Long-Term Follow-up Study of Hospitalizations for Acute Coronary Syndrome in Kobe-City and Other Districts Under the Hyogo Smoking Ban Legislation　- A Nationwide Database Study.

BACKGROUND: Hyogo Prefecture has managed smoking ban legislation with partial restrictions in public places (Hyogo-L) since 2013. Previous studies have reported a significant decrease in admissions for acute coronary syndrome (ACS) in Kobe-city, but not in other districts of Hyogo Prefecture in the 2 years after Hyogo-L. The aim of the present study was to define the long-term effect of Hyogo-L.Methods and Results: The JROAD-DPC dataset was used to collect information on the number of hospitalizations for ACS in Hyogo Prefecture, and in Osaka-city without smoking ban legislation, from April 2013 to March 2020. Poisson regression analysis was performed to calculate incident rate ratios (IRRs) and 95% confidence intervals (CIs). ACS records of 3,101 in Kobe-city, 11,375 in areas of Hyogo Prefecture other than Kobe-city and 11,079 in Osaka-city were collected for admissions. The incidence of ACS reduced significantly over time in Kobe-city [IRR (95% CI); 0.96 (0.94-0.97)], but did not reduce in the others. The decrease in Kobe-city was observed in ACS patients without smoking, hypertension, and hyperlipidemia, but not in those with such risk factors. CONCLUSIONS: The long-term ACS reduction or non-reduction under Hyogo-L was determined at the initial period and the same scenario continued, supporting the importance of legislation and compliance with the smoking ban. The lowering effect was remarkable in ACS patients without risk factors such as non-smoking.

Safety Profile and Effectiveness of Rivaroxaban for Patients With Venous Thromboembolism in Japan　- Results From Post-Marketing Surveillance (XASSENT).

BACKGROUND: The incidence of venous thromboembolism (VTE; pulmonary embolism [PE] and/or deep vein thrombosis [DVT]) in Japan is increasing, but relatively small numbers of patients from Japan have been included in studies investigating rivaroxaban (a direct factor Xa inhibitor) for the treatment of VTE and preventing its recurrence.Methods and Results: An open-label, prospective, observational study (XASSENT [NCT02558465]) investigated the safety profile and effectiveness of rivaroxaban for ≤2 years in the treatment of VTE and prevention of its recurrence in Japanese clinical practice. Primary outcomes were major bleeding and symptomatic recurrent VTE. Statistical analyses were exploratory and descriptive. Overall, 2,540 patients were enrolled (safety analysis population [SAP], n=2,387; effectiveness analysis population [EAP], n=2,386). In the SAP, >80% of patients received the approved rivaroxaban dose, the mean (standard deviation) age was 66.6 (15.0) years, ≈74% were >50 kg, and 43% had a creatinine clearance ≥80 mL/min. PE+DVT, PE only, and DVT only were reported in 42%, 8%, and 50% of patients, respectively, and active cancer in 17% of patients. Major bleeding was reported in 69 patients (2.89%; 3.60%/patient-year; SAP) and symptomatic PE/DVT recurrence in 26 patients (1.09%; 1.36%/patient-year; EAP) during the treatment period. CONCLUSIONS: XASSENT provided information on the expected proportions of bleeding and VTE recurrence during rivaroxaban treatment in Japanese clinical practice; no new concerns of safety or effectiveness were found.

Rivaroxaban treatment for asymptomatic venous thromboembolism: insights from the J'xactly study.

