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1. Hydrogel‐Sheathed hiPSC‐Derived Heart Microtissue Enables Anchor‐Free Contractile Force Measurement

Author: Yuta Kurashina, Keisuke Fukada, Shun Itai, Shuichi Akizuki, Ryo Sato, Akari Masuda, Hidenori Tani, Jun Fujita, Keiichi Fukuda, Shugo Tohyama, and Hiroaki Onoe
Subjects: anchor‐free, contractile force, engineered heart microtissue, hiPSC‐derived cardiomyocytes, hydrogel, Science
Abstract: Abstract In vitro reconstruction of highly mature engineered heart tissues (EHTs) is attempted for the selection of cardiotoxic drugs suitable for individual patients before administration. Mechanical contractile force generated in the EHTs is known to be a critical indicator for evaluating the EHT response. However, measuring contractile force requires anchoring the EHT in a tailored force‐sensing cell culture chamber, causing technical difficulties in the stable evaluation of contractile force in long‐term culture. This paper proposes a hydrogel‐sheathed human induced pluripotent stem cell (hiPSC)‐derived heart microtissue (H3M) that can provide an anchor‐free contractile force measurement platform in commonly used multi‐well plates. The contractile force associated with tissue formation and drug response is calculated by motion tracking and finite element analysis on the bending angle of the hydrogel sheath. From the experiment of the drug response, H3M is an excellent drug screening platform with high sensitivity and early testing capability compared to conventionally anchored EHT. This unique platform would be useful and versatile for regenerative therapy and drug discovery research in EHT.
Published: 2023
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2. Novel exterior cover design for radiant heat resistance of firefighting robots in large-scale petrochemical complex fires

Author: Jun Fujita, Yoshihiro Tamura, Hisanori Amano, Kazunori Ohno, and Satoshi Tadokoro
Subjects: Water cannon robot, Radiant heat resistance, Fireproof clothing, Vaporization by mist nozzle, Thermal equilibrium model, Technology, Mechanical engineering and machinery, TJ1-1570, Control engineering systems. Automatic machinery (General), TJ212-225, Machine design and drawing, TJ227-240, Technology (General), T1-995, Industrial engineering. Management engineering, T55.4-60.8, Automation, T59.5, Information technology, T58.5-58.64
Abstract: Abstract Fires in petrochemical complexes are inaccessible because of the intense radiant heat from flames. Therefore, water cannon robots require radiant heat countermeasures to perform firefighting safely. Conventional radiant heat countermeasures employ a self-spraying method, wherein the water cannon robot requires a water tank of capacity 1.5 m3 (= 1500 L) to function for 7–8 min in an environment with a 20 kW/m2 radiation heat. However, the water cannon robot has size limitations because it is transported on one transport vehicle (10 t truck) to the site, and only a tank of capacity ~ 0.02 m3 can be installed on the robot. To overcome these drawbacks, this study proposes a method that utilizes a mountable radiant heat-resistant exterior cover that works with a small amount of water. The cover is made of radiant heat-shielding fireproof clothing with an aluminum coating that reflects 90% of the radiant heat on the surface and a mist nozzle that sprays water on the back surface. The remaining 10% is removed by the heat of vaporization of water sprayed on the back of the clothing and natural convection. The amount of water required for cooling was reduced to 1/80th of that compared to self-spraying because of the use of the developed cover. The proposed method of radiation reflection via vaporization and natural convection can be employed to protect firefighting robots.
Published: 2022
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3. Advanced gastric cancer with abdominal wall invasion treated with curative resection after chemotherapy: a case report

Author: Naohiko Nakamura, Shinichi Kinami, Jun Fujita, Daisuke Kaida, Yasuto Tomita, Takashi Miyata, Hideto Fujita, Nobuhiko Ueda, and Hiroyuki Takamura
Subjects: Gastric cancer, T4b, Abdominal wall invasion, Gastrectomy, Case report, Medicine
Abstract: Abstract Introduction In patients with gastric cancer, 6–27% of patients are diagnosed with T4b disease that invades adjacent organs, and curative resection can improve the prognosis of these patients. Case presentation A 70-year-old Japanese man presented with an abdominal tumor and was diagnosed with advanced gastric cancer (L-Circ type 3 T4b N2 M0 H0 stage IVA, based on the 15th edition of the Japanese Classification of Gastric Carcinoma) with extensive abdominal wall invasion. We performed open gastrojejunal bypass for gastric obstruction and initiated a chemotherapeutic regimen comprising S-1 (120 mg/day) and oxaliplatin (100 mg/m2). Upper gastrointestinal endoscopy performed after the administration of six courses of the S-1 and oxaliplatin regimen revealed a persistent primary lower gastric wall lesion; however, the diameter of the abdominal wall invasion and metastatic lymph nodes was significantly reduced, in addition to decreased serum carcinoembryonic antigen and carbohydrate antigen 19-9 levels. Subsequently, the patient underwent distal gastrectomy with D2 lymphadenectomy combined with transverse colon and abdominal wall resection. We performed radical en bloc resection and achieved a tumor-free resection margin. Simple abdominal wall closure was performed without mesh or musculocutaneous flap placement. