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Masaki Tago,1 Risa Hirata,1 Hiromizu Takahashi,2 Shun Yamashita,1,3 Masayuki Nogi,4,5 Kiyoshi Shikino,6 Yosuke Sasaki,7 Takashi Watari,8 Taro Shimizu9 1Department of General Medicine, Saga University Hospital, Saga, Japan; 2Department of General Medicine, Faculty of Medicine, Juntendo University, Tokyo, Japan; 3Education and Research Center for Community Medicine, Faculty of Medicine, Saga University, Saga, Japan; 4Hospitalist Division, The Queen’s Medical Center, Honolulu, HI, USA; 5Department of General Internal Medicine, Kameda Medical Center, Chiba, Japan; 6Department of General Medicine, Chiba University Hospital, Chiba, Japan; 7Department of General Medicine and Emergency Care, Toho University School of Medicine, Tokyo, Japan; 8General Medicine Center, Shimane University Hospital, Shimane, Japan; 9Department of Diagnostic and Generalist Medicine, Dokkyo Medical University, Tochigi, JapanCorrespondence: Masaki Tago, Department of General Medicine, Saga University Hospital, 5-1-1 Nabeshima, Saga, 849-8501, Japan, Tel +81 952 34 3238, Fax +81 952 34 2029, Email tagomas@cc.saga-u.ac.jpAbstract: Hospital Medicine in the United States has achieved significant progress in the accumulation of evidence. This development has influenced the increasing societal demand for General Medicine in Japan. Generalists in Japan actively engage in a wide range of interdisciplinary clinical practices, education, and management. Furthermore, Generalists have also contributed to advances in research. However, there is limited evidence regarding the benefits of General Medicine in Japan in all these areas, with most of the evidence derived from single-center studies. In Japan, the roles of Generalists are diverse, and the comprehensive definition of General Medicine makes it difficult to clearly delineate its scope. This results in an inadequate accumulation of evidence regarding the benefits of General Medicine, potentially making it less attractive to the public and younger physicians. Therefore, it is necessary to categorize General Medicine and collect clear evidence regarding its benefits.Keywords: classification, evidence, general medicine

Aims: Congestive heart failure (HF) is a common complication in patients with acute myocardial infarction (AMI). The estimated plasma volume status [ePVS = (100 - haematocrit)/haemoglobin] is used as the blood plasma volume index to determine the presence of congestion in patients with HF. However, the clinical impact of ePVS at discharge in patients with AMI remains unclear. This study aimed to investigate whether ePVS at discharge could determine the long-term prognosis in patients with AMI., Methods and Results: We retrospectively identified patients with AMI with ePVS measured at discharge between January 2012 and December 2020. The primary endpoint was post-discharge all-cause death. The patients were divided into two groups according to an ePVS cut-off value of 5.5%, which is commonly used in HF. In total, 1012 patients with AMI were included. The median age was 70 years (range, 61-78 years), and 76.4% of the patients were male. The ePVS > 5.5% (high-ePVS) group included 365 patients (36.1%), and the all-cause mortality rate in the total cohort was 17.7%. The log-rank test revealed that the high-ePVS group had a significantly higher rate of all-cause death than the ePVS ≤ 5.5% (low-ePVS) group (P < 0.001). Multivariate Cox proportional hazards model analysis revealed that high ePVS was associated with post-discharge all-cause death, independent of other risk factors (hazard ratio = 1.879; 95% confidence interval = 1.343-2.629, P < 0.001)., Conclusions: High ePVS at discharge was independently associated with high post-discharge all-cause mortality in patients with AMI. Our study suggests that ePVS at discharge in patients with AMI could serve as a novel prognostic marker., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Tuberculous peritonitis (TB peritonitis) is one of the most challenging forms of extrapulmonary TB to diagnose. While tumor markers can be elevated in patients with TB peritonitis, FDG-PET/CT can aid in distinguishing TB peritonitis from malignancies, if an apron-like omentum pattern is seen. Laparoscopy is crucial for accurate and early diagnosis., Competing Interests: The authors have no conflict of interest to declare., (© 2024 The Author(s). Clinical Case Reports published by John Wiley & Sons Ltd.)

Background: Although a tool for sharing patient prognosis among all medical staff is desirable in heart failure (HF) cases, only a few simple HF prognostic scores are available. We previously presented the A 2 B score, a simple user-friendly HF risk score, and validated it in a small single-center cohort. In the present study, we validated it in a larger nationwide cohort., Methods and Results: We examined the 2-year mortality in relation to the A 2 B scores in 3483 patients from a Japanese nationwide cohort and attempted to stratify their prognoses according to the scores. The A 2 B score was determined by assigning points for age, anemia, and brain natriuretic peptide (BNP) level at discharge: age (<65 years, 0; 65-74 years, 1; ≥75 years, 2), anemia (hemoglobin ≥12 g/dL, 0; 10-11.9 g/dL, 1; <10 g/dL, 2), and BNP (<200 pg/mL, 0; 200-499 pg/mL, 1; ≥500 pg/mL, 2). Hemoglobin and BNP levels were applied to the data at discharge. The 2-year survival rates for A 2 B scores 1, 2, 3, 4, 5, and 6 were 94.1%, 83.2%, 74.1%, 63.5%, 51.6%, and 41.5%, respectively; the mortality rate increased by ≈10% for each point increase (c-index, 0.702). The A 2 B score was applicable in HF cases with reduced or preserved ejection fraction and remained useful when BNP was substituted with N-terminal proBNP (c-index, 0.749, 0.676, and 0.682, respectively)., Conclusions: The A 2 B score showed a good prognostic value for HF in a large population even when BNP was replaced with N-terminal proBNP.

Introduction: Basic fibroblast growth factor (bFGF, FGF2) and integrin α6β1 are important for maintaining the pluripotency of human pluripotent stem cells (hPSCs). Although bFGF-integrin binding contributes to biofunctions in cancer cells, the relationship in hPSCs remains unclear., Methods: To investigate the relationship between bFGF and integrin in human induced pluripotent stem cells (hiPSCs), we generated recombinant human bFGF wild-type and mutant proteins, that do not bind to integrin, FGFR, or both. We then cultured hiPSCs with these recombinant bFGF proteins. To evaluate the abilities of recombinant bFGF proteins in maintaining hPSC properties, pluripotent markers, ERK activity, and focal adhesion structure were analyzed through flow cytometry, immunofluorescence (IF), and immunoblotting (IB)., Result: We identified an interaction between bFGF and integrin α6β1 in vitro and in hiPSCs. The integrin non-binding mutant was incapable of inducing the hPSC properties, such as proliferation, ERK activity, and large focal adhesions at the edges of hiPSC colonies. Signaling induced by bFGF-FGFR binding was essential during the first 24 h after cell seeding for maintaining the properties of hPSCs, followed by a shift towards intracellular signaling via the bFGF-integrin interaction. The mixture of the two bFGF mutants also failed to maintain hPSC properties, indicating that bFGF binds to both FGFR and integrin., Conclusion: Our study demonstrates that the integrin-bFGF-FGFR ternary complex maintains the properties of hPSCs via intracellular signaling, providing insights into the functional crosstalk between bFGF and integrins in hiPSCs., Competing Interests: K. S. is a co-founder and shareholder of Matrixome, Inc. Y.T. holds a position as a Project Leader at Matrixome Inc., (© 2023 The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V.)