BACKGROUND: An established treatment strategy for asymptomatic pulmonary embolism (PE) or deep vein thrombosis (DVT) remains uncertain in Japan; therefore, in this study, we clarify the characteristics and outcomes of symptomatic compared to asymptomatic patients with PE or DVT. METHODS: This prospective, multicenter sub-analysis of the J'xactly study in Japan included 1,016 patients (mean age, 68; 41% male) with venous thromboembolism (VTE) treated with rivaroxaban. RESULTS: Asymptomatic PE patients (47% of PE patients) were more likely to have active cancer and asymptomatic proximal DVT at lower severity than symptomatic PE patients, despite no differences in age, sex, or the proportion receiving intensive 30 mg/day-rivaroxaban. Patients with asymptomatic DVT (34% of DVT patients) were older, had higher rates of female sex, active cancer, and distal DVT, and received shorter, less intense rivaroxaban treatment. Incidences did not differ between asymptomatic and symptomatic PE patients for recurrent symptomatic VTE (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.22-1.62; P = 0.31) or major bleeding (HR, 0.68; 95% CI, 0.20-2.33; P = 0.58), nor between asymptomatic and symptomatic DVT patients for recurrent symptomatic VTE (HR, 0.56; 95% CI, 0.23-1.40; P = 0.21) and major bleeding (HR, 1.47; 95% CI, 0.54-3.97; P = 0.45). CONCLUSIONS: The real-world composite adverse event rate for treatment with rivaroxaban, as physician-adjusted for dose and duration, was similar for asymptomatic and symptomatic patients regardless of the presence of PE or DVT, suggesting a favorable safety profile for potential rivaroxaban treatment for asymptomatic VTE.

A cutoff-based method with charge-distribution-data driven pair potentials for efficiently estimating electrostatic interactions in molecular systems.

We introduce a simple cutoff-based method for precise electrostatic energy calculations in the molecular dynamics (MD) simulations of point-particle systems. Our method employs a theoretically derived smooth pair potential function to define electrostatic energy, offering stability and computational efficiency in MD simulations. Instead of imposing specific physical conditions, such as dielectric environments or charge neutrality, we focus on the relationship represented by a single summation formula of charge-weighted pair potentials. This approach allows an accurate energy approximation for each particle, enabling a straightforward error analysis. The resulting particle-dependent pair potential captures the charge distribution information, making it suitable for heterogeneous systems and ensuring an enhanced accuracy through distant information inclusion. Numerical investigations of the Madelung constants of crystalline systems validate the method's accuracy.

Postoperative cerebral infarction and arrhythmia after pulmonary lobectomy in Japan: a retrospective analysis of 77,060 cases in a national clinical database.

PURPOSE: To investigate the incidence of postoperative cerebral infarction after curative lobectomy, its association with the type of lobectomy, and how postoperative new-onset arrhythmia contributes to postoperative cerebral infarction. METHODS: The subjects of this analysis were 77,060 patients who underwent curative lobectomy for lung cancer between 2016 and 2018 according to the National Clinical Database. Incidences of postoperative cerebral infarction and postoperative new-onset arrhythmia were analyzed. Moreover, mediation analysis was performed to evaluate the causal pathway between postoperative new-onset arrhythmia and postoperative cerebral infarction. RESULTS: Postoperative cerebral infarction occurred in 110 (0.7%) patients after left upper lobectomy and in 85 (0.7%) patients after left lower lobectomy. Left upper lobectomy and left lower lobectomy were associated with a higher likelihood of postoperative cerebral infarction than right lower lobectomy. Left upper lobectomy was the strongest independent predictor of postoperative new-onset arrhythmia. However, in the mediation analysis, the odds ratio for cerebral infarction did not change after the addition of the factor of postoperative new-onset arrhythmia. CONCLUSION: Cerebral infarction occurred significantly more often not only after left upper lobectomy, but also after left lower lobectomy. Postoperative new-onset arrhythmia was less likely to be related to cerebral infarction after left upper lobectomy.

Directing a dispersion cannula tip toward the aortic root during thoracic aortic arch surgery does not adversely affect cardiac function.

