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The efficacy of convolutional neural network (CNN)-enhanced electrocardiography (ECG) in detecting hypertrophic cardiomyopathy (HCM) and dilated HCM (dHCM) remains uncertain in real-world applications. This retrospective study analyzed data from 19,170 patients (including 140 HCM or dHCM) in the Shinken Database (2010-2017). We evaluated the sensitivity, positive predictive rate (PPR), and F1 score of CNN-enhanced ECG in a ''basic diagnosis'' model (total disease label) and a ''comprehensive diagnosis'' model (including disease subtypes). Using all-lead ECG in the "basic diagnosis" model, we observed a sensitivity of 76%, PPR of 2.9%, and F1 score of 0.056. These metrics improved in cases with a diagnostic probability of ≥ 0.9 and left ventricular hypertrophy (LVH) on ECG: 100% sensitivity, 8.6% PPR, and 0.158 F1 score. The ''comprehensive diagnosis'' model further enhanced these figures to 100%, 13.0%, and 0.230, respectively. Performance was broadly consistent across CNN models using different lead configurations, particularly when including leads viewing the lateral walls. While the precision of CNN models in detecting HCM or dHCM in real-world settings is initially low, it improves by targeting specific patient groups and integrating disease subtype models. The use of ECGs with fewer leads, especially those involving the lateral walls, appears comparably effective., (© 2024. Springer Nature Japan KK, part of Springer Nature.)

Pericardial effusion (PE) presentation varies from an incidental finding to a life-threatening situation; thus, its etiology and clinical course remain unknown. The aim of the present study was to retrospectively investigate these factors.We analyzed 171 patients (0.4%) who presented with PE among 34,873 patients who underwent echocardiography between 2011 and 2021 at our hospital. Clinical and prognostic information was retrieved from electronic medical records. The primary endpoints were all-cause death, hospitalization due to heart failure (HF), and other cardiovascular events such as cardiovascular death, acute coronary syndrome, elective percutaneous coronary intervention, and stroke.The etiologies of PE were as follows: idiopathic (32%), HF-related (18%), iatrogenic (11%), cardiac surgery-related (10%), radiation therapy-related (9%), malignancy (8%), pericarditis/myocarditis (8%), myocardial infarction-related (2%), and acute aortic dissection (2%). Patients with idiopathic/HF etiology were more likely to be older than the others.During a mean follow-up period of 2.5 years, all-cause death occurred in 21 patients (12.3%), cardiovascular events in 10 patients (5.8%), and hospitalization for HF in 24 patients (14.0%). All-cause death was frequently observed in patients with malignancy (44% per person-year). Cardiovascular events were mostly observed in patients with radiation therapy-related and malignancy (8.6% and 7.3% per person-year, respectively).The annual incidence of hospitalization for HF was the highest in patients with HF-related (25.1% per person-year), followed by radiation therapy-related (10.4% per person-year).This retrospective study is the first, to the best of our knowledge, to reveal the contemporary prevalence of PE, its cause, and outcome in patients who visited a cardiovascular hospital in an urban area of Japan.

Background: The potential of utilizing artificial intelligence with electrocardiography (ECG) for initial screening of aortic dissection (AD) is promising. However, achieving a high positive predictive rate (PPR) remains challenging., Methods and Results: This retrospective analysis of a single-center, prospective cohort study (Shinken Database 2010-2017, N = 19,170) used digital 12-lead ECGs from initial patient visits. We assessed a convolutional neural network (CNN) model's performance for AD detection with eight-lead (I, II, and V1-6), single-lead, and double-lead (I, II) ECGs via five-fold cross-validation. The mean age was 63.5 ± 12.5 years for the AD group (n = 147) and 58.1 ± 15.7 years for the non-AD group (n = 19,023). The CNN model achieved an area under the curve (AUC) of 0.936 (standard deviation [SD]: 0.023) for AD detection with eight-lead ECGs. In the entire cohort, the PPR was 7 %, with 126 out of 147 AD cases correctly diagnosed (sensitivity 86 %). When applied to patients with D-dimer levels ≥1 μg/dL and a history of hypertension, the PPR increased to 35 %, with 113 AD cases correctly identified (sensitivity 86 %). The single V1 lead displayed the highest diagnostic performance (AUC: 0.933, SD: 0.03), with PPR improvement from 8 % to 38 % within the same population., Conclusions: Our CNN model using ECG data for AD detection achieved an over 30% PPR when applied to patients with elevated D-dimer levels and hypertension history while maintaining sensitivity. A similar level of performance was observed with a single-lead V1 ECG in the CNN model., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Suzuki has received lecture fees from Daiichi Sankyo and Bristol-Myers Squibb. Dr. Yamashita has received research funding and/or lecture fees from Daiichi Sankyo, Bayer Yakuhin, Bristol-Myers Squibb, Pfizer, Nippon Boehringer Ingelheim, Ono Pharmaceutical, and Toa Eiyo. J Motogi, T Umemoto, W Matsuzawa, T Takayanagi, A Hyodo, and K Satoh are employee at Nihon Kohden Corporation., (© 2024 The Authors.)

Background: We developed a convolutional neural network (CNN) model to detect atrial fibrillation (AF) using the sinus rhythm ECG (SR-ECG). However, the diagnostic performance of the CNN model based on different ECG leads remains unclear. Methods and Results: In this retrospective analysis of a single-center, prospective cohort study, we identified 616 AF cases and 3,412 SR cases for the modeling dataset among new patients (n=19,170). The modeling dataset included SR-ECGs obtained within 31 days from AF-ECGs in AF cases and SR cases with follow-up ≥1,095 days. We evaluated the CNN model's performance for AF detection using 8-lead (I, II, and V1-6), single-lead, and double-lead ECGs through 5-fold cross-validation. The CNN model achieved an area under the curve (AUC) of 0.872 (95% confidence interval (CI): 0.856-0.888) and an odds ratio of 15.24 (95% CI: 12.42-18.72) for AF detection using the eight-lead ECG. Among the single-lead and double-lead ECGs, the double-lead ECG using leads I and V1 yielded an AUC of 0.871 (95% CI: 0.856-0.886) with an odds ratio of 14.34 (95% CI: 11.64-17.67). Conclusions: We assessed the performance of a CNN model for detecting AF using eight-lead, single-lead, and double-lead SR-ECGs. The model's performance with a double-lead (I, V1) ECG was comparable to that of the 8-lead ECG, suggesting its potential as an alternative for AF screening using SR-ECG., Competing Interests: S.S. received lecture fees from Daiichi Sankyo and Bristol-Myers Squibb. T.Y. received research funds and/or lecture fees from Daiichi Sankyo, Bayer Yakuhin, Bristol-Myers Squibb, Pfizer, Nippon Boehringer Ingelheim, Eisai, Mitsubishi Tanabe Pharm, Ono Pharmaceutical, and Toa Eiyo. The remaining authors have nothing to disclose., (Copyright © 2024, THE JAPANESE CIRCULATION SOCIETY.)