Background: Several guidelines recommend the measurement of N-terminal pro-B-type natriuretic peptide (NT-proBNP) to diagnose heart failure (HF); however, no screening criteria for measuring NT-proBNP in asymptomatic patients exist. We develop/validate a clinical prediction model for elevated NT-proBNP to support clinical outpatient decision-making., Methods: In this multicenter cohort study, we used a derivation cohort (24 facilities) from 2017 to 2021 and a validation cohort at one facility from 2020 to 2021. Patients were aged ≥65 years with at least one risk factor of HF. The primary endpoint was NT-proBNP ≥125 pg/mL. The final model was selected using backward stepwise logistic regression analysis. Diagnostic performance was evaluated for sensitivity and specificity, the area under the curve (AUC), and calibration. In total, 1645 patients (derivation cohort, n = 837; validation cohort, n = 808) were included, of whom 378 (23.0 %) had NT-proBNP ≥125 pg/mL. Body mass index, age, systolic blood pressure, estimated glomerular filtration rate, cardiothoracic ratio, and heart disease were used as predictors and aggregated into a BASE-CH score of 0-11 points., Results: Internal validation resulted in an AUC of 0.74 and an external validation AUC of 0.70., Conclusions: Based on available clinical and laboratory variables, we developed and validated a new risk score to predict NT-proBNP ≥125 pg/mL in patients at risk for HF or with pre-HF., Competing Interests: Declaration of competing interest Saito Y. received research funds from Otsuka Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Bristol-Myers Squibb Company, Actelion Pharmaceuticals Japan Ltd., Kyowa Kirin Co., Ltd., Kowa Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Teijin Pharma Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Nihon Medi-Physics Co., Ltd., Novartis Pharma K.K., Pfizer Japan Inc., and Fuji Yakuhin Co., Ltd.; research expenses from Novartis Pharma K.K., Roche Diagnostics K.K., Amgen Inc., Bayer Yakuhin, Ltd., Astellas Pharma Inc., and Actelion Pharmaceuticals Japan Ltd.; speakers' bureau/honorarium from Alnylam Japan K.K., AstraZeneca K.K., Otsuka Pharmaceutical Co., Ltd., Kowa Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Tsumura & Co., Teijin Pharma Ltd., Toa Eiyo Ltd., Nippon Shinyaku Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., Bayer Yakuhin Ltd., Pfizer Japan Inc., Bristol-Myers Squibb Company, and Mochida Pharmaceutical Co., Ltd.; and consultation fees from Ono Pharmaceutical Co., Ltd. and Novartis Pharma K.K. Masuda I. received research funds from Astra Zeneca K.K., Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Astellas Pharma Inc., Bayer Yakuhin, Ltd., Nippon Boehringer Ingelheim Co., Mitsubishi Tanabe Pharma Co., Ltd.,Daiichi Sankyo Co., Ltd., Kowa Company, Ltd., MSD K.K., Shionogi & Co., Ltd., Sumitomo Pharma Co., Ltd., Novartis Pharma K.K., Teijin Pharma Ltd., Otsuka Pharmaceutical Co., Ltd.; and manuscript fees from OMRON HEALTHCARE Co., Ltd. The other authors have no financial conflicts of interest to disclose., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Optically transparent materials that are air permeable have potentially numerous applications, including in wearable devices. From the perspective of sustainable development, 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)-oxidized cellulose nanofibers with widths of 3-4 nm have attracted considerable attention as starting materials for the preparation of clearly transparent nanofiber paper (denoted as conventional nanopaper). However, conventional nanopaper that is prepared from a water dispersion of TEMPO-oxidized cellulose nanofibers by direct drying exhibits poor air permeability owing to its densely packed layered structure. In this study, we prepared a clearly transparent and air-permeable nanopaper by applying filtration-based solvent exchange from high-surface-tension water to low-surface-tension ethanol and hexane, followed by drying under continuous vacuum filtration. The resulting hexane-exchanged nanopaper had a porous structure with individually dispersed and thin nanofiber networks and interlayer pore spaces. Owing to the tailored porous structures, the hexane-exchanged nanopaper provides similar clear transparency (total light transmittance and haze at 600 nm: 92.9% and 7.22%, respectively) and 10 6 times higher air permeability (7.8 × 10 6 mL μm m -2 day -1 kPa -1 ) compared to the conventional nanopaper. This study will facilitate the development of clearly transparent and air-permeable nanopapers to extend their functional applications., Competing Interests: The authors declare no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Remarkable progress has been made in the development of carbonized chitin nanofiber materials for various functional applications, including solar thermal heating, owing to their N- and O-doped carbon structures and sustainable nature. Carbonization is a fascinating process for the functionalization of chitin nanofiber materials. However, conventional carbonization techniques require harmful reagents, high-temperature treatment, and time-consuming processes. Although CO 2 laser irradiation has progressed as a facile and second-scale high-speed carbonization process, CO 2 -laser-carbonized chitin nanofiber materials and their applications have not yet been explored. Herein, we demonstrate the CO 2 -laser-induced carbonization of chitin nanofiber paper (denoted as chitin nanopaper) and investigate the solar thermal heating performance of the CO 2 -laser-carbonized chitin nanopaper. While the original chitin nanopaper was inevitably burned out by CO 2 laser irradiation, CO 2 -laser-induced carbonization of the chitin nanopaper was achieved by pretreatment with calcium chloride as a combustion inhibitor. The CO 2 -laser-carbonized chitin nanopaper exhibits excellent solar thermal heating performance; its equilibrium surface temperature under 1 sun irradiation is 77.7 °C, which is higher than those of the commercial nanocarbon films and the conventionally carbonized bionanofiber papers. This study paves the way for the high-speed fabrication of carbonized chitin nanofiber materials and their application in solar thermal heating toward the effective utilization of solar energy as heat., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Aims: Heart failure (HF) with preserved ejection fraction (HFpEF) is a complex syndrome with a poor prognosis. Phenotyping is required to identify subtype-dependent treatment strategies. Phenotypes of Japanese HFpEF patients are not fully elucidated, whose obesity is much less than Western patients. This study aimed to reveal model-based phenomapping using unsupervised machine learning (ML) for HFpEF in Japanese patients., Methods and Results: We studied 365 patients with HFpEF (left ventricular ejection fraction >50%) as a derivation cohort from the Nara Registry and Analyses for Heart Failure (NARA-HF), which registered patients with hospitalization by acute decompensated HF. We used unsupervised ML with a variational Bayesian-Gaussian mixture model (VBGMM) with common clinical variables. We also performed hierarchical clustering on the derivation cohort. We adopted 230 patients in the Japanese Heart Failure Syndrome with Preserved Ejection Fraction Registry as the validation cohort for VBGMM. The primary endpoint was defined as all-cause death and HF readmission within 5 years. Supervised ML was performed on the composite cohort of derivation and validation. The optimal number of clusters was three because of the probable distribution of VBGMM and the minimum Bayesian information criterion, and we stratified HFpEF into three phenogroups. Phenogroup 1 (n = 125) was older (mean age 78.9 ± 9.1 years) and predominantly male (57.6%), with the worst kidney function (mean estimated glomerular filtration rate 28.5 ± 9.7 mL/min/1.73 m 2 ) and a high incidence of atherosclerotic factor. Phenogroup 2 (n = 200) had older individuals (mean age 78.8 ± 9.7 years), the lowest body mass index (BMI; 22.78 ± 3.94), and the highest incidence of women (57.5%) and atrial fibrillation (56.5%). Phenogroup 3 (n = 40) was the youngest (mean age 63.5 ± 11.2) and predominantly male (63.5 ± 11.2), with the highest BMI (27.46 ± 5.85) and a high incidence of left ventricular hypertrophy. We characterized these three phenogroups as atherosclerosis and chronic kidney disease, atrial fibrillation, and younger and left ventricular hypertrophy groups, respectively. At the primary endpoint, Phenogroup 1 demonstrated the worst prognosis (Phenogroups 1-3: 72.0% vs. 58.5% vs. 45%, P = 0.0036). We also successfully classified a derivation cohort into three similar phenogroups using VBGMM. Hierarchical and supervised clustering successfully showed the reproducibility of the three phenogroups., Conclusions: ML could successfully stratify Japanese HFpEF patients into three phenogroups (atherosclerosis and chronic kidney disease, atrial fibrillation, and younger and left ventricular hypertrophy groups)., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Risk stratification is important in patients with acute heart failure (AHF), and a simple risk score that accurately predicts mortality is needed. The aim of this study is to develop a user-friendly risk-prediction model using a machine-learning method., Methods: A machine-learning-based risk model using least absolute shrinkage and selection operator (LASSO) regression was developed by identifying predictors of in-hospital mortality in the derivation cohort (REALITY-AHF), and its performance was externally validated in the validation cohort (NARA-HF) and compared with two pre-existing risk models: the Get With The Guidelines risk score incorporating brain natriuretic peptide and hypochloremia (GWTG-BNP-Cl-RS) and the acute decompensated heart failure national registry risk (ADHERE)., Results: In-hospital deaths in the derivation and validation cohorts were 76 (5.1 %) and 61 (4.9 %), respectively. The risk score comprised four variables (systolic blood pressure, blood urea nitrogen, serum chloride, and C-reactive protein) and was developed according to the results of the LASSO regression weighting the coefficient for selected variables using a logistic regression model (4 V-RS). Even though 4 V-RS comprised fewer variables, in the validation cohort, it showed a higher area under the receiver operating characteristic curve (AUC) than the ADHERE risk model (AUC, 0.783 vs. 0.740; p = 0.059) and a significant improvement in net reclassification (0.359; 95 % CI, 0.10-0.67; p = 0.006). 4 V-RS performed similarly to GWTG-BNP-Cl-RS in terms of discrimination (AUC, 0.783 vs. 0.759; p = 0.426) and net reclassification (0.176; 95 % CI, -0.08-0.43; p = 0.178)., Conclusions: The 4 V-RS model comprising only four readily available data points at the time of admission performed similarly to the more complex pre-existing risk model in patients with AHF., Competing Interests: Declaration of competing interest Dr. Yuya Matsue is affiliated to a department endowed by Philips Respironics, ResMed, Teijin Home Healthcare, and Fukuda Denshi and received an honorarium from Otsuka Pharmaceutical Co and Novartis Japan. Dr. Keisuke Kida received honorariums from Daichi Sankyo Co., Ono Pharmaceutical Co., Ltd., AstraZeneca K.K., Otsuka Pharmaceutical Co., Ltd., and Novartis Pharmaceuticals Co., Ltd. Dr. Takahiro Okumura received research honoraria from Ono Yakuhin, Otsuka, Novartis, and Astrazeneca and research grants from Ono Yakuhin, Amgen Astellas, Pfizer, Alnylam, and Alexion (not in connection with the submitted work). Dr. Yoshihiko Saito received research funds from Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Actelion Pharmaceuticals Japan Ltd., Kyowa Kirin Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Chugai Pharmaceutical Co., Ltd., Nihon Medi-Physics Co., Ltd., Fuji Yakuhin Co., Ltd.; research expences from Roche Diagnostics K.K., Otsuka Pharmaceutical Co., Ltd., Terumo Corporation, Kowa Company, Abbott Medical Japan LLC, Alnylam Japan K.K. Cmic Holdings Co., Ltd.; Speakers' bureau/honorarium from Alnylam Japan K.K., AstraZeneca K.K., Amicus Therapeutics, Inc., Amgen K.K. Edwards Lifesciences Corporation, Otsuka Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Kowa Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Tsumura & Co., Toa Eiyo Ltd., Nippon Shinyaku Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., Bayer Yakuhin Ltd., Mochida Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K.; Consultation fees from AstraZeneca K.K., Novartis Pharma K.K., Nippon Boehringer Ingelheim Co., Ltd.; Other remuneration (supervisor) from Towa Pharmaceutical Co., Ltd. The other authors have nothing to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Sustainable biomass-derived carbons have attracted research interest because of their ability to effectively absorb and convert solar light to thermal energy, a phenomenon known as solar thermal heating. Although their carbon-based molecular and nanoporous structures should be customized to achieve enhanced solar thermal heating performance, such customization has insufficiently progressed. In this study, we transformed a chitin nanofiber/water dispersion into paper, referred to as chitin nanopaper, with subwavelength nanoporous structures by spatially controlled drying, followed by temperature-controlled carbonization without any pretreatment to customize the carbon-based molecular structures. The optimal carbonization temperature for enhancing the solar absorption and solar thermal heating performance of the chitin nanopaper was determined to be 400 °C. Furthermore, we observed that the nitrogen component, which afforded nitrogen-doped carbon structures, and the high morphological stability of chitin nanofibers against carbonization, which maintained subwavelength nanoporous structures even after carbonization, contributed to the improved solar absorption of the carbonized chitin nanopaper. The carbonized chitin nanopaper exhibited a higher solar thermal heating performance than the carbonized cellulose nanopaper and commercial nanocarbon materials, thus demonstrating significant potential as an excellent solar thermal material.

