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Pulmonary embolism (PE) and deep vein thrombosis (DVT) can be considered as one clinical entity, venous thromboembolism (VTE). However, the potential differences between PE and DVT might have to be taken into consideration for the decision-making of the optimal treatment strategies.The COMMAND VTE Registry is a multicenter registry enrolling 3027 consecutive patients with acute symptomatic VTE. The current study population consisted of 1715 PE patients with or without DVT and 1312 DVT only patients.The adjusted risk for recurrent VTE was not significantly different between the PE and DVT only groups (HR 1.22, 95%CI 0.93-1.60, P = 0.15). PE patients developed recurrent VTE events more often as PE than as DVT only (62% and 38%). The adjusted excess mortality risk of PE patients relative to DVT only patients was significant (HR 1.29, 95%CI 1.11-1.50, P 0.001), with markedly higher cumulative 30-day incidence of all-cause death in PE patients (6.4% and 1.4%, P 0.001). The most frequent cause of deaths was cancer death in both groups, and second most frequent cause of deaths in PE patients was fatal PE, most of which developed within 30 days.The risk for recurrent VTE was not significantly different between PE and DVT, although PE was more likely to develop recurrent VTE as PE. The mortality risk of PE seemed to be higher than that of DVT, which was more remarkable in the short term due to PE death, and less remarkable in the long term due to cancer death.

BACKGROUND The recently proposed VTE-BLEED score to predict the risk of major bleeding in patients with venous thromboembolisms (VTEs) on prolonged anticoagulation therapy was validated externally in randomized controlled trials and in a selected cohort, but not applied in non-selective cohorts. OBJECTIVES The present study aimed to evaluate the generalizability of the VTE-BLEED score in a non-selective cohort. PATIENTS/METHODS The COMMAND VTE Registry is a multicenter retrospective registry enrolling consecutive patients with acute symptomatic VTEs among 29 centers in Japan. The present study population consisted of 2124 patients with prolonged anticoagulation therapy beyond 30 days, including 2008 (95%) patients with a first VTE episode and 1075 (51%) with unprovoked VTEs, who were divided into 1445 patients (68%) with a VTE-BLEED score of ≥2 (high-risk group) and 679 (32%) with a VTE-BLEED score of

Statins, which are considered as essential for primary and secondary prevention of atherosclerotic diseases, were also reported to reduce first venous thromboembolism (VTE). However, the effect of statins on VTE recurrence remains conflicting. We aimed to examine the association between statin use and VTE recurrence in a large observational study in Japan. The COMMAND VTE Registry is a multicenter registry enrolling consecutive 3027 patients with acute symptomatic VTE in 29 centers in Japan between January 2010 and August 2014. In the current study, the entire cohort was divided into statin group (N = 437) and no-statin group (N = 2590) according to the status of statin use at baseline. The statin group as compared with the no-statin group was older (statin group 71.2 vs no-statin group 66.5 years, p0.001), included more women (67% vs 60%, p = 0.008), and less frequently had active cancer (12% vs 25%, p0.001). There was no significant difference in the clinical presentation of VTE (pulmonary embolism, 58% vs 56%, p = 0.44). The cumulative 3-year incidence of recurrent VTE was significantly lower in the statin group than the no-statin group (3.8% vs 8.8%, p0.001). After adjusting for confounders including active cancer, statin use was associated with significantly lower risk for recurrent VTE (Hazard ratio 0.49, 95% confidence interval 0.29 to 0.78, p = 0.002). The results were consistent in a sensitivity sub-group analysis with and without active cancer. In conclusion, statin use was associated with significantly lower risk for the recurrent VTE in patients with VTE.