Background: This study sought to develop an artificial intelligence-derived model to detect the dilated phase of hypertrophic cardiomyopathy (dHCM) on digital electrocardiography (ECG) and to evaluate the performance of the model applied to multiple-lead or single-lead ECG., Methods: This is a retrospective analysis using a single-center prospective cohort study (Shinken Database 2010-2017, n = 19,170). After excluding those without a normal P wave on index ECG (n = 1,831) and adding dHCM patients registered before 2009 (n = 39), 17,378 digital ECGs were used. Totally 54 dHCM patients were identified of which 11 diagnosed at baseline, 4 developed during the time course, and 39 registered before 2009. The performance of the convolutional neural network (CNN) model for detecting dHCM was evaluated using eight-lead (I, II, and V1-6), single-lead, and double-lead (I, II) ECGs with the five-fold cross validation method., Results: The area under the curve (AUC) of the CNN model to detect dHCM (n = 54) with eight-lead ECG was 0.929 (standard deviation [SD]: 0.025) and the odds ratio was 38.64 (SD 9.10). Among the single-lead and double-lead ECGs, the AUC was highest with the single lead of V5 (0.953 [SD: 0.038]), with an odds ratio of 58.89 (SD:68.56)., Conclusion: Compared with the performance of eight-lead ECG, the most similar performance was achieved with the model with a single V5 lead, suggesting that this single-lead ECG can be an alternative to eight-lead ECG for the screening of dHCM., Competing Interests: Dr. Suzuki received lecture fees from Daiichi Sankyo and Bristol-Myers Squibb. Dr. Yamashita received research funds and/or lecture fees from Daiichi Sankyo, Bayer Yakuhin, Bristol-Myers Squibb, Pfizer, Nippon Boehringer Ingelheim, Eisai, Mitsubishi Tanabe Pharm, Ono Pharmaceutical, and Toa Eiyo. J Motogi, T Umemoto, W Matsuzawa, T Takayanagi, A Hyodo, and K Satoh are employee at Nihon Kohden Corporation.The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Shinya Suzuki reports a relationship with Public Interest Incorporated Foundation The Cardiovascular Institute that includes: speaking and lecture fees. Takeshi Yamashita reports a relationship with Public Interest Incorporated Foundation The Cardiovascular Institute that includes: funding grants and speaking and lecture fees., (© 2023 The Author(s).)

High alkaline phosphatase (ALP) levels are reported to be associated with an increased risk of cardiovascular events in patients with chronic kidney disease (CKD). Given the pathological link with CKD, a similar relationship may exist in patients with atrial fibrillation (AF). We retrospectively evaluated 1,719 patients with AF and normal hepatic function who were registered in the Shinken Database between November 2011 and March 2017. Study patients were divided into three groups according to ALP value tertiles with cut-offs of 175 and 227 IU/L (normal range: 95-350 IU/L). Each group's incidence rate was recorded, and the risks of cardiovascular events and each component for patients in the middle and high ALP tertiles were compared with those in the low tertile and evaluated using Cox regression models. The additional predictive value of the high ALP tertile over the existing risk scores for the components of cardiovascular events was evaluated via receiver operating characteristic (ROC) curve analysis. During the median follow-up of 731 days (IQR: 444-1095 days), 137 cardiovascular events occurred, with incidence rates of 2.94%, 3.44%, and 6.19%/person-year for the low, middle, and high ALP tertiles, respectively. Of these cardiovascular events, heart failure had the highest incidence rates (1.34%, 1.89%, and 4.29%/person-year for the low, middle, and high ALP tertiles, respectively) and the incidence rates of the other components of cardiovascular event were similar in each ALP groups. Multivariate Cox regression analysis yielded hazard ratios of 1.22 (95% confidence interval [CI] 0.70-1.96) and 1.62 (95% CI 1.06-2.48) for cardiovascular events and 1.66 (95% CI 0.87-3.15) and 2.50 (95% CI 1.39-4.48) for heart failure admission in the middle and high ALP tertiles, respectively. By ROC curve analysis for heart failure admission showed that the high ALP tertile lacked significant additive predictive value over the existing risk scores. High serum ALP levels, even those in the normal range, were significantly associated with an increased risk of cardiovascular events, especially heart failure admission in patients with AF., (© 2022. Springer Japan KK, part of Springer Nature.)

Globalization of pharmaceutical supply chains has expanded and manufacturers are required to manufacture products in compliance with the pharmacopoeial standards used in all exporting countries/regions to ensure product quality. International harmonization has been facilitated by the Pharmacopoeial Discussion Group consisting of the Japanese Pharmacopoeia, the United States Pharmacopeia, and the European Pharmacopoeia. However, since the pharmacopoeias have been developed individually under the regulatory framework of each country/region, differences exist between these pharmacopoeias. When using pharmacopoeias, an understanding of common pharmacopoeial rules is essential. Clarifying the similarities and differences in the General Notices of the pharmacopoeias widely referenced worldwide is considered valuable for those already using one or two of them to access the remaining pharmacopoeias. In this study, we compared the existence of items and the contents described in the General Notices of the three pharmacopoeias to clarify the differences. Investigation of the existence of items revealed that more than 70% of the 105 items in General Notices in the three pharmacopoeias were in the entire pharmacopoeias (for Japan, including Japanese laws and notifications). Furthermore, investigating contents revealed that approximately 20% of the 105 items have some differences such as numerical values and test conditions. However, it was shown that most of the items did not have major differences. It is expected that the three pharmacopoeias will be utilized simultaneously by understanding the similarities and differences shown in this study.