Background The fractional excretion of urea nitrogen (FEUN) has been used as a renal blood flow index related to cardiac output, and the estimated plasma volume status (ePVS) as a body fluid volume index. However, the usefulness of their combination in acute decompensated heart failure (HF) management is unclear. We investigated the effect of 4 hemodynamic categories according to the high and low FEUN and ePVS values at discharge on the long-term prognosis of patients with acute decompensated HF. Methods and Results Between April 2011 and December 2018, we retrospectively identified 466 patients with acute decompensated HF with FEUN and ePVS values at discharge. Primary end point was postdischarge all-cause death. Secondary end points were (1) the composite of all-cause death and HF readmission, and (2) HF readmission in a time-to-event analysis. The patients were divided into 4 groups according to the high/low FEUN (≥35%, <35%) and ePVS (>5.5%, ≤5.5%) values at discharge: high-FEUN/low-ePVS, high-FEUN/high-ePVS, low-FEUN/low-ePVS, and low-FEUN/high-ePVS groups. During a median follow-up period of 28.1 months, there were 173 all-cause deaths (37.1%), 83 cardiovascular deaths (17.8%), and 121 HF readmissions (26.0%). The Kaplan-Meier curve analysis showed that the high-FEUN/low-ePVS group had a better prognosis than the other groups (log-rank test, P <0.001). In the multivariable Cox regression analysis, the low-FEUN/high-ePVS group had a higher mortality than the high-FEUN/low-ePVS group (hazard ratio, 2.92 [95% CIs, 1.73-4.92; P <0.001]). Conclusions The new classification of the 4 hemodynamic profiles using the FEUN and ePVS values may play an important role in improving outcomes in patients with stable acute decompensated HF.

Background: Hospitalist turnover is exceedingly high, placing financial burdens on hospital medicine groups (HMGs). Following training, many begin their employment in medicine as early-career hospitalists, the majority being millennials., Objective: To understand what elements influence millennial hospitalists' recruitment and retention., Design: We developed a survey that asked participants to rate the level of importance of 18 elements (4-point Likert scale) in their decision to choose or remain at an HMG., Participants: The survey was electronically distributed to hospitalists born in or after 1982 across 7 HMGs in the USA., Main Measures: Elements were grouped into four major categories: culture of practice, work-life balance, financial considerations, and career advancement. We calculated the means for all 18 elements reported as important across the sample. We then calculated means by averaging elements within each category. We used unpaired t-tests to compare differences in means for categories for choosing vs. remaining at an HMG., Key Results: One hundred forty-four of 235 hospitalists (61%) responded to the survey. 49.6% were females. Culture of practice category was the most frequently rated as important for choosing (mean 96%, SD 12%) and remaining (mean 96%, SD 13%) at an HMG. The category least frequently rated as important for both choosing (mean 69%, SD 35%) and remaining (mean 76%, SD 32%) at an HMG was career advancement. There were no significant differences between respondent gender, race, or parental status and ratings of elements for choosing or remaining with HMGs., Conclusion: Culture of practice at an HMG may be highly important in influencing millennial hospitalists' decision to choose and stay at an HMG. HMGs can implement strategies to create a millennial-friendly culture which may help improve recruitment and retention., (© 2022. The Author(s), under exclusive licence to Society of General Internal Medicine.)