INTRODUCTION: Neurologic complications of open thoracic aortic surgery are devastating problems in patients with severely diseased aortas. This study aimed to clarify whether directing the aortic cannula tip toward the aortic root affects the postoperative cardiac function in patients undergoing open thoracic aortic surgery. METHODS: A total of 16 patients who underwent total or partial arch replacement between January 2014 and April 2019 were enrolled and divided into two groups. Ascending aorta perfusion was performed by placing the cannula tip toward the aortic root (reversed direction group, seven patients) or toward the aortic arch (standard direction group, nine patients). Intraoperative and perioperative data, including mortality, morbidity, and postoperative cardiac function, were compared between the groups. RESULTS: There were no hospital deaths or stroke events in either group. The aortic cross-clamping time was 102.4 ± 20.3 minutes in the reversed direction group and 87.1 ± 9.9 minutes in the standard direction group (p = 0.049). Furthermore, the intubation time was 28.4 ± 12.9 hours in the reversed direction group and 12.4 ± 6.8 hours in the standard direction group (p = 0.022). Both times were significantly longer in the reverse direction group. Postoperative serum creatine kinase-MB levels were significantly lower in the reversed direction group (6.2 ± 3.3 U/L vs 13.3 ± 4.8 U/L, respectively, p = 0.006). The cardiac output and cardiac index did not significantly differ. CONCLUSIONS: Directing the aortic cannula tip toward the aortic root does not adversely affect the postoperative cardiac function after aortic arch surgery.

Clinical Implication of the Right Ventricular/Left Ventricular Diameter Ratio in Patients with Pulmonary Thromboembolism.

The role of the right to left ventricular (RV/LV) diameter ratio in predicating long-term outcomes in patients with pulmonary thromboembolisms (PTEs) treated with direct oral anticoagulants is unclear.We investigated the association between the RV/LV diameter ratio and clinical outcomes in PTE patients under rivaroxaban from the data of a multicenter, prospective, observational study (J'xactly Study) in Japanese patients with acute venous thromboembolisms (VTEs) including deep vein thromboses, PTEs, or both. Of a total of 1,039 patients with an acute VTE (from December 2016 to April 2018), 429 were diagnosed with PTEs, however, the population in this study consists of 216 patients in whom the RV/LV diameter ratio measured on the axial CT or transthoracic echocardiogram was available.The RV/LV diameter ratio increased significantly with the severity of the PTE classification (nonmassive 0.79 [0.67-0.93], submassive 1.10 [0.83-1.31], massive 1.13 [0.94-1.19], arrest or collapse 1.38 [0.66-2.38], P < 0.001). During a median follow-up of 624 (550-690) days, a sum of the composite adverse events including recurrent VTEs, acute coronary syndrome, ischemic strokes, death from any cause, or major bleeding events occurred in 26 patients (12.0%, 7.58 events per 100 patient-years). Multivariate analysis revealed that an RV/LV diameter ratio ≥ 1.0 had no association with the incidence of composite adverse events (HR 1.34, 95% confidence interval 0.59-2.91, P = 0.48).In summary, in Japanese PTE patients under rivaroxaban, the RV/LV diameter ratio measured on the CT or transthoracic echocardiogram was associated with the PTE severity, but not with the clinical outcomes.

A practical guide for perioperative smoking cessation.

The perioperative management of patients who are smokers presents anesthesiologists with various challenges related to respiratory, circulatory, and other clinical problems. Regarding 30-day postoperative outcomes, smokers have higher risks of mortality and complications than non-smokers, including death, pneumonia, unplanned tracheal intubation, mechanical ventilation, cardiac arrest, myocardial infarction, and stroke. Given the benefits of smoking cessation and the adverse effects of smoking on perioperative patient management, patients should quit smoking long before surgery. However, anesthesiologists cannot address these issues alone. The Japanese Society of Anesthesiologists established guidelines in 2015 (published in a medical journal in 2017) to enlighten surgical staff members and patients regarding perioperative tobacco cessation. The primary objective of perioperative smoking cessation is to reduce the risks of adverse cardiovascular and respiratory events, wound infection, and other perioperative complications. Perioperative preparations constitute a powerful teachable moment, a "golden opportunity" for smoking cessation to achieve improved primary disease outcomes and prevent the occurrence of tobacco-related conditions. This review updates the aforementioned guidelines as a practical guide to cover the nuts and bolts of perioperative smoking cessation. Its goal is to assist surgeons, anesthesiologists, and other medical professionals and to increase patients' awareness of smoking risks before elective surgery.