There is still uncertainty about the optimal usage of thrombolysis for acute pulmonary embolisms (PEs), leading to a widely varying usage in the real world. The COMMAND VTE Registry is a multicenter retrospective registry enrolling consecutive patients with acute symptomatic venous thromboembolisms (VTEs) in Japan. The present study population consisted of 1549 patients with PEs treated with tissue plasminogen activator (t-PA) thrombolysis (N = 180, 12%) or without thrombolysis (N = 1369). Thrombolysis with t-PA was implemented in 33% of patients with severe PEs, and 9.2% of patients with mild PEs with a wide variation across the participating centers. Patients with t-PA thrombolysis were younger, and less frequently had active cancer, history of major bleeding, and anemia. At 30 days, t-PA thrombolysis as compared to no thrombolysis was associated with similar mortality rates (5.0% vs. 6.9%, P = 0.33), but a lower adjusted mortality risk (OR 0.41; 95% CI 0.18–0.90, P = 0.03), while it was associated with a trend for higher rates of major bleeding (5.6% vs. 2.9%, P = 0.06) and a significantly higher adjusted risk for major bleeding (OR 2.39; 95% CI 1.06–5.36, P = 0.03). In patients with severe PEs, the mortality rates at 30 days were significantly lower in the t-PA thrombolysis group than no thrombolysis group (15% vs. 37%, P = 0.006). In the present real-world VTE registry in Japan, t-PA thrombolysis was not infrequently implemented, not only in patients with severe PEs, but also in patients with mild PEs. A substantial mortality risk reduction might be suggested with t-PA thrombolysis in patients with severe PEs.

BACKGROUND It remains controversial whether sex category is a risk for recurrent venous thromboembolism (VTE) and major bleeding among VTE patients.Methods and Results:The COMMAND VTE Registry is a multicenter registry enrolling 3,027 consecutive acute symptomatic VTE patients from 29 centers in Japan between January 2010 and August 2014. We compared the clinical characteristics and outcomes of men and women. Men accounted for 1,169 (39%) and women 1,858 (61%). Compared with women, men were younger (64.9±14.7 vs. 68.6±15.6 years old, P

The influence of anemia on the long-term clinical outcomes has not been fully evaluated in patients with venous thromboembolism (VTE). We evaluated the influence of anemia among 3012 patients in the COMMAND VTE Registry with a median follow-up period of 1219 days. The outcomes measures were ISTH major bleeding, recurrent VTE and all-cause death. There were 1012 patients (34%) with moderate/severe anemia (Hb ≤ 10.9 g/dl), 615 patients (20%) with mild anemia (Hb 11.0–12.9 g/dl for men, and 11.0–11.9 g/dl for women), and 1385 patients (46%) without anemia. The cumulative 5-year incidence of major bleeding was significantly higher in patients with anemia (moderate/severe anemia: 17.6%, mild anemia: 12.1%, and no anemia: 8.7%, P

There is a paucity of data on patients with deep vein thrombosis (DVT) in upper extremities.The COMMAND VTE Registry is a retrospective multicenter registry enrolling 3027 consecutive patients with acute symptomatic venous thromboembolism (VTE) in Japan. The current study population included 2498 patients with upper or lower extremities DVT.There were 74 patients (3.0%) with upper extremities DVT and 2424 patients with lower extremities DVT. Patients with upper extremities DVT more often had active cancer (58%) and central venous catheter use (22%). The proportion of concomitant pulmonary embolism at diagnosis was lower in patients with upper extremities DVT than in those with lower extremities DVT (14% and 51%, P 0.001). Discontinuation of anticoagulation therapy was more frequent in patients with upper extremities DVT (63.8% and 29.8% at 1-year, P 0.001). The cumulative 3-year incidence of recurrent VTE was not different between the 2 groups (9.8% and 7.4%, P = 0.43). After adjusting confounders, the risks of upper extremities DVT relative to lower extremities DVT for recurrent VTE remained insignificant (HR 0.94, 95%CI 0.36-2.01, P = 0.89).The prevalence of patients with DVT in upper extremities was 3.0% in the current large-scale real-world registry. Patients with DVT in upper extremities more often had active cancer at diagnosis and central venous catheter use as a transient risk factor for VTE, and less often had concomitant PE. Patients with DVT in upper extremities had similar long-term risk for recurrent VTE as those with DVT in lower extremities despite shorter duration of anticoagulation.