We clarified the association between changes in the number of foundational medications for heart failure (FMHF) during hospitalization for worsening heart failure (HF) and post-discharge prognosis. We retrospectively analyzed a combined dataset from three large-scale registries of hospitalized patients with HF in Japan (NARA-HF, WET-HF, and REALITY-AHF) and patients diagnosed with HF with reduced or mildly reduced left ventricular ejection fraction (HFr/mrEF) before admission. Patients were stratified by changes in the number of prescribed FMHF classes from admission to discharge: angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, beta-blockers, and mineralocorticoid receptor blockers. Primary endpoint was the combined endpoint of HF rehospitalization and all-cause death within 1 year of discharge. The cohort comprised 1113 patients, and 482 combined endpoints were observed. Overall, FMHF prescriptions increased in 413 (37.1%) patients (increased group), remained unchanged in 607 (54.5%) (unchanged group), and decreased in 93 (8.4%) (decreased group) at discharge compared with that during admission. In the multivariable analysis, the increased group had a significantly lower incidence of the primary endpoint than the unchanged group (hazard ratio 0.56, 95% confidence interval 0.45-0.60; P < 0.001). In conclusion, increase in FMHF classes during HF hospitalization is associated with a better prognosis in patients with HFr/mrEF., (© 2022. The Author(s).)

Aims: Acute heart failure (AHF) is a clinical syndrome with a poor prognosis and a major public health concern worldwide. The aim of this study was to investigate whether carperitide administration improves the 1 year prognosis of patients with AHF and to check whether there is an optimal dose of the drug., Methods and Results: We analysed the data of COOPERATE-HF-J (the Consortium for Pooled Data Analysis regarding Hospitalized Patients with Heart Failure in Japan), combining two cohorts (NARA-HF and REALITY-AHF), which included 2435 patients with acute decompensated heart failure. The patients were divided into no carperitide (NO-ANP, n = 1098); very low-dose carperitide (VLD-ANP, <0.02 μg/kg/min, n = 593); and low-dose carperitide groups (LD-ANP, ≥0.02 μg/kg/min, n = 744). The primary endpoint was cardiovascular mortality within 1 year after admission. The secondary endpoints were all-cause mortality and rehospitalization due to worsening heart failure within 1 year after admission. The median carperitide doses in the VLD-ANP and LD-ANP groups were 0.013 and 0.025 μg/kg/min, respectively. Kaplan-Meier analysis showed that cardiovascular mortality and all-cause mortality were significantly lower in the LD-ANP group than in the NO-ANP and VLD-ANP groups (P < 0.001 and P = 0.002, respectively). Multivariable Cox regression analysis for cardiovascular and all-cause mortality revealed that LD-ANP was significantly associated with lower cardiovascular and all-cause mortality within 1 year after admission, even after adjusting other covariates (hazard ratio: 0.696 and 0.791, 95% confidence interval: 0.513-0.944 and 0.628-0.997, P = 0.020 and 0.047, respectively)., Conclusions: Low-dose carperitide was significantly associated with lower cardiovascular and all-cause mortality within 1 year after admission. Our results suggest the necessity for well-designed randomized controlled trials to determine the doses of carperitide that could improve clinical outcomes in patients with AHF., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Biomass-derived three-dimensional (3D) porous nanocarbons have attracted much attention due to their high surface area, permeability, electrical conductivity, and renewability, which are beneficial for various electronic applications, including energy storage. Cellulose, the most abundant and renewable carbohydrate polymer on earth, is a promising precursor to fabricate 3D porous nanocarbons by pyrolysis. However, the pyrolysis of cellulosic materials inevitably causes drastic carbon loss and volume shrinkage. Thus, polydopamine doping prior to the pyrolysis of cellulose nanofiber paper is proposed to fabricate the 3D porous nanocarbons with improved yield and volume retention. Our results show that a small amount of polydopamine (4.3 wt%) improves carbon yield and volume retention after pyrolysis at 700 °C from 16.8 to 26.4% and 15.0 to 19.6%, respectively. The pyrolyzed polydopamine-doped cellulose nanofiber paper has a larger specific surface area and electrical conductivity than cellulose nanofiber paper that without polydopamine. Owing to these features, it also affords a good specific capacitance up to 200 F g -1 as a supercapacitor electrode, which is higher than the recently reported cellulose-derived nanocarbons. This method provides a pathway for the effective fabrication of high-performance cellulose-derived 3D porous nanocarbons.

Background Maintaining euvolemia is crucial for improving prognosis in acute decompensated heart failure (ADHF). Although fractional excretion of urea nitrogen (FEUN) is used as a body fluid volume index in patients with acute kidney injury, the clinical impact of FEUN in patients with ADHF remains unclear. This study aimed to investigate whether FEUN can determine the long-term prognosis in patients with ADHF. Methods and Results We retrospectively identified 466 patients with ADHF who had FEUN measured at discharge between April 2011 and December 2018. The primary endpoint was post-discharge all-cause death. Patients were divided into two groups according to a FEUN cut-off value of 35%, commonly used in pre-renal failure. The FEUN <35% (low-FEUN) group included 224 patients (48.1%), and the all-cause mortality rate for the total cohort was 37.1%. The log-rank test revealed that the low-FEUN group had a significantly higher rate of all-cause death compared to the FEUN equal to or greater than 35% (high-FEUN) group ( P <0.001). Multivariate Cox proportional hazards model analysis revealed that low-FEUN was associated with post-discharge all-cause death, independently of other heart failure risk factors (hazard ratio, 1.467; 95% CI, 1.030-2.088, P =0.033). The risk of low-FEUN compared to high-FEUN in post-discharge all-cause death was consistent across all subgroups; however, the effects tended to be modified by renal function (threshold: 60 mL/min/1.73 m 2 , interaction P =0.069). Conclusions Our study suggests that FEUN may be a novel surrogate marker of volume status in patients with ADHF requiring diuretics.

Rationale: Malignant infiltration accounts for 0.5% of acute liver failure cases, with non-Hodgkin's lymphoma the predominant cause. Adult T-cell lymphoma/leukemia (ATLL) is a rarer source of acute hepatitis, with only 3 cases reported and all resulting in immediate deterioration with death. ATLL rises from human T-lymphocytic virus-1 (HTLV-1), commonly found in Japan (southern and northern islands), the Caribbean, Central and South America, intertropical Africa, Romania, and northern Iran. In Micronesia, HTLV-1 infection amongst native-born is absent or exceedingly rare., Patient Concerns: A 77-year-old Marshallese man presented to the emergency department with a 1-week history of generalized weakness, fatigue, and nausea. The physical exam revealed a cervical papulonodular exanthem and scleral icterus., Diagnosis: Laboratory studies were remarkable for aspartate-aminotransferase of 230 IU/L (reference range [RR]: 0-40), alanine-aminotransferase of 227 IU/L (RR: 0-41), alkaline phosphatase of 133 IU/L (RR: 35-129), and total bilirubin of 4.7 mg/dL (RR: 0-1.2), supporting acute liver injury. Platelet count was 11.6x104/μL (RR: 15.1-42.4 × 104), hemoglobin was 13.8 g/dL (RR: 13.7-17.5), and white blood cell count was 7570/μL (RR: 3800-10,800) with 81.8% neutrophils (RR: 34.0-72.0) and 10.4% lymphocytes (RR: 12.0-44.0). The peripheral blood smear demonstrated abnormal lymphocytes with occasional flower cell morphology. HTLV-1/2 antibody tested positive. The skin and liver biopsies confirmed atypical T-cell infiltrate. The diagnosis of ATLL was established., Interventions: The patient elected for palliative chemotherapy with cyclophosphamide, vincristine, and prednisone (CVP). He began antiviral treatment with zidovudine 250 mg bis in die (BID) indefinitely. Ursodiol and cholestyramine were added for his hyperbilirubinemia., Outcomes: Four weeks from admission, the patient returned to near baseline functional status and was discharged home., Lessons: This case highlights that ATLL can initially present as isolated acute hepatitis, and how careful examination of peripheral blood-smear may elucidate hepatitis etiology. We also present support for utilizing ursodiol with cholestyramine for treating a hyperbilirubinemia. Moreover, unlike prior reports of ATLL presenting as liver dysfunction, combined antiviral and CVP chemotherapy was effective in this case. Lastly, there are seldom demographic reports of HTLV-1 infection from the Micronesian area, and our case represents the first indexed case of HTLV-1-associated-ATLL presenting as acute liver failure in a Marshallese patient., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Atrial fibrillation (AF) and mitral regurgitation (MR) are frequently combined in patients with heart failure (HF). However, the effect of AF on the prognosis of patients with HF and MR remains unknown. Methods and Results: We studied 867 patients (mean age 73 years; 42.7% female) with acute decompensated HF (ADHF) in the NARA-HF registry. Patients were divided into 4 groups based on the presence or absence of AF and MR at discharge. Patients with severe MR were excluded. The primary endpoint was the composite of cardiovascular (CV) death and HF-related readmission. During the median follow-up of 621 days, 398 patients (45.9%) reached the primary endpoint. In patients with MR, AF was associated with a higher incidence of the primary endpoint regardless of left ventricular function; however, in patients without MR, AF was not associated with CV events. Cox multivariate analyses showed that the incidence of CV events was significantly higher in patients with AF and MR than in patients with MR but without AF (hazard ratio 1.381, P=0.036). Similar findings were obtained in subgroup analysis of patients with AF and only mild MR. Conclusions: The present study demonstrated that AF is associated with poor prognosis in patients with ADHF with mild to moderate MR, but not in those without MR., Competing Interests: None., (Copyright © 2021, THE JAPANESE CIRCULATION SOCIETY.)