Flexibility and Cell Permeability of Cyclic Ras-Inhibitor Peptides Revealed by the Coupled Nosé-Hoover Equation.

Quantifying the cell permeability of cyclic peptides is crucial for their rational drug design. However, the reasons remain unclear why a minor chemical modification, such as the difference between Ras inhibitors cyclorasin 9A5 and 9A54, can substantially change a peptide's permeability. To address this question, we performed enhanced sampling simulations of these two 11-mer peptides using the coupled Nosé-Hoover equation (cNH) we recently developed. The present cNH simulations realized temperature fluctuations over a wide range (240-600 K) in a dynamic manner, allowing structural samplings that were well validated by nuclear Overhauser effect measurements. The derived structural ensembles were comprehensively analyzed by all-atom structural clustering, mapping the derived clusters onto principal components (PCs) that characterize the cyclic structure, and calculating cluster-dependent geometric and chemical properties. The planar-open conformation was dominant in aqueous solvent, owing to inclusion of the Trp side chain in the main-chain ring, while the compact-closed conformation, which favors cell permeation due to its compactness and high polarity, was also accessible. Conformation-dependent cell permeability was observed in one of the derived PCs, demonstrating that decreased cell permeability in 9A54 is due to the high free energy barrier separating the two conformations. The origin of the change in free energy surface was determined to be loss of flexibility in the modified residues 2-3, resulting from the increased bulkiness of their side chains. The derived molecular mechanism of cell permeability highlights the significance of complete structural dynamics surveys for accelerating drug development with cyclic peptides.

Human aortic valve interstitial cells obtained from patients with aortic valve stenosis are vascular endothelial growth factor receptor 2 positive and contribute to ectopic calcification.

Since aortic valve stenosis (AVS) is the most frequent and serious valvular heart disease in the elderly, and is accompanied by irreversible valve calcification, medicinal prevention of AVS is important. Although we recently demonstrated that human aortic valve interstitial cells (HAVICs) obtained from patients with AVS were highly sensitive to ectopic calcification stimulation, the cell types contributing to calcification are unknown. We aimed to immunocytochemically characterize HAVICs and identify their contribution to valve calcification. HAVICs were isolated from patients with AVS and cultured on non-coated dishes. Immunocytochemical features and HAVIC differentiation were analyzed in passage 1 (P1). The immunohistochemical features of the calcified aortic valve were analyzed. Most cultured P1 HAVICs were CD73-, CD90-, and CD105-positive, and CD45-and CD34-negative. HAVICs were vascular endothelial growth factor receptor 2 (VEGFR2)-positive; however, approximately half were α-smooth muscle actin (SMA)-positive, colonized, and easily differentiated into osteoblastic cells. Calcified aortic valve immunohistochemistry showed that all cells were positive for VEGFR2 and partly α-SMA. Further, VEGFR2-positive cells were more sensitive to tumor necrosis factor-α-induced ectopic calcification with or without α-SMA positivity. We conclude that HAVICs obtained from patients with AVS are VEGFR2-positive undifferentiated mesenchymal cells and may contribute to aortic valve ectopic calcification.

Flow analysis during mock circulation in normal and aortic arch aneurysm models through an aortic cannula toward the aortic arch and root.