Glasgow prognostic score (GPS) has been used to evaluate inflammatory response and nutritional status. This study aimed to investigate the impact of nutritional status on cardiac prognosis by using GPS in patients after undergoing percutaneous coronary intervention (PCI). We included 862 patients who underwent PCI for stable angina pectoris between 2015 and 2018. We used the original cutoff values, which were an albumin (Alb) level of 3.5 g/dl and a C-reactive protein (CRP) level of 0.3 mg/dl. We categorized them into the three groups: originally defined GPS (od-GPS) 0 (high Alb and low CRP), 1 (low Alb or high CRP), and 2 (low Alb and high CRP). Major adverse clinical events (MACEs) included all-cause death, nonfatal myocardial infarction, revascularization, and hospitalization for heart failure. The median follow-up period was 398.5 days. During the follow-up, MACEs occurred in 136 patients. Od-GPS 2 had higher prevalence rates in terms of chronic kidney disease (CKD; 31.7% [229/722] vs. 44.9% [53/118] vs. 63.6% [14/22], p < 0.001), hemodialysis (6.4% [46/722] vs. 14.4% [17/118] vs. 31.8% [7/22], p < 0.001), and heart failure cases (HF; 9.1% [66/722] vs. 14.4% [17/118] vs. 27.3% [6/22], p = 0.007), with higher creatinine (1.17 ± 1.37 mg/dl vs. 1.89 ± 2.60 mg/dl vs. 3.49 ± 4.01 mg/dl, p < 0.001) and brain natriuretic peptide levels (104.1 ± 304.6 pg/ml vs. 242.4 ± 565.9 pg/ml vs. 668.1 ± 872.2 pg/ml, p < 0.001) and lower low-density lipoprotein cholesterol (101.5 ± 32.9 mg/dl vs. 98.2 ± 28.8 mg/dl vs. 77.1 ± 24.3 mg/dl, p = 0.002) than od-GPS 0 and 1.Od-GPS 2 (HR 2.42; 95% CI 1.16-5.02; p = 0.018), od-GPS 1 (HR 2.09; 95% CI 1.40-3.13; p < 0.001), diabetes (HR 1.41; 95% CI 1.00-1.99; p = 0.048), CKD (HR 2.10; 95% CI 1.49-2.96; p < 0.001), and HF (HR 1.64; 95% CI 1.05-2.56; p = 0.029) were independent predictors of MACEs. A scoring system using CRP and Alb levels with a milder definition than GPS suitably predicted the risk of MACEs in the patients who underwent PCI., (© 2021. Springer Japan KK, part of Springer Nature.)

Acute eosinophilic pneumonia is a rare but severe side effect of daptomycin, which has been recommended as empirical antimicrobial drug therapy for blood culture-negative prosthetic valve endocarditis. Here, we present a case of an 82-year-old man who developed fever, cough, and shortness of breath after 23-day treatment with daptomycin for prosthetic valve endocarditis. Bilateral ground-glass opacities were observed on computed tomography with peripheral eosinophilia of 640/μL (7%). Cessation of daptomycin and commencement of corticosteroid therapy improved his symptoms. This case highlights the importance of prompt diagnosis of acute eosinophilic pneumonia in endocarditis patients treated with daptomycin. < Learning objective: Acute eosinophilic pneumonia is a rare but severe side effect of daptomycin, which has been recommended as empirical antimicrobial drug therapy for blood culture-negative endocarditis. As an alternative to vancomycin for treatment of methicillin-resistant Staphylococcus aureus , the use of daptomycin for culture-negative endocarditis is increasing. Daptomycin-induced acute eosinophilic pneumonia requires withdrawal of daptomycin and commencement of oral prednisolone. Careful prescription of oral antibiotics is needed in febrile patients with prosthetic valves.>., Competing Interests: None., (© 2021 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

The incidence of ischemic stroke (IS) increases in patients with enlarged left atrium (LA) irrespective of whether or not the existence of atrial fibrillation (AF). In such situation, it is unclear whether the impact of LA on incidence of IS still significant in young, non-AF patients with enlarged LA who are primarily unconcerned on anticoagulation therapy. The study population consisted of 18,511 consecutive patients not receiving oral anticoagulants and undergoing echocardiography with measurement of LAD at baseline. The incidence rate of ischemic stroke was calculated in 3 groups according to left atrial dimension (LAD; < 30, 30-45 and ≥ 45 mm) in AF and non-AF patients. Further subgroup analysis was performed in stratification by elderly and young (aged ≥ 65 and < 65 years, respectively). The incidences of IS (per 100 patient-years) were 0.11 and 0.71 in non-AF and AF patients with LAD < 30 mm, respectively, which increased to 0.58 and 1.35 in LAD ≥ 45 mm (adjusted hazard ratios [HRs]; 1.95 [95% confidence intervals, CIs: 0.76-5.01] and 1.22 [95% CIs: 0.27-5.58], interaction P was 0.246). In non-AF patients, the incidences of IS were 0.30 and 0.04 in elderly and young patients with LAD < 30 mm, which increased to 0.67 and 0.48 in LAD ≥ 45 mm (adjusted HRs; 1.34 [95% CIs: 0.43-4.15] and 4.21 [95% CIs: 0.77-23.12], interaction P was 0.158). The incidence of IS significantly increased with increase of LAD in non-AF, especially in non-AF and young patients, although the difference was not independent of other clinical factors. The impact of LAD on IS was numerically larger in non-AF than in AF, and larger in young and non-AF than in elderly counterpart, although a significant interaction was not observed in this small population. Further studies with large population are necessary to judge whether these population with enlarged LA need antithrombotic therapy., (© 2021. Springer Japan KK, part of Springer Nature.)

Aim: Although polypharmacy has been associated with poor clinical outcomes, whether taking an increased number of medications is harmful or beneficial for older adult patients treated for cardiovascular diseases might require further discussion., Methods: We analyzed data of 2089 patients aged ≥75 years in a single hospital-based cohort. The study population was divided into three groups according to the tertiles of the number of medications at baseline: <3 (n = 647), 3-7 (n = 707) and ≥8 (n = 735)., Results: The cumulative incidences of all-cause death at 3 years among patients taking less than three, three to seven and eight or more medications were 3.7%, 4.1% and 7.8%, respectively (log-rank test P = 0.015). In a Cox regression analysis, taking eight or more total medications (vs 0-2) was independently associated with all-cause death (hazard ratio 1.67, 95% CI 1.01-2.78). For predicting mortality using the number of medications, the maximum Youden Index was 7. In subgroups with certain heart diseases, no regular tendency of an increase in the risk of all-cause death was observed with an increase in the number of medications., Conclusions: The number of medications taken was independently associated with mortality among older adult patients, with a relatively high cut-off point. This association was not observed in patients with certain heart diseases, possibly indicating the merit - rather than the harm - of medical treatment in the cardiovascular field. Geriatr Gerontol Int 2021; 21: 985-995., (© 2021 Japan Geriatrics Society.)

