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Abstract Background Recurrence of atrial fibrillation (AF) after pulmonary vein isolation (PVI) is associated with left atrial (LA) remodeling; however, its association with right atrial (RA) remodeling remains unclear. Objective This study aimed to identify whether RA structural remodeling could predict recurrence of AF after PVI. Methods This study prospectively analyzed 245 patients with AF who had undergone PVI. RA and LA volumes were determined by contrast‐enhanced computed tomography. Atrial structural remodeling was defined as an atrial volume of ≥110 mL according to previous reports and receiver operating characteristic curve analysis. Results After excluding 32 patients, 213 patients were analyzed. During a follow‐up period of 12 months, 41 patients (19%) demonstrated atrial arrhythmia recurrence after PVI. With the Cox proportional‐hazards model, RA structural remodeling was the only predictor of arrhythmia recurrence (hazard ratio, 1.012; 95% confidence interval 1.003‐1.021; P = .009). Kaplan–Meier analysis showed that arrhythmia recurrence was more frequent in the RA structural remodeling group compared with the group without RA remodeling (log‐rank, P

Heart failure (HF) is challenging public medical and healthcare systems. This study aimed to develop and validate a novel deep learning-based prognostic model to predict the risk of all-cause mortality for patients with HF. We also compared the performance of the proposed model with those of classical deep learning- and traditional statistical-based models. The present study enrolled 730 patients with HF hospitalized at Toho University Ohashi Medical Center between April 2016 and March 2020. A recurrent neural network-based model (RNNSurv) involving time-varying covariates was developed and validated. The proposed RNNSurv showed better prediction performance than those of a deep feed-forward neural network-based model (referred as “DeepSurv”) and a multivariate Cox proportional hazard model in view of discrimination (C-index: 0.839 vs. 0.755 vs. 0.762, respectively), calibration (better fit with a 45-degree line), and ability of risk stratification, especially identifying patients with high risk of mortality. The proposed RNNSurv demonstrated an improved prediction performance in consideration of temporal information from time-varying covariates that could assist clinical decision-making. Additionally, this study found that significant risk and protective factors of mortality were specific to risk levels, highlighting the demand for an individual-specific clinical strategy instead of a uniform one for all patients.

Abstract Background Dabigatran is a direct thrombin inhibitor and an anticoagulant that is prescribed to prevent ischemic stroke and systemic embolism in non-valvular atrial fibrillation. Dabigatran (150 mg twice daily) is non-inferior to warfarin for the prevention of stroke and systemic embolism. A dose reduction to 110 mg twice daily should be considered for patients with decreased renal function, elderly patients, and those with a history of gastrointestinal bleeding. A small number of patients are prescribed 75 mg twice daily; however, excessive dose reduction below that indicated on the package insert may decrease the effectiveness of dabigatran. In this study, we investigated the incidence of thromboembolic events and hemorrhagic complications in patients receiving different doses of dabigatran, including patients receiving the very low-dose of 75 mg twice daily. Methods Five hospitals in Meguro and Setagaya areas of Tokyo were included in this study. The subjects were patients receiving dabigatran in the hospitals from March 2011 to February 2014. Thromboembolic events (stroke, systemic embolism, and transient cerebral ischemic attack) and hemorrhagic complications occurring before December 2014 were retrospectively evaluated. Results A total of 701 subjects received dabigatran during the study period: 187 patients (26.7%) received 150 mg twice daily (normal dose), 488 patients (69.6%) received 110 mg twice daily (low-dose), and 26 patients (3.7%) received 75 mg twice daily (very low-dose). Thromboembolism occurred in 4 (2.1%), 11 (2.3%), and 3 patients (11.5%), in the normal dose, low-dose, and very low-dose groups, respectively. The odds ratio of the 75 mg dose to the 150 and 110 mg doses was 5.73 (95% CI, 1.55–21.2; p = 0.009), and the incidence with the 75 mg dose was higher than that with the other doses. Although the number of events was limited, it should be noted that 3 patients in the very low-dose group had thromboembolic events. Conclusions The results suggest that sufficient anticoagulation efficacy may not be maintained when the dabigatran dose is excessively reduced to 75 mg twice daily.