Chitin, a natural polysaccharide polymer, forms highly crystalline nanofibers and is expected to have sophisticated engineering applications. In particular, for development of next-generation heat-transfer and heat-insulating materials, analysis of the thermal conductivity is important, but the thermal conductivity properties of chitin nanofiber materials have not been reported. The thermal conductivity properties of chitin nanofiber materials are difficult to elucidate without excluding the effect of adsorbed water and analyzing the influence of surface amino groups. In this study, we aimed to accurately evaluate the thermal conductivity properties of chitin nanofiber films by changing the content of surface amino groups and measuring the thermal diffusivity under dry conditions. Chitin and deacetylated-chitin nanofiber films with surface deacetylation of 5.8% and 25.1% showed in-plane thermal conductivity of 0.82 and 0.73 W/mK, respectively. Taking into account that the films had similar crystalline structures and almost the same moisture contents, the difference in the thermal conductivity was concluded to only depend on the amino group content on the fiber surfaces. Our methodology for measuring the thermal diffusivity under conditioned humidity will pave the way for more accurate analysis of the thermal conductivity performance of hydrophilic materials.

Objective: Pulmonary arterial hypertension is characterized by abnormal proliferation of pulmonary artery smooth muscle cells and vascular remodeling, which leads to right ventricular (RV) failure. Bsg (Basigin) is a transmembrane glycoprotein that promotes myofibroblast differentiation, cell proliferation, and matrix metalloproteinase activation. CyPA (cyclophilin A) binds to its receptor Bsg and promotes pulmonary artery smooth muscle cell proliferation and inflammatory cell recruitment. We previously reported that Bsg promotes cardiac fibrosis and failure in the left ventricle in response to pressure-overload in mice. However, the roles of Bsg and CyPA in RV failure remain to be elucidated. Approach and Results: First, we found that protein levels of Bsg and CyPA were upregulated in the heart of hypoxia-induced pulmonary hypertension (PH) in mice and monocrotaline-induced PH in rats. Furthermore, cardiomyocyte-specific Bsg-overexpressing mice showed exacerbated RV hypertrophy, fibrosis, and dysfunction compared with their littermates under chronic hypoxia and pulmonary artery banding. Treatment with celastrol, which we identified as a suppressor of Bsg and CyPA by drug screening, decreased proliferation, reactive oxygen species, and inflammatory cytokines in pulmonary artery smooth muscle cells. Furthermore, celastrol treatment ameliorated RV systolic pressure, hypertrophy, fibrosis, and dysfunction in hypoxia-induced PH in mice and SU5416/hypoxia-induced PH in rats with reduced Bsg, CyPA, and inflammatory cytokines in the hearts and lungs., Conclusions: These results indicate that elevated Bsg in pressure-overloaded RV exacerbates RV dysfunction and that celastrol ameliorates RV dysfunction in PH model animals by suppressing Bsg and its ligand CyPA. Thus, celastrol can be a novel drug for PH and RV failure that targets Bsg and CyPA. Graphic Abstract: A graphic abstract is available for this article.

Iron is an essential trace element in the body. However, in heart failure (HF), iron is only recognized as the cause of anemia. Actually, iron itself affects myocardial exercise tolerance and cardiac function via mitochondrial function. Therefore, it is necessary to clarify the pathological significance of iron in acute HF, irrespective of concomitant anemia. We investigated the impact of serum iron level at discharge on the prognosis of 615 patients emergently admitted with acute decompensated HF (ADHF). Patients were divided into two groups according to the median level of serum iron (62 µg/dL). The endpoint was the composite outcome, which included all-cause mortality and readmission for HF. During the mean follow-up period of 32.1 months, there were 333 events. Kaplan-Meier analysis showed that the incidence of the composite outcome was significantly higher in the Low iron group (P < 0.0001). In the multivariate analysis adjusted with factors including hemoglobin and ferritin levels, low serum iron was an independent predictor for the composite outcome (hazard ratio, 1.500; 95% confidence interval, 1.128-1.976; P = 0.0044). Low serum iron was an independent predictor of poor prognosis in ADHF, irrespective of hemoglobin or ferritin level, providing a new concept that iron may play a role in the pathophysiology of ADHF via non-hematopoietic roles.

As a renewable nanomaterial, transparent nanopaper is one of the promising materials for electronic devices. Although conventional evaporation drying method endows nanopaper with superior optical properties, the long fabrication time limits its widely use. In this work, we propose a multi-stage drying method to achieve high-speed fabrication of clear transparent nanopaper. Drying experiments reveal that nanopaper's drying process can be separated into two periods. For the conventional single-stage evaporation drying, the drying condition is kept the same. In our newly proposed multi-stage drying, the relative humidity (RH), which is the key parameter for both drying time and haze, is set differently during these two periods. Applying this method in a humidity-controllable environmental chamber, the drying time can be shortened by 35% (from 11.7 h to 7.6 h) while maintaining the same haze level as that from single-stage drying. For a conventional humidity-uncontrollable oven, a special air flow system is added. The air flow system enables decrease of RH by removing water vapor at the water/air interface during the earlier period, thus fabricating clear transparent nanopaper in a relatively short time. Therefore, this humidity-controlled multi-stage drying method will help reduce the manufacturing time and encourage the widespread use of future nanopaper-based flexible electronics.

It is essential to build multiaxis oriented nanocellulose films in the plane for developing thermal or optical management films. However, using conventional orientation techniques, it is difficult to align nanocelluloses in multiple directions within the plane of single films rather than in the thickness direction like the chiral nematic structure. In this study, we developed the liquid-phase three-dimensional (3D) patterning technique by combining wet spinning and 3D printing. Using this technique, we produced a checkered film with multiaxis oriented nanocelluloses. This film showed similar retardation levels, but with orthogonal molecular axis orientations in each checkered domain as programmed. The thermal transport was enhanced in the domain with the oriented pattern parallel to the heat flow. This liquid-phase 3D patterning technique could pave the way for bottom-up design of differently aligned nanocellulose films to develop sophisticated optical and thermal materials.