Objectives: Sinus plication has emerged as a promising tool that can lead to better stability in bicuspid aortic valve (BAV) repair. However, the mechanisms underlying the efficacy of this technique are unclear. We evaluated the hydrodynamic effect of sinus plication using the experimental pulsatile flow simulator and our original BAV model in vitro., Methods: Based on the computed tomography data of a BAV patient who had undergone aortic valvuloplasty, a BAV model (group C, n = 6) was developed with bovine pericardium and vascular prosthesis (J-graft Shield Neo Valsalva 24 mm). We performed sinus plication (group SP, n = 6) in the BAV model and compared hydrodynamic data with the control model in the pulsatile flow simulator. Non-fused cusp angle, annulus diameter and effective height were measured by ultrasonography., Results: The average flow was significantly increased in group SP compared to group C (4.24 ± 0.14 l/min vs 4.14 ± 0.15 l/min, respectively, P = 0.034). The mean transvalvular pressure gradient and regurgitant fraction were significantly decreased in group SP compared to group C (11.6 ± 4.3 mmHg vs 16.6 ± 5.0 mmHg, respectively, P = 0.009 and 14.1 ± 2.0% vs 17.4 ± 2.1%, respectively, P = 0.001). Ultrasound measurement indicated that non-fused cusp angle was significantly increased in group SP compared to group C (163.8° ± 9.2° vs 153.0° ± 4.6°, respectively, P = 0.012)., Conclusions: Sinus plication in the BAV model significantly increased the commissural angle. It was effective in not only controlling regurgitation but also improving valve opening. These finding should be confirmed by evaluating cusp stress and/or long-term durability in the future studies., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Older adults with atrial fibrillation (AF) have highly diverse risk levels for mortality, heart failure (HF), thromboembolism (TE), and major bleeding (MB), thus an integrated risk-pattern algorithm is warranted., Methods: We analyzed 573 AF patients aged ≥ 75 years from our single-center cohort (Shinken Database 2010-2018). The 3-year risk scores (risk probability) for mortality (M-score), HF (HF-score), TE (TE-score), and MB (MB-score) were estimated for each patient by logistic regression analysis. Using the four risk scores, cluster analysis was performed with Ward's linkage hierarchical algorithm., Results: Three clusters were identified: Clusters 1 (n = 429, 74%), 2 (n = 24, 5%), and 3 (n = 120, 21%). The clusters were characterized as standard risk (Cluster 1), high TE- and MB-risk (Cluster 2), and high M- and HF-risk (Cluster 3). Oral anticoagulants were prescribed for over 80% of the patients in each cluster. Catheter ablation for AF was performed only in Cluster 1 (8.9%). Compared with Cluster 1, Cluster 2 was more closely associated with males, asymptomatic AF, history of cerebral infarction or transient ischemic attack, history of intracranial hemorrhage, high HAS-BLED score (≥3), and low body mass index (<18.0 kg/m 2 ). Cluster 3 was more closely associated with old age, heart failure, and low estimated creatinine clearance (<30 mL/min)., Conclusion: The cluster analysis identified those at a high risk for all-cause death and HF or a high risk for TE and MB and could support decision making in older adults with AF., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Aim: Polypharmacy is known to be a risk factor for falls or bone fracture (F/F) in elderly patients. However, this relationship is not fully described in patients with non-valvular atrial fibrillation (NVAF), for which F/F may lead to serious clinical outcomes, including major bleeding., Methods: We analyzed 509 elderly (aged ≥75 years) patients with NVAF who had recently visited a hospital specializing in cardiology, of which 272 patients had paroxysmal atrial fibrillation (PAF) and 237 had persistent/permanent atrial fibrillation (PeAF). Patients were divided into four groups according to the number of medications: ≤3, 4-6, 7-9, and ≥10. The relationship between the number of medications and incidence rate of F/F in AF patients was analyzed. In addition, this relationship was analyzed in patients with each AF type., Results: Cumulative incidence of F/F at 3 years in the respective categories was 3.7%, 5.4%, 4.3% and 5.7% for PAF, and 5.2%, 7.5%, 7.8% and 25.0% for PeAF (log-rank test, P = 0.930 and 0.003, respectively). In a multivariable model, patients with ≥10 medications showed a significantly higher risk for F/F compared with those with ≤3 medications as reference only in PeAF (adjusted hazard ratio 4.82, 95%CI 1.42-16.33), without significant interaction (P = 0.081)., Conclusions: Elderly NVAF patients using ≥10 medications showed a higher risk for F/F. In subgroup analysis, this association was observed only in patients with PeAF, although there was no significant interaction between number of medications and AF type. Geriatr Gerontol Int 2021; 21: 802-809., (© 2021 Japan Geriatrics Society.)

Background: It has been reported that a large decline in estimated glomerular filtration rate (eGFR) over time is associated with increased incidence of cardiovascular disease. We investigated whether this association differs according to the baseline eGFR., Methods: A total of 4666 patients (male 71%) with measurements of eGFR at both baseline and 1 year and that had no cardiovascular events at 1-year follow-up were retrieved from the Shinken Database between June 2004 and March 2015. The study population was divided into three groups by baseline eGFR (mL/min/1.73 m 2 ): high (≥60, n = 1650), intermediate (45-59, n = 1947), and low (<45, n = 1069) eGFR groups. Each eGFR group was further divided into two groups by eGFR slope (change at 1 year, <-10 and ≥-10 mL/min/1.73 m 2 ). The patient characteristics and the incidences of cardiovascular events within 3 years (after 1-year follow-up) were compared between the negatively large eGFR slope (<-10) and others (≥-10) in each eGFR group., Results: A total of 187 cardiovascular events occurred during the mean follow-up of 2.8 ± 0.6 years. The adjusted hazard ratios of eGFR slope (<-10 with reference to ≥-10) were 2.37 (95% CI, 1.28-4.40), 3.10 (95% CI, 1.78-5.40), and 2.66 (95% CI, 1.15-6.13) in the high, middle, and low eGFR groups, respectively. Similar results were found in patients with structural heart disease, but not in those without., Conclusions: Decline in eGFR was associated with an increase in cardiovascular events, and this effect was consistent regardless of the baseline eGFR., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Diagnosis of atrial fibrillation (AF) based on electrocardiogram (ECG) with sinus rhythm remains a major challenge. Obtaining a panoramic view with hundreds of automatically measured ECG parameters at sinus rhythm on the predictive capability for AF would be informative., Methods: We used a single-center database of a specialist cardiovascular hospital (Shinken Database 2010-2017; n = 19,170). We analyzed 12,863 index ECGs with sinus rhythm after excluding those showing AF rhythm, other atrial tachyarrhythmia, pacing beat, or indeterminate axis, and those of patients with structural heart diseases. We used 438 automatically measured ECG parameters in the MUSE data management system. The predictive models were developed using random forest algorithm with the 10-fold cross-validation method., Results: In 12,863 index ECGs with sinus rhythm, a predictive capability for current paroxysmal AF (n = 1131) by c-statistics was 0.99981 ± 0.00037 for training dataset and 0.91337 ± 0.00087 for testing dataset, respectively. Excluding AF at baseline (n = 11,732), a predictive capability for newly developed AF (n = 98) by c-statistics was 0.99973 ± 0.00086 for training dataset and 0.99160 ± 0.00038 for testing dataset, respectively. The distribution of parameter importance was mostly similar among P, QRS, and ST-T segment for both current and newly developed AF., Conclusions: This study intended to provide panoramic information in relation between ECG parameters and AF. The parameter importance of ECG parameters for predicting AF was mostly similar in P, QRS, and ST-T segment in models for both current and future AF., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Resting 12-lead electrocardiography is widely used for the detection of cardiac diseases. Electrocardiogram readings have been reported to be affected by aging and, therefore, can predict patient mortality., Methods: A total of 12,837 patients without structural heart disease who underwent electrocardiography at baseline were identified in the Shinken Database among those registered between 2010 and 2017 (n = 19,170). Using 438 electrocardiography parameters, predictive models for all-cause death and cardiovascular (CV) death were developed by a support vector machine (SVM) algorithm., Results: During the observation period of 320.4 days, 55 all-cause deaths and 23 CV deaths were observed. In the SVM prediction model, the mean c-statistics of 10 cross-validation models with training and testing datasets were 0.881 ± 0.027 and 0.927 ± 0.101, respectively, for all-cause death and 0.862 ± 0.029 and 0.897 ± 0.069, respectively for CV death. For both all-cause and CV death, high values of permutation importance in the ECG parameters were concentrated in the QRS complex and ST-T segment., Conclusions: Parameters acquired from 12-lead resting electrocardiography could be applied to predict the all-cause and CV deaths of patients without structural heart disease. The ECG parameters that greatly contributed to the prediction were concentrated in the QRS complex and ST-T segment.

