without IHD (HR, 1.12; P=0.22; P for interaction=0.12). Furthermore, when the patients were stratified by nephropathy, DM was associated with worse prognosis only in the IHD patients with nephropathy. Conclusions The prognostic impact of DM was more evident in patients with IHD than in those without IHD, particularly when complicated with nephropathy.

Background The purposes of this study were to determine whether adjuvant chemotherapy (AC) improved the prognosis of patients with high-risk upper urinary tract urothelial carcinoma (UTUC)and to identify the patients who benefited from AC. Methods Among a multi-center database of 1014 patients who underwent RNU for UTUC, 344 patients with ≥ pT3 or the presence of lymphovascular invasion (LVI) were included. Cancer-specific survival (CSS) estimates were calculated by the Kaplan-Meier method, and groups were compared by the log-rank test. Each patient’s probability of receiving AC depending on the covariates in each group was estimated by logistic regression models. Propensity score matching was used to adjust the confounding factors for selecting patients for AC, and log-rank tests were applied to these propensity score-matched cohorts. Cox proportional hazards regression modeling was used to identify the variables with significant interaction with AC. Variables included age, pT category, LVI, tumor grade, ECOG performance status and low sodium or hemoglobin score, which we reported to be a prognostic factor of UTUC. Results Of the 344 patients, 241 (70%) had received RNU only and 103 (30%) had received RNU+AC. The median follow-up period was 32 (range 1–184) months. Overall, AC did not improve CSS (P = 0.12). After propensity score matching, the 5-year CSS was 69.0% in patients with RNU+AC versus 58.9% in patients with RNU alone (P = 0.030). Subgroup analyses of survival were performed to identify the patients who benefitted from AC. Subgroups of patients with low preoperative serum sodium (≤ 140 mEq/ml) or hemoglobin levels below the normal limit benefitted from AC (HR 0.34, 95% CI 0.15–0.61, P = 0.001). In the subgroup of patients with normal sodium and normal hemoglobin levels, 5-year CSS was 77.7% in patients with RNU+AC versus 80.2% in patients with RNU alone (P = 0.84). In contrast, in the subgroup of patients with low sodium or low hemoglobin levels, 5-year CSS was 71.0% in patients with RNU+AC versus 38.5% in patients with RNU alone (P < 0.001). Conclusions High-risk UTUC patients, especially subgroups of patients with lower sodium and hemoglobin levels, could benefit from AC after RNU.

Background:Microalbuminuria, traditionally defined as urinary albumin/creatinine ratio (UACR) ≥30 mg/g, is a risk factor for mortality even in patients with preserved glomerular filtration rate (GFR). The prognostic impact of subclinical microalbuminuria, however, remains unknown in patients with chronic heart failure (CHF).Methods and Results:In the Chronic Heart Failure Analysis and Registry in the Tohoku District 2 Study, we enrolled 2,039 consecutive symptomatic CHF patients (median age, 67.4 years; 68.9% male) after excluding those on hemodialysis. On classification and regression tree analysis, UACR=10.2 mg/g and 27.4 mg/g were identified as the first and second discriminating points to stratify the risk for composite of death, acute myocardial infarction, HF admission and stroke, therefore subclinical microalbuminuria was defined as UACR ≥10.2 and 60 ml·min–1·1.73 m–2, n=1,129) or mildly reduced eGFR (30–59.9 ml·min–1·1.73 m–2, n=789), respectively. In patients with severely reduced GFR (eGFR 80% had microalbuminuria or macroalbuminuria, and only 9.1% were free from any composite endpoints.Conclusions:Subclinical microalbuminuria was associated with increased risk of cardiovascular events in CHF patients with mildly reduced or preserved renal function. (Circ J 2014; 78: 2890–2898)

Background:Although the need for nursing care (NC) in heart failure (HF) patients is recognized, detailed information on the current status in Japan is lacking.Methods and Results:In the CHART-2 Study, we obtained information on daily life, physical ability, nutrition and mental status for 4,174 patients (mean age, 67.1±10.8 years; 73.3% male) out of 10,219 patients. We examined the prevalence, baseline characteristics and clinical outcomes of stage B and C/D HF patients requiring NC. The prevalence of HF requiring NC was significantly higher in stage C/D (38.6%) than in stage B (30.4%; P

Background The gender differences in patients with chronic heart failure (CHF) remain to be fully elucidated in the Japanese population. Methods and results We examined gender differences in clinical characteristics, treatment and long-term outcome in 4,736 consecutive CHF patients in stage C/D (mean age, 69 years) out of 10,219 patients registered in the CHF Registry, named CHART-2 Study (NCT 00418041). Compared with male patients (68%, n=3,234), female patients (32%, n=1,502) were 3.8 years older and had lower prevalence of ischemic heart disease, diabetes, smoking, myocardial infarction and cancer. At baseline, women had higher prevalence of preserved left ventricular function but had higher NYHA functional class and increased brain natriuretic peptide level. In women, aspirin, β-blockers and statins were less frequently used and diuretics were more frequently used. Crude mortality rate was similar between the genders during the median 3.1-year follow-up (52.4/1,000 and 47.3/1,000 person-years for women and men, respectively, P=0.225). On multivariate Cox regression analysis, women had a reduced risk of mortality (adjusted HR, 0.791; 95% CI: 0.640-0.979, P=0.031). Conclusions Substantial gender differences exist in stage C/D CHF patients in real-world practice in Japan. Although female CHF patients had better survival than male patients after adjustment for baseline differences, crude mortality rate was similar between the genders, possibly reflecting relatively severer clinical manifestations in women.

Aims It is still controversial whether elevated baseline heart rate (HR) is associated with higher mortality in patients with heart failure (HF) with preserved ejection fraction (HFpEF). We compared the impacts of baseline HR on mortality in patients with HFpEF and those with HF with reduced ejection fraction (HFrEF). Methods and results We enrolled consecutive 2688 patients in Stage C or D HF with sinus rhythm from our Chronic Heart Failure Analysis and Registry in the Tohoku District 2 (CHART-2) Study (n = 10 219). The prognostic impact of HR increase was compared between the two groups, defined as left ventricular ejection fraction of 50% (HFpEF). Cox regression analysis revealed that elevated baseline HR was associated with increased all-cause mortality in both groups [hazard ratio for the highest tertile (HH) 1.77 in HFrEF, P = 0.008; HH1.82 in HFpEF, P = 0.001]. However, as for mode of death, elevated HR was associated with cardiovascular (CV) death in HFpEF (HH 2.17, P = 0.012), but the association was modest in HFrEF (HH1.49, P = 0.14): in particular, impact on HF death was different between HFpEF (HH 3.79, P = 0.020) and HFrEF (HH 1.07, P = 0.864). In contrast, the prognostic impact of baseline HR on non-CV death was noted only in patients with HFrEF. β-Blocker therapy was associated with reduced HF mortality in HFrEF (hazard ratio 0.49, P = 0.038) but not in HFpEF (hazard ratio 0.64, P = 0.321). Conclusions Elevated HR was associated with increased CV death in HFpEF compared with HFrEF, although its impact on all-cause mortality was comparable between the two groups.