Background Insulin beneficially affects myocardial functions during myocardial ischemia. It increases glucose-derived ATP production, decreases oxygen consumption, suppresses apoptosis of cardiomyocytes, and promotes the survival of cardiomyocytes. Patients with chronic heart failure generally have high insulin resistance, which is correlated with poor outcomes. The role of insulin in acute decompensated heart failure (ADHF) remains unclear. This study aimed to investigate the prognostic value of serum insulin level at the time of admission for long-term outcomes in patients with ADHF. Methods and Results We enrolled 1074 consecutive patients who were admitted to our department for ADHF. Of these 1074 patients, we studied the impact of insulin on the prognosis of ADHF in 241 patients without diabetes mellitus. The patients were divided into groups according to low, intermediate, and high tertiles of serum insulin levels. Primary end points were all-cause death and cardiovascular death. During a mean follow-up of 21.8 months, 71 all-cause deaths and 38 cardiovascular deaths occurred. Kaplan-Meier analysis showed that all-cause and cardiovascular mortality was significantly higher in the low-insulin group than those in the intermediate- and high-insulin groups (log-rank P =0.0046 and P =0.038, respectively). Moreover, according to the multivariable analysis, low serum insulin was an independent predictor of all-cause and cardiovascular mortality (hazard ratio, 2.37 [95% CI, 1.24-4.65; P =0.009] and 2.94 [95% CI, 1.12-8.19; P =0.028], respectively). Conclusions Low serum insulin levels were associated with increased risk of all-cause and cardiovascular death in ADHF patients without diabetes mellitus.

Plasmonic nanoparticles, such as gold nanoparticles (AuNPs), have been actively applied in solar vapor generation for seawater desalination and water purification, owing to their photothermal heating performances. Such nanoparticles have been frequently anchored within porous supporting materials to ensure easy handling and water absorption. However, there has been limited progress in improving the transport efficiency of light to nanoparticles within porous supports to achieve more effective photothermal heating. Here, we show an enhanced light absorption of AuNPs by supporting on a cellulose paper with tailored porous structures for efficient photothermal heating. The paper consists of AuNP-anchored cellulose nanofibers and cellulose pulp as the top and bottom layers, respectively, which provides dual-layered porous nano-microstructures in the perpendicular direction. Then, the bottom layer with pulp-derived microstructures reflects the transmitted light back to AuNPs within the top layer, which improves their light absorptivity. Thus, under 1 sun illumination, the dual-layered paper demonstrates superior performance in photothermal heating (increases from 28 °C to 46 °C) and solar vapor generation (1.72 kg m -2 h -1 ) compared with the single-layered AuNP-anchored cellulose nanofiber paper even at the same AuNP content. Furthermore, the water evaporation rate per AuNP content of the dual-layered paper is more than 2 times higher than those of the state-of-the-art AuNP-anchored porous materials under the same light irradiation. This strategy enables the efficient use of precious plasmonic nanoparticles for further development of solar vapor generation., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: Countermeasure development for early rehospitalization for heart failure (re-HHF) is an urgent and important issue in Western countries and Japan., Methods and results: Of 1,074 consecutive NARA-HF study participants with acute decompensated HF admitted to hospital as an emergency between January 2007 and December 2016, we excluded 291 without follow-up data, who died in hospital, or who had previous HF-related hospitalizations, leaving 783 in the analysis. During the median follow-up period of 895 days, 241 patients were re-admitted for HF. The incidence of re-HHF was the highest within the first 30 days of discharge (3.3% [26 patients]) and remained high until 90 days, after which it decreased sharply. Within 90 days of discharge, 63 (8.0%) patients were re-admitted. Kaplan-Meier analysis revealed that patients with 90-day re-HHF had worse prognoses than those without 90-day re-HHF in terms of all-cause death (hazard ratio [HR] 2.321, 95% confidence interval [CI] 1.654-3.174; P<0.001) and cardiovascular death (HR 3.396, 95% CI 2.153-5.145; P<0.001). Multivariate analysis indicated that only male sex was an independent predictor of 90-day re-HHF., Conclusions: The incidence of early re-HHF was lower in Japan than in Western countries. Its predictors are not related to the clinical factors of HF, indicating that a new comprehensive approach might be needed to prevent early re-HHF.

Thermal transport modulating materials show great potential to address the heat problems in a wide range of engineering fields. However, tuning the thermal conductivity of solid-state materials is practically difficult because it requires specific or extreme stimulation, such as chemical composition change, a phase transition, or large applied fluctuations, to change the internal bulk structures. Here, we report reversible switching of the in-plane thermal diffusivity of densely packed cellulose nanofiber (CNF) films by ∼15% by simple mechanical strain as small as 0.3%. From analysis of the stress relaxation profiles and the different bulk densities of the CNF films, the interfacial elastic dynamics between the strongly hydrogen bonded CNFs were found to exhibit thermal diffusivity modulation by tuning the interfacial thermal resistance, rather than changing the bulk structure of the CNFs. Our concept of interfacial-elasticity-driven thermal diffusivity switching has the potential to enhance the on/off rate and extensibility toward practical use owing to the high designability of the interfacial conditions., Competing Interests: The authors declare no competing financial interest., (This journal is © The Royal Society of Chemistry.)

Background Circulating proteins are exposed to vascular endothelial layer and influence their functions. Among them, adipsin is a member of the trypsin family of peptidases and is mainly secreted from adipocytes, monocytes, and macrophages, catalyzing the rate-limiting step of the alternative complement pathway. However, its pathophysiological role in cardiovascular disease remains to be elucidated. Here, we examined whether serum adipsin levels have a prognostic impact in patients with coronary artery disease. Methods and Results In 370 consecutive patients undergoing diagnostic coronary angiography, we performed a cytokine array analysis for screening serum levels of 50 cytokines/chemokines and growth factors. Among them, classification and regression analysis identified adipsin as the best biomarker for prediction of their long-term prognosis (median 71 months; interquartile range, 55-81 months). Kaplan-Meier curve showed that higher adipsin levels (≥400 ng/mL) were significantly associated with all-cause death (hazard ratio [HR], 4.2; 95% CI, 1.7-10.6 [ P <0.001]) and rehospitalization (HR, 2.4; 95% CI, 1.7-3.5 [ P <0.001]). Interestingly, higher high-sensitivity C-reactive protein levels (≥1 mg/L) were significantly correlated with all-cause death (HR, 3.2; 95% CI, 1.7-5.9 [ P <0.001]) and rehospitalization (HR, 1.5, 95% CI, 1.1-1.9 [ P <0.01]). Importantly, the combination of adipsin (≥400 ng/mL) and high-sensitivity C-reactive protein (≥1 mg/L) was more significantly associated with all-cause death (HR, 21.0; 95% CI, 2.9-154.1 [ P <0.001]). Finally, the receiver operating characteristic curve demonstrated that serum adipsin levels predict the death caused by acute myocardial infarction in patients with coronary artery disease (C-statistic, 0.847). Conclusions These results indicate that adipsin is a novel biomarker that predicts all-cause death and rehospitalization in patients with coronary artery disease, demonstrating the novel aspects of the alternative complementary system in the pathogenesis of coronary artery disease.

Objective: Despite the recent progress in upfront combination therapy for pulmonary arterial hypertension (PAH), useful biomarkers for the disorder still remain to be developed. SeP (Selenoprotein P) is a glycoprotein secreted from various kinds of cells including pulmonary artery smooth muscle cells to maintain cellular metabolism. We have recently demonstrated that SeP production from pulmonary artery smooth muscle cells is upregulated and plays crucial roles in the pathogenesis of PAH. However, it remains to be elucidated whether serum SeP levels could be a useful biomarker for PAH. Approach and Results: We measured serum SeP levels and evaluated their prognostic impacts in 65 consecutive patients with PAH and 20 controls during follow-up (mean, 1520 days; interquartile range, 1393-1804 days). Serum SeP levels were measured using a newly developed sol particle homogeneous immunoassay. The patients with PAH showed significantly higher serum SeP levels compared with controls. Higher SeP levels (cutoff point, 3.47 mg/L) were associated with the outcome (composite end point of all-cause death and lung transplantation) in patients with PAH (hazard ratio, 4.85 [1.42-16.6]; P <0.01). Importantly, we found that the absolute change in SeP of patients with PAH (ΔSeP) in response to the initiation of PAH-specific therapy significantly correlated with the absolute change in mean pulmonary artery pressure, pulmonary vascular resistance (ΔPVR), and cardiac index (ΔCI; R =0.78, 0.76, and -0.71 respectively, all P <0.0001). Moreover, increase in ΔSeP during the follow-up predicted poor outcome of PAH., Conclusions: Serum SeP is a novel biomarker for diagnosis and assessment of treatment efficacy and long-term prognosis in patients with PAH.