Background: Ischemic stroke (IS) and major bleeding, which are serious adverse events in patients with atrial fibrillation (AF), could have seasonal variations, but there are few reports., Methods and results: In the Shinken Database 2004-2016 (n=22,018), 3,581 AF patients (average age, 63.5 years; 2,656 men, 74.2%; 1,388 persistent AF, 38.8%) were identified. Median CHADS 2 and HAS-BLED scores were both 1 point. Oral anticoagulants were prescribed for 2,082 (58.1%) patients (warfarin, 1,214; direct oral anticoagulants [DOACs], 868). Incidence and observation period (maximum 3 years) of IS, extracranial hemorrhage (ECH), and intracranial hemorrhage (ICH) were counted separately for the northern hemisphere seasons. During the mean follow-up period of 2.4 years, there were totals of 90 IS, 73 ECH, and 33 ICH cases. The respective incidence rates per 1,000 patient-years in spring, summer, autumn, and winter were 8.5, 8.8, 7.5, and 16.8 for IS, 7.2, 9.7, 3.8, and 13.1 for ECH, and 2.7, 1.9, 3.8, and 7.0 for ICH. The number of patients with DOACs relatively increased among those with ECH in summer., Conclusions: Significant seasonal variations were observed for IS, ECH, and ICH events in AF patients, and were consistently the highest in winter. A small peak of ECH was observed in summer, which seemed, in part, to be related to increased DOAC use.

Initial screening for proteinuria by urine dipstick test (UDT) may be useful for predicting clinical outcomes. The Shinken Database includes all the new patients visiting the Cardiovascular Institute Hospital in Tokyo, Japan. Patients for whom UDT was performed at their initial visit between 2004 and 2010 (n = 7131) were divided into three groups according to the test results: negative, trace, and positive (1+ to 4+) proteinuria. During the mean follow-up period of 3.4 years, 233 (3.1%) deaths, 255 (3.6%) heart failure (HF) events, and 106 (1.5%) ischemic stroke (IS) events occurred. Prevalence of atherothrombotic risks increased with an increase in the amounts of proteinuria. The incidence of all-cause death, HF and IS events increased significantly from negative to trace to positive proteinuria groups (log rank test, P for trend < 0.001). Multivariate analysis revealed independent association between proteinuria and all-cause death [hazard ratio (HR): 1.50, 95% confidence interval (CI) 1.07-2.10], HF (HR: 1.55, 95% CI 1.14-2.12), and IS (HR: 2.08, 95% CI 1.26-3.45). Even trace proteinuria was independently associated with HF (HR: 1.64, 95% CI 1.07-2.53) and IS (HR: 2.17, 95% CI 1.14-4.11) and with all-cause death (HR: 1.56, 95% CI 0.99-2.47). In conclusions, dipstick proteinuria was independently associated with cardiovascular events and death, suggesting that the UDT is a useful tool for evaluating patients' risk for such adverse events.

Treatment and prognosis of elderly patients with atrial fibrillation (AF) may differ by the experience of fall or bone fracture. However, their current status is still unclear. From our institute database between 2010 and 2015, 674 AF patients with age ≥ 70 years were selected and were divided into those who experienced fall or fracture during the observation period (F/F group; n = 49) and those who did not (non-F/F group; n = 625). We compared the treatment and prognosis between the 2 groups. Patients in the F/F group were older (79 vs 76 years, P < 0.001) and had more comorbidities compared with those in the non-F/F group. The prescription rate of oral anticoagulant was similar between the two groups (77.6% vs 68.2%, P = 0.201), where warfarin was predominant. The F/F group was not associated with higher incidence of ischemic stroke. The F/F group was associated with a higher incidence of heart failure events (adjusted odds ratio (OR) 3.88; 95% confidence intervals (Cl) 1.70-8.85; P = 0.001), and cardiovascular events (OR 3.43; 95% Cl 1.71-6.85; P < 0.001). In elderly AF patients in a cardiovascular hospital, the experience of fall or fracture did not affect the prescription of oral anticoagulants and the incidence of ischemic stroke, but it was significantly associated with increase of heart failure.

Background: Frailty and cognitive impairment are well-known risk factors of delirium after cardiac surgery. Frailty is closely associated with cognitive impairment. This study aimed to examine how frailty and cognitive impairment affect the incidence of delirium after cardiac surgery in older patients., Methods: In total, 89 patients (aged ≥65 years) who underwent cardiac surgery between April 2016 and December 2017 were included (74.9 ± 5.5 years, male 64.1%). They were divided according to the combination of frailty and mild cognitive impairment (MCI): Group 1, non-frailty and non-MCI; Group 2, non-frailty and MCI; Group 3, frailty and non-MCI; and Group 4, frailty and MCI. Frailty was defined as a score of at least 3 points according to the Japanese version of the Cardiovascular Health Study criteria, and MCI was defined as a Montreal Cognitive Assessment score less than 26. Delirium was evaluated using the Intensive Care Delirium Screening Checklist, and a score of 4 or higher indicated delirium. Multivariate logistic regression analysis was performed to examine the influence of the combination of frailty and MCI on delirium after cardiac surgery., Results: In total, 31 patients (34.8%) showed postoperative delirium. Multivariate analysis-adjusted baseline characteristics (reference, Group 1) showed that only Group 4 had a risk of delirium after cardiac surgery (odds ratio, 7.494; 95% confidence interval 1.539-36.494)., Conclusion: Preoperative coexistence of frailty and MCI poses the greatest risk of delirium after cardiac surgery. Therefore, attention should be paid to both physical and cognitive function prior to surgery. Further studies are warranted to investigate the optimal intervention for high-risk patients., (Copyright © 2020 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

The relationship between myocardial bridging (MB) and coronary spasms during spasm provocation testing (SPT) remains unclear. We aimed to investigate whether MB was correlated with the SPT by ergonovine (ER) injections in a retrospective observational study. Of the 3340 patients who underwent a first coronary angiography, 166 underwent SPT using ER injections and were divided into 2 groups: MB(+) (n = 23), and MB(-) (n = 143). MB was defined as an angiographic reduction in the diameter of the coronary artery during systole. The patients who had severe organic stenosis in the left anterior descending coronary artery were excluded. The MB(+) group more frequently had diabetes mellitus and chronic kidney disease, and a thicker interventricular septum thickness. The rate of SPT-positivity was higher in the MB(+) group than MB(-) group (56.5% vs. 22.4%, P = 0.001). A multivariate regression analysis showed that the presence of MB was independently associated with SPT-positivity (odds ratio 5.587, 95% confidence interval 2.061-15.149, P = 0.001). In conclusion, coronary spasms during provocation tests with ER independently correlated with the MB. MB may predict coronary spasms.