The aim of this study was to elucidate flow patterns of two different types of aortic cannulas inserted from the ascending aorta toward the aortic arch and root by mock circulation in a normal aortic arch and an aortic arch aneurysm model. Extracorporeal circulation was established using a centrifugal pump, a transparent glass normal aortic arch model, and an aortic arch aneurysm model for measurement by particle image velocimetry. The Stealthflow and Dispersion cannulas were used to elucidate the characteristics of the flow pattern and velocity under the condition of the cannula tip toward the aortic arch and aortic root. In the normal aortic arch model, high-velocity exit flow ranging from 0.7 to 0.8 m/s was detected in the proximal aortic arch by directing the cannula tip toward the aortic arch, whereas flow velocity in the aortic arch was < 0.2 m/s by directing the cannula tip toward the aortic root. In the aortic arch aneurysm model, high-velocity exit flow ranging from 0.5 to 0.8 m/s was detected in the aortic arch by directing the cannula tip toward the aortic arch, whereas flow velocity in the aortic arch was decreased to less than 0.2 m/s by directing the cannula tip toward the aortic root. Directing the aortic cannula tip toward the aortic root allowed the high-velocity exit flow to attenuate in velocity, so that flow velocity in the aortic arch was sufficiently reduced by reversed flow and vortex formation in both the normal and aortic arch aneurysm models.

The utility of extracorporeal membrane oxygenation in patients with circulatory collapse by electrical storm.

In patients experiencing electrical storm, intensive care using extracorporeal membrane oxygenation (ECMO) is an efficient treatment to overcome a hemodynamically unstable condition. The aim of this study was to examine the utility of ECMO in patients with circulatory collapse by electrical storm. We retrospectively examined 17 consecutive patients receiving veno-arterial ECMO for electrical storm between January 2016 and December 2018 in our institution. We compared survivors (n = 11) and non-survivors (n = 6). Thirteen were weaned from ECMO, of whom 11 patients (64.7%) survived and were discharged from hospital, while 6 patients died (35.3%). In comparisons between survivors and non-survivors, blood pH before starting ECMO was significantly higher in survivors (pH 7.32) than in non-survivors (pH 6.89, p = 0.027). Blood lactate level was significantly lower in survivors (6.2 mmol/L) than in non-survivors (12.2 mmol/L, p = 0.044). Complications of hypoxic ischemic encephalopathy were found in 4 non-survivors (66.7%), compared to survivors (0%, p = 0.006). Durations of intensive care unit stay and hospital stay were significantly longer in survivors (271 h, 62 days) than in non-survivors (50 h, 3 days, respectively). Outcomes of treatment using ECMO in patients with circulatory collapse due to electrical storm proved satisfactory. Increases in blood lactate level and decreases in blood pH before starting ECMO were thought to be related to mortality due to suspected irreversible organ damage by hypoxia before ECMO.

Coronary artery bypass grafting after sternal turnover procedure and a review of the literature.

We report a case of complete revascularization after a sternal turnover procedure through median sternotomy in a patient with multivessel coronary artery disease. The patient had unusual anatomical features, such as the anterior protrusion of the middle-to-distal sternum and absent bilateral internal thoracic arteries (ITAs). The single-blade sternum retractor and the Omni-Tract retractors are simple and reliable tools for lifting and widening the thoracic wall around the xiphoid process. The bilateral radial arteries and the great saphenous vein were used as bypass grafts. Computed tomography was used to visualize the sternum supplied by the superior epigastric arteries (SEAs); presurgical abdominal ultrasonography revealed the course and crossing point of the developed SEAs. Since ITAs were absent, we preserved the SEAs to prevent sternal ischemia. No sternal complications or graft occlusion were observed during follow-up.

Coronary artery bypass for Takayasu's arteritis involving the aortic root in a child.

The patient was a 12-year-old female who presented with angina pectoris, aortic root dilatation, and aortic regurgitation (AR) caused by Takayasu's arteritis (TA). After the management of systemic inflammation, she underwent off-pump coronary artery bypass with the radial artery (RA), which extended from the left axillary artery to the left descending coronary artery, via left mini-thoracotomy. Postoperative angiography revealed the growth of the RA graft. The patient is well 4 years after surgery without progression of AR. Off-pump coronary artery bypass is a palliative therapy. Moreover, it could be a feasible option in a child with TA involving the aortic root.

Clinical evaluation of a new dispersive aortic cannula.