The influence of thrombocytopenia on the long-term clinical outcomes has not been thoroughly evaluated in patients with venous thromboembolism (VTE). This study sought to elucidate association of baseline thrombocytopenia with bleeding, recurrent VTE, and mortality risk. We evaluated the influence of baseline thrombocytopenia among 3,012 patients whose baseline platelet counts were available in the COMMAND VTE Registry in Japan with a median follow-up period of 1,219 days. Baseline thrombocytopenia was classified as follows: mild: 100,000 to 150,000/μl; moderate: 50,000 to 99,999/μl; and severe

Post-thrombotic syndrome (PTS) is the most common chronic complication of deep vein thrombosis (DVT). Identifying high-risk patients for the development of PTS might be useful for its prevention. The COMMAND VTE Registry is a multicenter registry that enrolled 3027 consecutive patients with acute symptomatic venous thromboembolisms (VTEs) in Japan between January 2010 and August 2014. The current study population consisted of 1298 patients with lower extremities DVTs who completed 3-year follow-up for those who developed PTS and those without PTS. We investigated risk factors for the development of PTS at the time of DVT diagnosis, using a multivariable logistic regression analysis. Of the entire 1298 study patients, 169 (13%) patients were diagnosed with PTS within 3 years. The rate for anticoagulation discontinuation during follow-up was not significantly different between those with and without PTS. Chronic kidney disease (OR 2.21, 95% CI 1.45–3.39, P

BACKGROUND Venous thromboembolism (VTE) has a long-term risk of recurrence, which can be prevented by anticoagulation therapy.Methods and Results:The COMMAND VTE Registry is a multicenter registry enrolling 3,027 consecutive patients with acute symptomatic VTE between January 2010 and August 2014. The entire cohort was divided into the transient risk (n=855, 28%), unprovoked (n=1,477, 49%), and cancer groups (n=695, 23%). The rate of anticoagulation discontinuation was highest in the cancer group (transient risk: 37.3% vs. unprovoked: 21.4% vs. cancer: 43.5% at 1 year, P

It has been proven that the use of an inferior vena cava filter (IVCF) is effective in decreasing the incidence of pulmonary embolism (PE) in high-risk spinal surgery patients. A case of fatal PE after spinal surgery in a 78-year-old woman who had a history of pulmonary hypertension due to peripheral PE treated with a permanent IVCF and anticoagulant therapy for 3 years is reported. The patient had experienced an episode of recurrent PE during the withdrawal of anticoagulants, but she had uneventfully undergone two orthopedic surgeries with a preoperative unfractionated heparin infusion instead of oral warfarin. Three months after the second operation, she underwent posterior lumbar spinal fusion. The following morning, she suddenly complained of chest discomfort and dyspnea with SpO(2) 78 %. An electrocardiogram showed a right bundle branch block. Then, 30 min later, she suddenly lost consciousness, and her carotid pulse was not palpable. The patient died 2 h and 30 min after onset. Acute PE probably occurred because of a massive thrombus above the IVCF. This case suggests that the efficacy of long- term use of a permanent IVCF is limited in cases when anticoagulants must be withdrawn, such as for orthopedic surgery.

All tests were performed for high-strength aluminum alloy plate with a notch on both sides. Firstly, the proposed simplified method for estimating the stress and strain at the notch root was investigated. The strain at the notch root was measured by a strain gage. The estimated strains and strain ranges were in good agreement with the experimental results. Next, fatigue tests were carried out under constant amplitude loading and two-step loading. In two-step loading, two stress levels were used as the primary stress amplitude and three cycle ratios were combined. The cycle ratio was defined as the ratio of cycles at the primary stress amplitude to the corresponding fatigue life. Fatigue test results were discussed using the equivalent stress amplitude, which was estimated by the stress amplitude and the mean stress at the notch root. Both the fatigue life and the fatigue limit under the secondary stress amplitude tended to lower, as the cycle ratio under the primary stress amplitude increased. However, the fatigue life under the secondary stress amplitude did not depend upon the magnitude of the primary stress amplitude, if the cycle ratio was same. Hence, the fatigue life under the secondary stress amplitude can be estimated by the equivalent stress amplitude without the effect of the primary stress amplitude.