In line with the recent globalization of the drug supply chain and promotion of the use of generic drugs worldwide, quality assurance is required for drugs globally. In particular, controlling impurities is one of the biggest areas of interest regarding pharmaceutical quality, and it is desirable that the latest scientific standards harmonized in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) are not only implemented in approval applications but also incorporated in pharmacopoeias which are public standards to ensure pharmaceutical quality more widely. However, incorporation into a pharmacopoeia takes time because careful consideration is required owing to the characteristics of a pharmacopoeia that is widely used for drugs, including those already on the market. To consider a smooth approach for the incorporation, we retrospectively examined approaches to incorporate the concepts of the ICH Q3C, Q3D, and M7 guidelines covering residual solvents, elemental impurities, and mutagenic impurities which are particularly toxic impurities into the European Pharmacopoeia, United States Pharmacopeia-National Formulary, and Japanese Pharmacopoeia, with approaches to implement these guidelines into approval processes in Europe, the U.S., and Japan. We also identified barriers and facilitators to this goal via cause and effect analysis. Moreover, we developed a logic model for the smooth incorporation of the concepts of impurity-related ICH guidelines. We expect that our proposed approach will be applied as a framework to smoothly incorporate the results of international harmonization activities for controlling impurities into each pharmacopoeia.

Objective The pharmacodynamic effect of warfarin varies among individuals, and its maintenance dose is widely distributed. Although many formulae for predicting the maintenance dose of warfarin have been developed, most of them are complex and not in practical use. Methods and Materials Among 12,738 new patients visiting the Cardiovascular Institute between 2004 and 2009, we identified 127 patients (66.6±8.8 years, 89 men) with atrial fibrillation for whom warfarin was newly started with an initial dose of 2 mg/day and the international normalized ratio (INR) at 1 year after warfarin was started was within the therapeutic range. The prediction models for the maintenance dose were developed by an exponential equation and a first-order equation. Results The initial response of the INR to the dose of 2 mg/day (initial INR) ranged from 1.00-3.24 (mean 1.43), while the maintenance dose of warfarin ranged from 0.5-14 mg (mean 3.8 mg). The maintenance dose showed an exponential correlation to the initial INR: (predicted maintenance dose) =5.522× (initial INR) -1.556 (R 2 =0.795, p<0.001). Excluding the patients with a poor response to the initial dose (initial INR <1.1, n=32) permitted a simple correlation with a first-order approximation: (predicted maintenance dose) =-2.009× (initial INR) +6.172 (R 2 =0.706, p<0.001). Conclusion We developed a simple formula for predicting the maintenance dose of warfarin using the initial response of the INR to low-dose warfarin.

In Japanese surveillance in an early phase after the approval of rivaroxaban, inappropriate underdose was frequently utilized. The aim of this study was to describe the prevalence and predictors of the inappropriate usage of rivaroxaban in a single-center, cardiovascular-specialized hospital. Consecutive 661 non-valvular atrial fibrillation (NVAF) patients treated with rivaroxaban between 2012 and 2017 were recruited. After excluding 30 patients without assessment of creatinine clearance (CCr), the proportion and predictors of inappropriate underdose were analyzed. Additionally, patient outcomes, including thromboembolism (ischemic stroke or systemic embolism) and major bleeding, were determined. In patients with CCr ≥ 50 mL/min (n = 532) and < 50 mL/min (n = 98), inappropriate underdose and overdose were used in 123 (23%) and 8 (8%), respectively. The predictors of inappropriate underdose (in patients with CCr ≥ 50 mL/min) were CCr [50-63 mL/min (the lowest tertile) compared to ≥ 64 mL/min], age ( ≥ 75 years), female gender, prescription of antiplatelet, and coexistence of heart failure. Although PT under rivaroxaban was lower in patients with inappropriate underdose than in those with an appropriate dose, no significant increase in the incidence of thromboembolism or major bleeding was observed within the mean follow-up of 683 days. Inappropriate underdose of rivaroxaban was frequently observed for NVAF patents even in a cardiovascular hospital, particularly in patients with CCr adjacent to the dose reduction criteria. The responses of PT and the incidence of adverse outcomes under an inappropriate dose of rivaroxaban should be further investigated.

Objectives: The advantage of valve-sparing root replacement (VSRR) over aortic root replacement with a composite valve graft (CVG) remains unclear. We compared these 2 procedures with regard to early outcomes with propensity score matching using the Japan Cardiovascular Surgery Database., Methods: Of 5303 patients from the Japan Cardiovascular Surgery Database who had undergone aortic root replacement in 2008 to 2017, emergent/urgent or redo cases and those with infective endocarditis or aortic stenosis were excluded (included n = 3841). Two propensity score-matched groups treated with VSRR or CVG replacement (n = 1164 each) were established., Results: Overall, VSRR was more frequently performed for younger patients with Marfan syndrome with lower operative risk and aortic regurgitation grade compared with CVG replacement. After matching, a weaker but similar trend still existed in baseline characteristics. Although more concomitant procedures were performed in the CVG group, myocardial ischemia and cardiopulmonary bypass time was significantly longer in the VSRR group (median, 193 and 245 minutes) than the CVG group (172 and 223 minutes, both P < .01). The CVG group was associated with a significantly greater incidence of postoperative stroke (2.5% vs 1.1%, P = .01) and prolonged ventilation >72 hours (7.0% vs 4.6%, P = .02). In-hospital mortality rates were significantly greater in the CVG group (1.8%) than the VSRR group (0.8%, P = .02)., Conclusions: In overall Japanese institutions, VSRR was more frequently performed for patients at low risk and was associated with better morbidity and mortality rates than CVG replacement. After matching, VSRR was also associated with better morbidity and mortality rates despite longer procedure time., (Copyright © 2019 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: Whether mild to moderate and moderate aortic regurgitation should be corrected surgically during other cardiovascular surgeries remains controversial. We evaluated the effectiveness of external suture annuloplasty in such cases., Methods: Among 95 patients undergoing aortic valve repair between December 2013 and March 2018, five patients with mild to moderate and moderate aortic regurgitation due to aortic annulus dilatation (type Ic lesion) underwent surgery for mitral regurgitation and/or thoracic aortic aneurysm. Aortic valves were repaired with external suture annuloplasty alone with a mean Hegar dilator size of 20.4 ± 0.8 (20.0-22.0) mm at the same time and were followed up echocardiographically., Results: There were no cases of mortality or major morbidity. Intraoperative direct measurement revealed ventriculoaortic junction size of 25.0 ± 0.8 (24.0-27.0) mm. The average cardiopulmonary bypass time and aortic cross-clamping time were 139 ± 46 (76-205) min and 105 ± 38 (58-172) min, respectively. Postoperative transthoracic echocardiogram during hospitalization showed trivial aortic regurgitation in all cases, with average ventriculoaortic junction size, aortic valve area, and peak and mean transvalvular gradient of 19.1 ± 0.7 (18.0-20.3) mm, 2.24 ± 0.48 (1.60-3.00) cm 2 , 6.4 ± 1.9 (4.0-9.2) mmHg, and 3.5 ± 1.1 (2.1-5.2) mmHg, respectively. Ventriculoaortic junction size was significantly decreased (P < 0.05). There have been no changes in ventriculoaortic junction size (P = 0.32) or other echocardiographic findings for 24 ± 6 (17-36) months after surgery., Conclusions: Although concomitant with other cardiac surgeries, mild to moderate and moderate aortic regurgitation could be repaired without clinically relevant additional surgical duration. External suture annuloplasty is a useful, safe, and secure treatment choice for type Ic lesion-induced aortic regurgitation.