Objective: Excessive proliferation and apoptosis resistance are special characteristics of pulmonary artery smooth muscle cells (PASMCs) in pulmonary arterial hypertension (PAH). However, the drugs in clinical use for PAH target vascular dilatation, which do not exert adequate effects in patients with advanced PAH. Here, we report a novel therapeutic effect of emetine, a principal alkaloid extracted from the root of ipecac clinically used as an emetic and antiprotozoal drug. Approach and Results: We performed stepwise screenings for 5562 compounds from original library. First, we performed high-throughput screening with PASMCs from patients with PAH (PAH-PASMCs) and found 80 compounds that effectively inhibited proliferation. Second, we performed the repeatability and counter assay. Finally, we performed a concentration-dependent assay and found that emetine inhibits PAH-PASMC proliferation. Interestingly, emetine significantly reduced protein levels of HIFs (hypoxia-inducible factors; HIF-1α and HIF-2α) and downstream PDK1 (pyruvate dehydrogenase kinase 1). Moreover, emetine significantly reduced the protein levels of RhoA (Ras homolog gene family, member A), Rho-kinases (ROCK1 and ROCK2 [rho-associated coiled-coil containing protein kinases 1 and 2]), and their downstream CyPA (cyclophilin A), and Bsg (basigin) in PAH-PASMCs. Consistently, emetine treatment significantly reduced the secretion of cytokines/chemokines and growth factors from PAH-PASMCs. Interestingly, emetine reduced protein levels of BRD4 (bromodomain-containing protein 4) and downstream survivin, both of which are involved in many cellular functions, such as cell cycle, apoptosis, and inflammation. Finally, emetine treatment ameliorated pulmonary hypertension in 2 experimental rat models, accompanied by reduced inflammatory changes in the lungs and recovered right ventricular functions., Conclusions: Emetine is an old but novel drug for PAH that reduces excessive proliferation of PAH-PASMCs and improves right ventricular functions.

Rationale: Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling with aberrant pulmonary artery smooth muscle cells (PASMCs) proliferation, endothelial dysfunction, and extracellular matrix remodeling., Objective: Right ventricular (RV) failure is an important prognostic factor in PAH. Thus, we need to elucidate a novel therapeutic target in both PAH and RV failure., Methods and Results: We performed microarray analysis in PASMCs from patients with PAH (PAH-PASMCs) and controls. We found a ADAMTS8 (disintegrin and metalloproteinase with thrombospondin motifs 8), a secreted protein specifically expressed in the lung and the heart, was upregulated in PAH-PASMCs and the lung in hypoxia-induced pulmonary hypertension (PH) in mice. To elucidate the role of ADAMTS8 in PH, we used vascular smooth muscle cell-specific ADAMTS8-knockout mice (ADAMTS ΔSM22 ). Hypoxia-induced PH was attenuated in ADAMTS ΔSM22 mice compared with controls. ADAMTS8 overexpression increased PASMC proliferation with downregulation of AMPK (AMP-activated protein kinase). In contrast, deletion of ADAMTS8 reduced PASMC proliferation with AMPK upregulation. Moreover, deletion of ADAMTS8 reduced mitochondrial fragmentation under hypoxia in vivo and in vitro. Indeed, PASMCs harvested from ADAMTS ΔSM22 mice demonstrated that phosphorylated DRP-1 (dynamin-related protein 1) at Ser637 was significantly upregulated with higher expression of profusion genes (Mfn1 and Mfn2) and improved mitochondrial function. Moreover, recombinant ADAMTS8 induced endothelial dysfunction and matrix metalloproteinase activation in an autocrine/paracrine manner. Next, to elucidate the role of ADAMTS8 in RV function, we developed a cardiomyocyte-specific ADAMTS8 knockout mice (ADAMTS8 ΔαMHC ). ADAMTS8 ΔαMHC mice showed ameliorated RV failure in response to chronic hypoxia. In addition, ADAMTS8 ΔαMHC mice showed enhanced angiogenesis and reduced RV ischemia and fibrosis. Finally, high-throughput screening revealed that mebendazole, which is used for treatment of parasite infections, reduced ADAMTS8 expression and cell proliferation in PAH-PASMCs and ameliorated PH and RV failure in PH rodent models., Conclusions: These results indicate that ADAMTS8 is a novel therapeutic target in PAH.

Rationale: Pulmonary arterial hypertension (PAH) is characterized by enhanced proliferation of pulmonary artery smooth muscle cells (PASMCs) accompanying increased production of inflammatory factors and adaptation of the mitochondrial metabolism to a hyperproliferative state. However, all the drugs in clinical use target pulmonary vascular dilatation, which may not be effective for patients with advanced PAH., Objective: We aimed to discover a novel drug for PAH that inhibits PASMC proliferation., Methods and Results: We screened 5562 compounds from original library using high-throughput screening system to discover compounds which inhibit proliferation of PASMCs from patients with PAH (PAH-PASMCs). We found that celastramycin, a benzoyl pyrrole-type compound originally found in a bacteria extract, inhibited the proliferation of PAH-PASMCs in a dose-dependent manner with relatively small effects on PASMCs from healthy donors. Then, we made 25 analogs of celastramycin and selected the lead compound, which significantly inhibited cell proliferation of PAH-PASMCs and reduced cytosolic reactive oxygen species levels. Mechanistic analysis demonstrated that celastramycin reduced the protein levels of HIF-1α (hypoxia-inducible factor 1α), which impairs aerobic metabolism, and κB (nuclear factor-κB), which induces proinflammatory signals, in PAH-PASMCs, leading to reduced secretion of inflammatory cytokine. Importantly, celastramycin treatment reduced reactive oxygen species levels in PAH-PASMCs with increased protein levels of Nrf2 (nuclear factor erythroid 2-related factor 2), a master regulator of cellular response against oxidative stress. Furthermore, celastramycin treatment improved mitochondrial energy metabolism with recovered mitochondrial network formation in PAH-PASMCs. Moreover, these celastramycin-mediated effects were regulated by ZFC3H1 (zinc finger C3H1 domain-containing protein), a binding partner of celastramycin. Finally, celastramycin treatment ameliorated pulmonary hypertension in 3 experimental animal models, accompanied by reduced inflammatory changes in the lungs., Conclusions: These results indicate that celastramycin ameliorates pulmonary hypertension, reducing excessive proliferation of PAH-PASMCs with less inflammation and reactive oxygen species levels, and recovered mitochondrial energy metabolism. Thus, celastramycin is a novel drug for PAH that targets antiproliferative effects on PAH-PASMCs.