Identifying patient prognostic phenotypes facilitates precision medicine. This study aimed to explore phenotypes of patients with heart failure (HF) corresponding to prognostic condition (risk of mortality) and identify the phenotype of new patients by machine learning (ML). A unsupervised ML was applied to explore phenotypes of patients in a derivation dataset (n = 562) based on their medical records. Thereafter, supervised ML models were trained on the derivation dataset to classify these identified phenotypes. Then, the trained classifiers were further validated on an independent validation dataset (n = 168). Finally, Shapley additive explanations were used to interpret decision making of phenotype classification. Three patient phenotypes corresponding to stratified mortality risk (high, low, and intermediate) were identified. Kaplan–Meier survival curves among the three phenotypes had significant difference (pairwise comparison p < 0.05). Hazard ratio of all-cause mortality between patients in phenotype 1 (n = 91; high risk) and phenotype 3 (n = 329; intermediate risk) was 2.08 (95%CI 1.29–3.37, p = 0.003), and 0.26 (95%CI 0.11–0.61, p = 0.002) between phenotype 2 (n = 142; low risk) and phenotype 3. For phenotypes classification by random forest, AUCs of phenotypes 1, 2, and 3 were 0.736 ± 0.038, 0.815 ± 0.035, and 0.721 ± 0.03, respectively, slightly better than the decision tree. Then, the classifier effectively identified the phenotypes for new patients in the validation dataset with significant difference on survival curves and hazard ratios. Finally, age and creatinine clearance rate were identified as the top two most important predictors. ML could effectively identify patient prognostic phenotypes, facilitating reasonable management and treatment considering prognostic condition.

Type 2 diabetes and obesity are associated with increased hepatic gluconeogenesis and lipogenesis, known as selective insulin resistance. Here Kubota et al. explain selective insulin resistance in the liver with the zonal distribution and selective insulin-mediated regulation of Irs1 and Irs2.

Background: The need for ways to minimize the number of implantable cardioverter-defibrillator (ICD) shocks is increasing owing to the risk of its adverse effects on life expectancy. Studies have shown that a longer detection time for ventricular tachyarrhythmia reduces the safety of therapies, in terms of syncope and mortality, but not substantially in terms of the success rate. We aimed to evaluate the effects of increased number of intervals to detect (NID) VF on the safety of ICD shock therapy and on the reduction of inappropriate shocks. Methods: The present study was a prospective, multicenter, randomized, crossover study. Randomized VF induction testing with NID 18/24 or 30/40 was performed to compare the success rate of defibrillation with a 25-J shock and the time to detection. Inappropriate shock episodes were simulated retrospectively to evaluate a possibility of episodes avoidable at NID 24/32 and 30/40. Results: Thirty-one consecutive patients implanted with an ICD or cardiac resynchronization therapy-defibrillator (CRT-D) were enrolled in this study. The success rate of defibrillation was 100% in both NID groups at the first shock. The time from VF induction to detection showed a significant increase in the NID 30/40 group (6.16±1.29 s vs. 9.00±1.31 s, p

There is little information on venous patency after pacing leads are inserted in veins during pacemaker or implantable cardioverter defibrillator (ICD) implantation. Herein we present a report on venous patency during the immediate postoperative period after permanent pacemaker or ICD implantation. Subjects and Methods: Twenty-five patients underwent a permanent pacemaker or ICD implantation by venous puncture method, and venography was performed 1 week later. We assessed the pacemaker-implantation side, approach used, implanted device, number of implanted leads, and clinical symptoms. Results: Narrowing of the vein was found in 14 patients (56%), including 7 patients (28%) with occlusion. Stenosis and occlusion were seen more in patients with left-sided implantation than those with right-sided implantation (71% vs. 25%, P < 0.05). ICD implantation was more frequently associated with venous stenosis or occlusion than pacemaker implantation (65% vs. 37.5%, P < 0.05). The approach used and the number of leads implanted did not correlate with venous stenosis or occlusion. Six of the 7 patients who developed complete occlusion showed clinical symptoms. Conclusion: Thrombus formation after pacemaker implantation can occur in the acute stage within 1 week. The incidence of venous stenosis or thrombus formation was higher with leftsided implantation and ICD.