Fatigue tests of rolled bolt-nut joints were carried out under constant-amplitude loading and two-step loading with three primary stresses. The bolted joints failed in the threaded region at the root of the first thread where the nut and bolt were engaged. Experimental results indicated that cycles to failure of the secondary nominal stress amplitude, where the nominal stress was the load divided by the area of net section in the threaded region, depended on the primary stress and its cycle ratio. In order to know the local stress under elastic-plastic condition at the thread root where fatigue failure occurred, a simplified method based on Neuber' rule and Glinka's rule was investigated. Equivalent stress amplitude, which was a fully reversed stress amplitude, was investigated from the estimated local stresses under the loading cycles and the relation of stress amplitude with mean stress. As a result of investigation of experimental data using the equivalent stress, cycles to failure of the secondary equivalent stress amplitude depended on the cycle ratio of the primary stress and did not depend so much on the primary stress. The fatigue life prediction method based on the above result was proposed. The estimated fatigue life was generally in good agreement with the experimental results.

Based on the previously proposed damage rule and life prediction method for rolled bolt-nut joints under two-step loading, life prediction method for three-step loading and three-level multi-step loading was investigated. The effect of load histories and change of material properties with damage accumulation was taken into account in the prediction method. Required material properties were obtained from fatigue tests under constant stress amplitude and two-step loading. In order to investigate applicability of the life prediction method, axial load controlled fatigue tests of rolled bolt-nut joints were carried out. Experiments indicated that the predicted results were in good agreement with the experimental results.

A simplified method for estimating the elastoplastic stress and strain distribution on 60°V notch section from a result of elastic analysis was presented. Elastic and elastoplastic analyses of 60°V notched bars and plates subjected to tensile force were carried out by FEM. It was found from these analyses that the distributions on notch section of equivalent strains obtained from equivalent stresses, stress ratios and strain ratios in elastic condition were analogous to those distributions in elastoplastic condition. The proposed simplified method was based on these analogies, the total strain theory and equilibrium condition of axial force. Good estimated results of the stress and strain distribution, the maximum notch strain and the plastic zone size were obtained. The maximum notch strain estimated by the simplified method was also compared with that by Neuber's and Glinka's methods.

Rotating bending fatigue tests were performed using smooth and precracked 0.25%C annealed steel specimens. The initiation and propagation of fatigue cracks were successively observed by the replication method, and the cumulative fatigue damage under two-step loading was investigated. Precracked specimens with four different precrack lengths, 150, 300, 450 and 700μm, were examined and the S-N curves for the precracked specimens with arbitrary crack lengths were estimated. The fatigue damage defined by Miner's rule under two-step loading was estimated from the crack propagation curve, the S-N curve of the smooth specimen and the estimated S-N curve for the precracked specimen. The estimated average value of the lower limit was 0.97, but it was 0.60 when the scatter of the experimental data in each specimen was considered.

We will show that the objective function of a constrained least square problem for estimating the term structure of the interest rates discussed in [4] is in fact convex in the feasible region defined by a set of linear constraints. This means that the algorithm developed in [4], which uses a linear or quadratic approximation to the objective function, generates a globally optimal solution of a constrained least square problem.

This paper proposes a new practical method for estimating forward rate curves using bond prices available in the market. It is intended to improve the least square estimation method proposed by Carleton and Cooper by imposing additional constraints to guarantee the smoothness of the forward rate curves. The resulting problem is a nonconvex minimization problem, for which we will propose an efficient algorithm for calculating an approximate optimal solution. Computational experiments show that this method can efficiently generate smooth forward rate curves without increasing the residual errors in terms of least square fitting. Also, we will compare this result with an alternative and more efficient constrained least absolute deviation method.