Background: Thoracic aortic aneurysm (TAA) and dissection are fatal diseases that cause aortic rupture and sudden death. The small GTP-binding protein GDP dissociation stimulator (SmgGDS) is a crucial mediator of the pleiotropic effects of statins. Previous studies revealed that reduced force generation in aortic smooth muscle cells (AoSMCs) causes TAA and thoracic aortic dissection., Methods: To examine the role of SmgGDS in TAA formation, we used an angiotensin II (1000 ng·min -1 ·kg -1 , 4 weeks)-induced TAA model., Results: We found that 33% of Apoe -/- SmgGDS +/- mice died suddenly as a result of TAA rupture, whereas there was no TAA rupture in Apoe -/- control mice. In contrast, there was no significant difference in the ratio of abdominal aortic aneurysm rupture between the 2 genotypes. We performed ultrasound imaging every week to follow up the serial changes in aortic diameters. The diameter of the ascending aorta progressively increased in Apoe -/- SmgGDS +/- mice compared with Apoe -/- mice, whereas that of the abdominal aorta remained comparable between the 2 genotypes. Histological analysis of Apoe -/- SmgGDS +/- mice showed dissections of major thoracic aorta in the early phase of angiotensin II infusion (day 3 to 5) and more severe elastin degradation compared with Apoe -/- mice. Mechanistically, Apoe -/- SmgGDS +/- mice showed significantly higher levels of oxidative stress, matrix metalloproteinases, and inflammatory cell migration in the ascending aorta compared with Apoe -/- mice. For mechanistic analyses, we primary cultured AoSMCs from the 2 genotypes. After angiotensin II (100 nmol/L) treatment for 24 hours, Apoe -/- SmgGDS +/- AoSMCs showed significantly increased matrix metalloproteinase activity and oxidative stress levels compared with Apoe -/- AoSMCs. In addition, SmgGDS deficiency increased cytokines/chemokines and growth factors in AoSMCs. Moreover, expressions of fibrillin-1 ( FBN1), α-smooth muscle actin ( ACTA2), myosin-11 ( MYH11), MYLLK, and PRKG1, which are force generation genes, were significantly reduced in Apoe -/- SmgGDS +/- AoSMCs compared with Apoe -/- AoSMCs. A similar tendency was noted in AoSMCs from patients with TAA compared with those from control subjects. Finally, local delivery of the SmgGDS gene construct reversed the dilation of the ascending aorta in Apoe -/- SmgGDS +/- mice., Conclusions: These results suggest that SmgGDS is a novel therapeutic target for the prevention and treatment of TAA.

Background: Excessive proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs) are key mechanisms of pulmonary arterial hypertension (PAH). Despite the multiple combination therapy, a considerable number of patients develop severe pulmonary hypertension (PH) because of the lack of diagnostic biomarker and antiproliferative therapies for PASMCs., Methods: Microarray analyses were used to identify a novel therapeutic target for PAH. In vitro experiments, including lung and serum samples from patients with PAH, cultured PAH-PASMCs, and high-throughput screening of 3336 low-molecular-weight compounds, were used for mechanistic study and exploring a novel therapeutic agent. Five genetically modified mouse strains, including PASMC-specific selenoprotein P (SeP) knockout mice and PH model rats, were used to study the role of SeP and therapeutic capacity of the compounds for the development of PH in vivo., Results: Microarray analysis revealed a 32-fold increase in SeP in PAH-PASMCs compared with control PASMCs. SeP is a widely expressed extracellular protein maintaining cellular metabolism. Immunoreactivity of SeP was enhanced in the thickened media of pulmonary arteries in PAH. Serum SeP levels were also elevated in patients with PH compared with controls, and high serum SeP predicted poor outcome. SeP-knockout mice ( SeP -/- ) exposed to chronic hypoxia showed significantly reduced right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary artery remodeling compared with controls. In contrast, systemic SeP-overexpressing mice showed exacerbation of hypoxia-induced PH. Furthermore, PASMC-specific SeP -/- mice showed reduced hypoxia-induced PH compared with controls, whereas neither liver-specific SeP knockout nor liver-specific SeP-overexpressing mice showed significant differences with controls. Altogether, protein levels of SeP in the lungs were associated with the development of PH. Mechanistic experiments demonstrated that SeP promotes PASMC proliferation and resistance to apoptosis through increased oxidative stress and mitochondrial dysfunction, which were associated with activated hypoxia-inducible factor-1α and dysregulated glutathione metabolism. It is important to note that the high-throughput screening of 3336 compounds identified that sanguinarine, a plant alkaloid with antiproliferative effects, reduced SeP expression and proliferation in PASMCs and ameliorated PH in mice and rats., Conclusions: These results indicate that SeP promotes the development of PH, suggesting that it is a novel biomarker and therapeutic target of the disorder.

Although postcapillary pulmonary hypertension (PH) is an important prognostic factor for patients with heart failure (HF), its pathogenesis remains to be fully elucidated. To elucidate the different roles of Rho-kinase isoforms, ROCK1 and ROCK2, in cardiomyocytes in response to chronic pressure overload, we performed transverse aortic constriction (TAC) in cardiac-specific ROCK1-deficient ( cROCK1 -/- ) and ROCK2-deficient ( cROCK2 -/- ) mice. Cardiomyocyte-specific ROCK1 deficiency promoted pressure-overload-induced cardiac dysfunction and postcapillary PH, whereas cardiomyocyte-specific ROCK2 deficiency showed opposite results. Histological analysis showed that pressure-overload-induced cardiac hypertrophy and fibrosis were enhanced in cROCK1 -/- mice compared with controls, whereas cardiac hypertrophy was attenuated in cROCK2 -/- mice after TAC. Consistently, the levels of oxidative stress were up-regulated in cROCK1 -/- hearts and down-regulated in cROCK2 -/- hearts compared with controls after TAC. Furthermore, cyclophilin A (CyPA) and basigin (Bsg), both of which augment oxidative stress, enhanced cardiac dysfunction and postcapillary PH in cROCK1 -/- mice, whereas their expressions were significantly lower in cROCK2 -/- mice. In clinical studies, plasma levels of CyPA were significantly increased in HF patients and were higher in patients with postcapillary PH compared with those without it. Finally, high-throughput screening demonstrated that celastrol, an antioxidant and antiinflammatory agent, reduced the expressions of CyPA and Bsg in the heart and the lung, ameliorating cardiac dysfunction and postcapillary PH induced by TAC. Thus, by differentially affecting CyPA and Bsg expressions, ROCK1 protects and ROCK2 jeopardizes the heart from pressure-overload HF with postcapillary PH, for which celastrol may be a promising agent., Competing Interests: The authors declare no conflict of interest.

Nanopaper prepared from holocellulose pulp is one of the best substrates for flexible electronics because of its high thermal resistance and high clear transparency. However, the clearness of nanopaper decreases with increasing concentration of the starting cellulose nanofiber dispersion-with the use of a 2.2 wt % dispersion, for example-resulting in translucent nanopaper with a high haze of 44%. To overcome this problem, we show that the dilution of this high-concentration dispersion with water followed by sonication for 10 s reduces the haze to less than 10% while maintaining the high thermal resistance of the nanopaper. Furthermore, the combination of water dilution and a short sonication treatment improves the clearness of the nanopaper, which would translate into cost savings for the transportation and storage of this highly concentrated cellulose nanofiber dispersion. Finally, we demonstrate the improvement of the electrical conductivity of clear transparent nanopaper prepared from an initially high-concentration dispersion by dropping and heating silver nanowire ink on the nanopaper. These achievements will pave the way toward the realization of the mass production of nanofiber-based flexible devices., Competing Interests: The authors declare no conflict of interest.

Optically transparent cellulose nanopaper is a promising candidate for flexible device substrates because of its light weight, surface smoothness, and high dimensional stability with respect to temperature. Conventionally, clear transparent nanopaper has been fabricated from cellulose nanofiber dispersions with quite low concentration: less than 0.5 wt%. However, this diluteness leads to several problems, such as huge energy consumption and long operation time for drying. Therefore, nanopaper should be fabricated from a concentrated dispersion to mitigate these problems. In this study, transparent nanopaper was fabricated from cellulose nanofiber dispersions with various concentrations (0.24-1.81 wt%). Optical experiments revealed that the haze of the transparent nanopaper increased monotonically with cellulose nanofiber dispersion concentration, when the cellulose nanofiber dispersion was prepared from holocellulose pulp and conventional over-drying was applied. Based on our insight into the origin of this increase in the haze of transparent nanopaper, we developed high-humidity drying, which successfully produced clear transparent nanopaper from a concentrated dispersion without prolonged drying time., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)