Introduction: It has become clear that the onset of heart failure is closely linked to right apex pacing, which lengthens the QRS duration and evokes discoordinate contraction of the left ventricle (LV). Currently, it is thought that the site inducing the shortest QRS duration is optimal for pacing. Objectives: The purpose of this study was to ascertain the pacing site inducing the shortest QRS duration and to examine the configuration of the 12-lead electrocardiogram and heart function while pacing at this site. Methods: Nine patients with normal heart function were enrolled. Pacing at right ventricular outflow, mid-interventricular septum (MS), and right ventricular apex was performed. QRS duration was measured and the configuration of the 12-lead electrocardiogram changed by pacing was studied. Output and LV dp/dt were calculated at each pacing site. Results: QRS duration became shorter with MS pacing and the pacing lead situated at the periphery of the coronary sinus and turned in a posterior direction. The configuration of the 12-lead electrocardiogram showed an Rs or rS pattern with II, III, and aVF leads. Output and LV dp/dt showed a tendency to increase with MS pacing. Conclusion: It is thought that mid-interventricular septum pacing shortens the QRS duration.

Pharmacological treatment for atrial fibrillation has a variety of purposes, such as pharmacological defibrillation, maintenance of sinus rhythm, heart rate control to prevent congestive heart failure and prevention of both cerebral infarction and atrial remodeling. Sodium channel blockers are superior to potassium channel blockers for atrial defibrillation, while both sodium and potassium channel blockers are effective in the maintenance of sinus rhythm. In general, digitalis or Ca antagonists are used to control heart rate during atrial fibrillation to prevent congestive heart failure, while amiodarone or bepridil also reduce heart rates during atrial fibrillation. Anticoagulant therapy with warfarin is recommended to prevent cerebral infarction and angiotensin converting enzyme antagonists or angiotensin II receptor blockers are also used to prevent atrial remodeling. One should select appropriate drugs for treatment of atrial fibrillation according to the patient's condition.

Directional cell rearrangement is a critical process underlying correct tissue deformation during morphogenesis. Although the involvement of F-actin regulation in cell rearrangement has been established, the role and regulation of actin binding proteins (ABPs) in this process are not well understood. In this study, we investigated the function of Coronin-1, a WD-repeat actin-binding protein, in controlling directional cell rearrangement in the Drosophila pupal wing. Transgenic flies expressing Coronin-1-EGFP were generated using CRISPR-Cas9. We observed that Coronin-1 localizes at the reconnecting junction during cell rearrangement, which is dependent on actin interacting protein 1 (AIP1) and cofilin, actin disassemblers and known regulators of wing cell rearrangement. Loss of Coronin-1 function reduces cell rearrangement directionality and hexagonal cell fraction. These results suggest that Coronin-1 promotes directional cell rearrangement via its interaction with AIP1 and cofilin, highlighting the role of ABPs in the complex process of morphogenesis. Key words: morphogenesis, cell rearrangement, actin binding proteins (ABPs)

Measuring mechanical parameters in tissues, such as the elastic modulus of cell-cell junctions, is essential to decipher the mechanical control of morphogenesis. However, their in vivo measurement is technically challenging. Here, we formulated an image-based statistical approach to estimate the mechanical parameters of epithelial cells. Candidate mechanical models are constructed based on force-cell shape correlations obtained from image data. Substitution of the model functions into force-balance equations at the cell vertex leads to an equation with respect to the parameters of the model, by which one can estimate the parameter values using a least-squares method. A test using synthetic data confirmed the accuracy of parameter estimation and model selection. By applying this method to Drosophila epithelial tissues, we found that the magnitude and orientation of feedback between the junction tension and shrinkage, which are determined by the spring constant of the junction, were correlated with the elevation of tension and myosin-II on shrinking junctions during cell rearrangement. Further, this method clarified how alterations in tissue polarity and stretching affect the anisotropy in tension parameters. Thus, our method provides a novel approach to uncovering the mechanisms governing epithelial morphogenesis.