INTRODUCTION: Cerebral injury is a serious complication in open-heart surgery. Once it occurs, it causes significant disability and death. We developed a novel dispersive aortic cannula named the Stealth Flow cannula and used it as a standard aortic cannula in cardiopulmonary bypass. The aim of this study was to evaluate the efficiency of this aortic cannula. METHODS: A total of 182 consecutive patients undergoing cardiac surgery using cardiopulmonary bypass were studied. The patients were divided into two groups: the Soft-Flow cannula group (n = 89) and the Stealth Flow cannula group (n = 93). Patients with a shaggy aortic arch were excluded from this study because the cannulae were inserted at the ascending aorta with a cannula tip directed toward the aortic root in these cases. Patients with multiple arterial perfusion sites were also excluded. Complications including early mortality, perioperative stroke, and intraoperative aortic injury were compared between the two groups. RESULTS: Age, operative procedure, cardiopulmonary bypass time, and the Japan SCORE were not significantly different between the groups. In comparisons between the Stealth Flow and Soft-Flow groups, the incidences of early mortality, perioperative stroke, intraoperative aortic dissection, and all complications were 1.08% versus 1.12% (p = 0.98), 1.1% versus 2.2% (p = 0.53), 0% versus 1.1% (p = 0.33), and 1.1% versus 3.4% (p = 0.29), respectively. The incidence of major cardiovascular events, including early death, perioperative stroke, and aortic dissection, was not different. CONCLUSIONS: The Stealth Flow cannula, which was designed based on our previous experimental study, contributed to reducing cerebral and aortic events as much as the Soft-Flow cannula in the present clinical study.

[Aortic Root Partial Reconstruction Combined with Intraoperative Aortic Dissection:Report of a Case].

A 73-year-old woman with Valsalva aneurysm and mitral regurgitation was introduced to our department. We performed combined operation including aortic root partial repair and mitral valve repair. After wenning from cardiopulmonary bypass, intraoperative aortic dissection was confirmed by transesophageal echocardiography from the ascending aorta to the descending aorta, entry was near to proximal anastomosis line of the ascending aorta. To avoid heart failure, the ascending aorta wrapping by prothesis graft was performed to protect from urgent rupture postoperative at first stage. According to contrast computed tomography (CT) findings, location of entry was correspond with aortic clamping. We performed partial aortic replacement including innominate artery reconstruction for her at fourth day postoperative for treating aortic dissection at second stage. Postoperative course was uneventful.

Menaquinone-4 Accelerates Calcification of Human Aortic Valve Interstitial Cells in High-Phosphate Medium through PXR.

Recently, we confirmed that in human aortic valve interstitial cells (HAVICs) isolated from patients with aortic valve stenosis (AVS), calcification is induced in high inorganic phosphate (high-Pi) medium by warfarin (WFN). Because WFN is known as a vitamin K antagonist, reducing the formation of blood clots by vitamin K cycle, we hypothesized that vitamin K regulates WFN-induced HAVIC calcification. Here, we sought to determine whether WFN-induced HAVIC calcification in high-Pi medium is inhibited by menaquinone-4 (MK-4), the most common form of vitamin K2 in animals. HAVICs obtained from patients with AVS were cultured in α-modified Eagle's medium containing 10% FBS, and when the cells reached 80%-90% confluency, they were further cultured in the presence or absence of MK-4 and WFN for 7 days in high-Pi medium (3.2 mM Pi). Intriguingly, in high-Pi medium, MK-4 dose-dependently accelerated WFN-induced HAVIC calcification and also accelerated the calcification when used alone (at 10 nM). Furthermore, MK-4 enhanced alkaline phosphatase (ALP) activity in HAVICs, and 7 days of MK-4 treatment markedly upregulated the gene expression of the calcification marker bone morphogenetic protein 2 (BMP2). Notably, MK-4-induced calcification was potently suppressed by two pregnane X receptor (PXR) inhibitors, ketoconazole and coumestrol; conversely, PXR activity was weakly increased, but in a statistically significant and dose-dependent manner, by MK-4. Lastly, in physiologic-Pi medium, MK-4 increased BMP2 gene expression and accelerated excess BMP2 (30 ng/ml)-induced HAVIC calcification. These results suggest that MK-4, namely vitamin K2, accelerates calcification of HAVICs from patients with AVS like WFN via PXR-BMP2-ALP pathway. SIGNIFICANCE STATEMENT: For aortic valve stenosis (AVS) induced by irreversible valve calcification, the most effective treatment is surgical aortic or transcatheter aortic valve replacement, but ∼20% of patients are deemed unsuitable because of its invasiveness. For effective drug treatment strategies for AVS, the mechanisms underlying aortic valve calcification must be elucidated. Here, we show that menaquinone-4 accelerates warfarin-induced calcification of AVS-patient human aortic valve interstitial cells in high inorganic phosphate medium; this effect is mediated by pregnane X receptor-bone morphogenetic protein 2-alkaline phosphatase signaling, which could be targeted for novel drug development.