Aims: Non-linear models by machine learning may identify different risk factors with different weighting in comparison to conventional linear models., Methods and Results: The analyses were performed in 15,933 patients included in the Shinken Database (SD) 2004-2014 (n = 22,022) for whom baseline data of blood sampling and ultrasound cardiogram and follow-up data at 2 years were available. Using non-linear models with machine learning software, 118 risk factors and their weighting of risk for all-cause mortality, heart failure (HF), acute coronary syndrome (ACS), ischemic stroke (IS), and intracranial hemorrhage (ICH) were identified, where the top two risk factors were albumin/hemoglobin, left ventricular ejection fraction/history of HF, history of ACS/anti-platelet use, history of IS/deceleration time, and history of ICH/warfarin use. The areas under the curve of the developed models for each event were 0.900, 0.912, 0.879, 0.758, and 0.753, respectively., Conclusion: Here, we described our experience with the development of models for predicting cardiovascular prognosis by machine learning. Machine learning could identify risk predicting models with good predictive capability and good discrimination of the risk impact., Competing Interests: Dr. Suzuki received research funding from Mitsubishi Tanabe Pharm, and Daiichi Sankyo. Dr. Yamashita has received research funds and/or lecture fees from Daiichi Sankyo, Bayer Yakuhin, Bristol-Myers Squibb, Pfizer, Nippon Boehringer Ingelheim, Eisai, Mitsubishi Tanabe Pharm, Ono Pharmaceutical, and Toa Eiyo. These do not alter our adherence to PLOS ONE policies on sharing data and materials.

Objectives: Several studies have suggested a possible relationship between atrial fibrillation (AF) and falls. However, whether the relationship depends on AF types is unclear. We investigated the relationship between sustaining AF and falls., Design: Single hospital-based cohort study with a follow-up of falls within 3 years after baseline., Setting and Participants: A total of 14,056 patients from our cohort between February 2010 and March 2016., Measures: Incidence of falls within 3 years by baseline cardiac rhythm was measured, and we investigated the effects of AF types on incidence of falls., Results: The study population was divided into younger (<75 years old; n = 11,808) and older (≥75 years old; n = 2248) groups, and then divided into 3 groups according to the baseline cardiac rhythm: sinus rhythm (SR), paroxysmal AF (PAF), and persistent AF (PeAF). There were more male patients in the PeAF group; these patients had more comorbidities both in the younger and older groups. The cumulative incidence rates of falls at 1 year in patients with SR, PAF, and PeAF were similar in the younger group (0.4%, 0.4%, and 0.6%, respectively; P = .496), whereas those were significantly different in the older group (2.3%, 2.7%, and 5.0%, respectively; P = .024). In multivariate analysis, both PAF [hazard ratio (HR) 1.179; 95% confidence interval (CI) 0.553-2.511, reference SR] and PeAF (HR 1.502; 95% CI 0.635-3.556) were not associated with falls in the younger group. In the older group, PeAF was independently associated with incidence of falls (HR 2.257; 95% CI 1.262-4.037), but PAF was not (HR 1.317; 95% CI 0.673-2.574)., Conclusions/implications: PeAF, not PAF, was associated independently with falls in older patients, suggesting the possible effect of irregular beats on physical frailty in the older population., (Copyright © 2018 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

A pharmacopoeia's core mission is to protect public health by creating and making available public standards to help ensure the quality of drugs. In recent years, pharmacopoeias around the world have harmonized their standards in the present context of globalized drug supply chains and markets. For example, the Pharmacopoeial Discussion Group has worked to harmonize excipient monographs and general chapters. In addition, the International Meeting of World Pharmacopoeias has been held by the WHO to discuss information exchange and international collaboration, among other topics. To contribute further to the protection of public health in the globalized drug market, we conducted a comparative study of the pharmacopoeias in Japan, Europe, and the United States. We aimed to examine current differences among the Japanese Pharmacopoeia, the European Pharmacopoeia, and the United States Pharmacopeia-National Formulary and to identify areas that require further collaboration among the three pharmacopoeias. In this study, we analyzed monographs and general chapters listed in the three pharmacopoeias. We identified the features of the monographs and general chapters listed in each pharmacopoeia, as well as differences across the pharmacopoeias. Moreover, on the basis of our findings, we suggest standards that require further collaboration among the pharmacopoeias in certain preferred areas. The comparison data produced by this study are expected to be used to develop strategies for future revisions of pharmacopoeias around the world.