Plant regeneration can occur via formation of a mass of pluripotent cells known as callus. Here, Ishihara et al. show that acquisition of regenerative capacity of callus-forming cells requires a lysine-specific demethylase that removes H3K4me2 to prime gene expression in response to regenerative cues.

Background and purpose: It is known that drug-eluting stents (DESs) are associated with in-stent restenosis (ISR). However, the characteristics of neointimal tissue components according to the mechanism and time course of DES ISR have not been fully examined. The aim of this study was to characterize the in-stent neointimal tissue components according to the phase of restenosis using radiofrequency signals from 40-MHz intravascular ultrasound (IVUS), called iMAP-IVUS (Boston Scientific Corp., Fremont, CA, USA). Methods: IVUS examinations were performed in 37 angina patients (37 lesions) who underwent repeated percutaneous coronary intervention (PCI) for the treatment of DES ISR. The patients were divided into two groups according to the phase of restenosis: the early ISR group (E-IRS; ≤1 year) and the late ISR group (L-ISR; >1 year). Results: There were 18 patients in the E-ISR group and 19 patients in the L-ISR group. The mean followup period between stent implantation and repeated PCI was 8.0 ± 2.2 months in the E-IRS group and 40.4 ± 23.9 months in the L-ISR group. The percentage of lipid components and relative necrotic volume were greater in the L-ISR group than in the E-ISR group (5.77 ± 1.81% vs. 4.51 ±1.71%, p<0.05 and 12.20 ± 2.97% vs. 8.61 ±2.33%, p< 0.001, respectively). Furthermore, there was a positive correlation between the follow-up duration after DES implantation in the L-ISR group and the presence of a necrotic plaque component (r=0.49, p < 0.05). Conclusions: There were differences in the neointimal plaque characteristics after DES implantation according to the phase of restenosis. This information may lead to a better understanding of the mechanisms of DES ISR. [ABSTRACT FROM AUTHOR]

Cells must resist or release tension/compression when proliferating and moving during development. Here the authors show that AIP1, together with cofilin, promotes local actin turnover to regulate linkage between actomyosin and cell junctions and resist mechanical load imposed by tissue stretching.

Background: In patients with left ventricular hypertrophy (LVH), LV midwall fractional shortening (FS) is used as a measure of LV systolic performance that is more physiologically appropriate than conventional FS. For evaluation of LV volume and ejection fraction (EF), 2-dimensional (2D) echocardiography is more accurate than M-mode echocardiography. The purpose of this study was to assess systolic performance by midwall EF using 2D speckle tracking echocardiography (STE). Methods: Sixty patients were enrolled in the study. Patients were divided into two groups with LVH (n = 30) and without LVH (control group, n = 30). LV systolic function was compared between the two groups and the relationships of left ventricular mass index (LVMI) with LV systolic parameters, including midwall EF, were investigated. Results: Midwall EF in the LVH group was significantly lower than that in the control group (42.8±4.4% vs. 48.1±4.1%, p <0.0001). Midwall FS was also significantly lower in the LVH group (13.4±2.8% vs. 16.1±1.5%, p <0.0001), but EF did not differ significantly between the two groups. There were significant correlations between midwall EF and LVMI (r=0.731, p <0.0001) and between midwall FS and LVMI (r=0.693, p <0.0001), with midwall EF having the higher correlation. Conclusions: These results show that midwall EF can be determined using 2D STE. Midwall EF can be used to monitor LV systolic dysfunction, which is not possible with conventional EF. Evaluation of midwall EF may allow assessment of new parameters of LV systolic function in patients with LV geometric variability. [ABSTRACT FROM AUTHOR]

In this article, we propose and evaluate a Zoo Walk Navigation System consistings of the Animal Contents Registering and Editing Web Management System and the Animal Contents Browsing and Acquiring Smartphone Application. The Animal Contents Registering and Editing Web Management System for zoo staff enables to register/edit various animal contents. Thereby, this web management system provides real-time and flesh zoo information to the Animal Contents Browsing and Acquiring Smartphone Application. On the other hand, the Animal Contents Browsing and Acquiring Smartphone Application for zoo visitors enables to browse various animal contents which zoo staff registered through the Animal Contents Registering and Editing Web Management System. The Animal Contents Browsing and Acquiring Smartphone Application has the animal guide browsing function, the animal quiz function, the beacon notification browsing function, the zoo map navigating function, and the AR camera function. Zoo visitors can enjoy a zoo park using this smartphone application. This system is the new type navigation system which zoo staff can renew contents to avoid contents obsolescence. And, this system always provides new information to zoo visitors in real time by the beacon notification function.