Correction to: Warfarin calcifies human aortic valve interstitial cells at high-phosphate conditions via pregnane X receptor.

In the original publication of the article, part of Fig. 1 was published incorrectly.

Molecular Interaction Mechanism of a 14-3-3 Protein with a Phosphorylated Peptide Elucidated by Enhanced Conformational Sampling.

Enhanced conformational sampling, a genetic-algorithm-guided multidimensional virtual-system coupled molecular dynamics, can provide equilibrated conformational distributions of a receptor protein and a flexible ligand at room temperature. The distributions provide not only the most stable but also semistable complex structures and propose a ligand-receptor binding process. This method was applied to a system consisting of a receptor protein, 14-3-3ε, and a flexible peptide, phosphorylated myeloid leukemia factor 1 (pMLF1). The results present comprehensive binding pathways of pMLF1 to 14-3-3ε. We identified four thermodynamically stable clusters of MLF1 on the 14-3-3ε surface and free-energy barriers among some clusters. The most stable cluster includes two high-density spots connected by a narrow corridor. When pMLF1 passes the corridor, a salt-bridge relay (switching) related to the phosphorylated residue of pMLF1 occurs. Conformations in one high-density spot are similar to the experimentally determined complex structure. Three-dimensional distributions of residues in the intermolecular interface rationally explain the binding constant changes resulting from the alanine mutation experiment for the residues. We also performed a simulation of nonphosphorylated peptide and 14-3-3ε, which demonstrated that the complex structure was unstable, suggesting that phosphorylation of the peptide is crucially important for binding to 14-3-3ε.

A Multicenter Prospective Observational Cohort Study to Investigate the Effectiveness and Safety of Rivaroxaban in Japanese Venous Thromboembolism Patients (The J'xactly Study).

BACKGROUND: There is insufficient real-world data on the current status of Japanese patients with venous thromboembolism (VTE) or its treatment and prevention with rivaroxaban.Methods and Results:In this multicenter, prospective, observational study conducted in Japan, 1,039 patients with acute symptomatic/asymptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE) with or without DVT prescribed rivaroxaban were enrolled at 152 institutions and observed for a median of 21.3 months. Mean age was 68.0±14.7 years, mean body weight was 60.3±14.1 kg, 59.0% were females, and 19.0% had active cancer. Incidences of recurrence or aggravation of symptomatic VTE (primary effectiveness outcome) and major bleeding (principal safety outcome) were 2.6% and 2.9% per patient-year, respectively. These outcomes did not differ between patients with DVT and those with PE (primary effectiveness outcome: 2.6% vs. 2.5% per patient-year, P=0.810; principal safety outcome: 3.5% vs. 2.4% per patient-year, P=0.394). The incidence of composite clinically relevant events, including recurrence or aggravation of symptomatic VTE, acute coronary syndrome, ischemic stroke, all-cause death, or major bleeding events, was 9.2% per patient-year. Multivariate analysis revealed that male sex, being underweight, having active cancer, chronic heart and lung disease, and previous stroke were independent determinants for composite clinically relevant events. CONCLUSIONS: In Japanese clinical practice, a single-drug approach with rivaroxaban was demonstrated to be a valuable treatment for a broad range of VTE patients.