Metastasis-associated protein, S100A4 is suggested as a marker for fibrosis in several organs. It also modulates DNA binding of p53 and affects its function. However, the functional role of S100A4 in the myocardium has remained unclear. Therefore, we investigated the role of S100A4 and its relationship with p53 in cardiac fibrosis. In Dahl-rat hypertensive heart disease model, S100A4 was upregulated in the hypertrophic myocardium and further activated during transition to heart failure (HF). It was expressed in various cells including fibroblasts. In in vitro cardiac fibroblasts, the knockdown of S100A4 significantly suppressed both cell proliferation and collagen expressions. S100A4 co-localized and interacted with p53 in the nucleus. S100A4 knockdown increased the expression of p53-downstream genes, p21 and mdm2, and concomitant knockdown of p53 recovered cell proliferation and collagen expression. Transverse aortic constriction (TAC) was performed in S100A4 knockout (KO) mice, which showed a similar baseline-phenotype to wild type (WT) mice. Although there was no difference in hypertrophic response, KO mice showed reduced interstitial fibrosis, decreased myofibroblasts, and suppressed expressions of collagens and profibrotic cytokines in the left ventricle. Also, DNA microarray analysis showed that S100A4 knockout in vivo had a significant impact on expressions of p53-associated genes. These findings suggest that S100A4 modulates p53 function in fibroblasts and thereby mediates myocardial interstitial fibrosis through two distinct mechanisms; cell proliferation and collagen expression. Blockade of S100A4 may have therapeutic potential in cardiac hypertrophy and HF by attenuating cardiac fibrosis.

Background— Although recent clinical trials have demonstrated the efficacy of the oral vasopressin (AVP) type 2 receptor (V2R) antagonist tolvaptan, its long-term effects on the myocardium and kidney in heart failure (HF) are not clear. We examined the chronic effects of tolvaptan administration on both the myocardium and kidney in a rat hypertensive HF model. Methods and Results— Not only circulating AVP level but also myocardial AVP and V1a receptor (V1aR) expressions, renal V1aR, and V2R expressions were significantly upregulated during the transition to HF. The animals were chronically treated with low-dose or high-dose (HD) tolvaptan or vehicle from the left ventricular (LV) hypertrophic stage. Chronic tolvaptan treatment persistently increased urine volume but did not affect blood pressure. In the HD group, the animal survival significantly improved (log-rank test, P P Conclusions— These results indicate that chronic tolvaptan treatment has beneficial effects by preventing not only the progression of LV dysfunction but also that of renal injury in hypertensive rats with HF. The underlying mechanism may be related to the suppression of myocardial and renal neurohumoral activation.

An embedded force doublet (EFD) model is proposed to express the presence of permanent strain in body force method (BFM). BFM is known as a boundary type method for elastic stress analysis based on the principle of superposition. In EFD model, the permanent strain is replaced by distributed force doublets. In an actual elastic–plastic analysis, the plastic region whose shape is not clear a priori, have to be discretized into elements where the magnitude of embedded force doublets is unknown to be determined numerically. In general, the determination process of magnitude of EFD is considerably difficult due to nonlinear nature of yield criterion and plastic constitutive relations. In this study, by introducing the automated Delaunay tessellation scheme for discretizing the prospective plastic region, appreciable reduction in input data was realized. Adding to this, in order to improve the computational efficiency, influence coefficients used for determining the magnitude of EFD are stored in a database. The effectiveness of these two inventions was examined by computing the elastic–plastic problem of an infinite medium with circular hole subjected to uniform internal pressure. The numerical solution was compared with Nadai’s closed form solution and found a good agreement.

Time-dependent thermal stress field was analyzed when a crack-face was heated locally in an infinite plate. From the beginning of heating, the crack closes partly on each side of the heat source and bears the compressive stress. The closed region size, growing with time, depends on the heating location and heat dissipation from the surfaces. At the nearer crack tip to the heat source, tip-closing occurs at first and then at the other tip. As long as some part of the crack remains open, the stress field has singularity at the open crack tip. The stress intensity factor there varies with time and attains to its maximum after a certain duration, showing the similarity to the previous study where a point ahead of the crack tip is heated. By the optical interference method, crack opening displacement was measured experimentally using center-cracked glass plates heated by CO2 laser beam. Measured displacements, varing with time, were well approximated by the analysis.