Understanding the mechanisms regulating development requires a quantitative characterization of cell divisions, rearrangements, cell size and shape changes, and apoptoses. We developed a multiscale formalism that relates the characterizations of each cell process to tissue growth and morphogenesis. Having validated the formalism on computer simulations, we quantified separately all morphogenetic events in the Drosophila dorsal thorax and wing pupal epithelia to obtain comprehensive statistical maps linking cell and tissue scale dynamics. While globally cell shape changes, rearrangements and divisions all significantly participate in tissue morphogenesis, locally, their relative participations display major variations in space and time. By blocking division we analyzed the impact of division on rearrangements, cell shape changes and tissue morphogenesis. Finally, by combining the formalism with mechanical stress measurement, we evidenced unexpected interplays between patterns of tissue elongation, cell division and stress. Our formalism provides a novel and rigorous approach to uncover mechanisms governing tissue development.

Organs develop distinctive morphologies to fulfill their unique functions. We used Drosophila embryonic gonads as a model to study how two different cell lineages, primordial germ cells (PGCs) and somatic gonadal precursors (SGPs), combine to form one organ. We developed a membrane GFP marker to image SGP behaviors live. These studies show that a combination of SGP cell shape changes and inward movement of anterior and posterior SGPs leads to the compaction of the spherical gonad. This process is disrupted in mutants of the actin regulator, enabled (ena). We show that Ena coordinates these cell shape changes and the inward movement of the SGPs, and Ena affects the intracellular localization of DE-cadherin (DE-cad). Mathematical simulation based on these observations suggests that changes in DE-cad localization can generate the forces needed to compact an elongated structure into a sphere. We propose that Ena regulates force balance in the SGPs by sequestering DE-cad, leading to the morphogenetic movement required for gonad compaction.

Neurons develop distinctive dendritic morphologies to receive and process information. Previous experiments showed that competitive dendro-dendritic interactions play critical roles in shaping dendrites of the space-filling type, which uniformly cover their receptive field. We incorporated this finding in constructing a new mathematical model, in which reaction dynamics of two chemicals (activator and suppressor) are coupled to neuronal dendrite growth. Our numerical analysis determined the conditions for dendritic branching and suggested that the self-organizing property of the proposed system can underlie dendritogenesis. Furthermore, we found a clear correlation between dendrite shape and the distribution of the activator, thus providing a morphological criterion to predict the in vivo distribution of the hypothetical molecular complexes responsible for dendrite elongation and branching.

Preprocedural chronic kidney disease and contrast-induced acute kidney injury are predictors of in-hospital death and long-term mortality. However, neither the time course of kidney function after percutaneous coronary intervention (PCI) nor the relation between the time course of kidney function and prognosis has been adequately studied. We studied 531 patients who underwent PCI for acute coronary syndrome. The continuous deterioration of kidney function (CDKF) was defined as a >25% increase in serum creatinine level or serum creatinine >0.5 mg/dl above baseline at 6 to 8 months after PCI. CDKF was observed in 87 patients (16.4%). Independent risk factors for CDKF were contrast-induced acute kidney injury, preprocedural hemoglobin level, and proteinuria. Patients with CDKF exhibited significant higher 5-year mortality rate than patients without CDKF (25% vs 9.4%, log-rank p [ 0.0006). Independent risk factors for 5-year mortality were age >75 year, anemia, New York Heart Association class III or IV, low ejection fraction, and CDKF. CDKF is associated with an increased risk of all-cause mortality of 5 years in patients with acute coronary syndrome undergoing PCI. [ABSTRACT FROM AUTHOR]