Objective: Although aortic valve-sparing operations are performed throughout Japan, the indications, specific repair techniques, and outcomes have not been reported in full. Thus, we conducted the first nationwide survey of aortic valve-sparing surgery., Methods: We mailed a questionnaire to 508 institutions across Japan to obtain information on elective aortic valve and aortic root surgeries performed in 2014. Included in the mailing was a secondary questionnaire that sought further information from institutions reporting aortic valve-sparing surgeries., Results: Two hundred and fifty (49%) institutions responded and reported a total of 7859 aortic valve operations and 771 aortic root operations. Aortic valve operations performed strictly for aortic regurgitation totaled 2080, 156 (8%) of which were aortic valve repairs. Of the 699 aortic root surgeries performed for aortic regurgitation, 236 (34%) were valve-sparing root replacement surgeries. The valve-sparing root replacement surgeries comprised aortic valve reimplantation (n = 173, 73%) and aortic root remodeling (n = 63, 27%). Five of 57 (9%) institutions were responsible for 42% (99/233) of the total aortic valve-sparing surgeries performed. Detailed information that was obtained for 233 patients who underwent aortic valve repair or valve-sparing root replacement showed 30-day mortality and reoperation for regurgitation after aortic valve repair (n = 97), aortic root remodeling (n = 37), and aortic valve reimplantation (n = 99) to be 1, 0, and 1% and 3, 3, and 1%, respectively., Conclusion: To date, aortic valve-sparing operations have been performed for limited patients at limited institution in Japan, but the early outcomes have been excellent.

Purpose: A gap analysis survey of international practices for Active Substance Master Files (ASMFs)/Drug Master Files (DMFs) of human use was conducted as a project of the ASMF/DMF working group of the International Generic Drug Regulators Pilot (IGDRP) to identify similarities and differences among ASMF/DMF procedures of 10 IGDRP members and 2 observers., Methods: We conducted a questionnaire survey and compared the following aspects: overall ASMF/DMF procedures, submission requirements for ASMFs/DMFs, assessment processes for ASMFs/DMFs, the technical requirements for active pharmaceutical ingredients (APIs), generation of assessment reports for ASMFs/DMFs, procedures for changing ASMF/DMF details, and Good Manufacturing Practice (GMP) inspection/certification of API manufacturers. Twelve organizations participated in this project: the Brazilian Health Surveillance Agency (Anvisa), the European Union (EU), Health Canada (HC), the Singapore Health Sciences Authority (HSA), the South African Medicines Control Council (MCC), the South Korean Ministry of Food and Drug Safety (MFDS), the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), the Swiss Agency for Therapeutic Products (Swissmedic), the Taiwan Food and Drug Administration (TFDA), the Australian Therapeutic Goods Administration (TGA), the European Directorate for the Quality of Medicines & HealthCare (EDQM) (Observer) and the Prequalification Team (PQT) of the World Health Organization (WHO), which includes the PQT-Medicines (Observer)., Results: Although there were many similarities among the participating agencies surveyed, there were also differences that should be discussed such as assessment processes of ASMFs/DMFs and Technical requirements for APIs., Conclusions: These differences revealed by this survey will be key considerations in order to facilitate the filing of ASMFs/DMFs globally and to establish a framework for sharing and utilizing information related to ASMFs/DMFs among IGDRP members in the future. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Generic drugs are interchangeable with original proprietary drugs, as they have the same active pharmaceutical ingredients, dosage forms, strength, quality, indications, effects, directions, and dosage. The cost of generic drugs is lower than original drugs, because the developmental cost is lower. The expansion of medical expenses is an important issue in many countries, including Japan, the USA, and Europe, and promotion of generic drugs has been demanded to solve this issue in Japan. Generic drug approval review in Japan is conducted by the Pharmaceuticals and Medical Devices Agency (PMDA), which reviews the equivalence of the original drugs from the viewpoint of quality, efficacy, and safety, based on documentation submitted by the generic drug applicants. However, the details of the generic drug review in Japan have not been reported. In this report, we introduce the application types, the number of applications and approvals, and the review timeline of generic drugs in Japan. In addition, we discuss recent consultations and future prospects.

Background: This study compares the midterm results of mitral valve repair using the biodegradable ring versus repair with non-ring annuloplasty techniques for congenital mitral valve disease in young children where it was not possible to use standard commercial rings., Methods: Between February 2006 and November 2011, 68 patients underwent mitral valve repair for congenital mitral valve disease. Thirty-nine (57%) patients underwent concomitant annuloplasty using the biodegradable ring (group A) and 29 (43%) patients using non-ring annuloplasty techniques (group B). The median age of repair was 2 years (range 1 month to 14 years)., Results: There were no hospital deaths or major postoperative morbidity. At a median follow-up of 3.8 years (range, 2 months to 5.1 years), overall survival at 5 years was 97% ± 3% for group A and 88% ± 8% for group B (p = 0.29). Freedom from valve failure was 90% ± 7% in group A and 74% ± 9% in group B (p = 0.026). The freedom from reoperation was 100% in group A and 84% ± 9% in group B (p = 0.04). The mean transmitral gradients were 4.3 ± 1.8 mm Hg in group A and 4.2 ±1.7 mm Hg in group B (p = 0.77)., Conclusions: Mitral valve repair using the biodegradable ring for congenital mitral valve disease was superior compared with non-ring annuloplasty repair. Excellent survival benefit, freedom from reoperation, and valve failure without significant elevation of transmitral gradients, suggests its important role in young children with smaller annular sizes where standard commercial rings are not available or recommended., (Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

The biosynthetic gene cluster for lariatins A and B, anti-mycobacterial peptide antibiotics with a unique "lasso" structure, was cloned from Gram-positive bacterium Rhodococcus jostii K01-B0171. Random transposition mutagenesis using IS1415 derivative was carried out to identify a chromosomal locus involved in lariatin biosynthesis and six independent lariatin non-producing variants were obtained. Arbitrary PCR revealed that one insertion was located near the region involved in lariatin biosynthesis. Using the lariatin gene as a probe, a genomic library of R. jostii K01-B0171 was screened by colony hybridization, and two clones were obtained. Sequence analysis of these clones revealed that the gene cluster for lariatin biosynthesis spanning about 4.5 kb consisted of five open reading frames (larA to larE). We proposed that the linear precursor LarA is processed by LarB, LarC, and LarD, and the mature lariatin is exported by LarE.

We present a case with a rare combination of tetralogy of Fallot with an absent pulmonary valve, and a single coronary artery with a major fistula to the main pulmonary artery. Myocardial ischemia developed in response to increasing shunt flow through the coronary fistula, resulting in heart failure. We ligated the coronary fistula and plicated the anterior wall of the dilated pulmonary arteries during the neonatal period. Complete repair through a transatrial-transpulmonary approach was performed at the age of 17 months. The postoperative course was excellent and the patient maintained a stable hemodynamic and respiratory state with no evidence of myocardial ischemia.

Two isozymes for human acyl-coenzyme A:diacylglycerol acyltransferase (DGAT), DGAT1 and DGAT2, were independently expressed in DGAT-deficient Saccharomyces cerevisiae to establish DGAT1- and DGAT2-S. cerevisiae. The selectivity of DGAT inhibitors of natural origin towards the isozymes was assessed in enzyme assays using the microsomal fractions prepared from DGAT1- and DGAT2-S. cerevisiae. Amidepsines and xanthohumol inhibited DGAT1 and DGAT2 with similar potency, whereas roselipins were found to inhibit DGAT2 selectively.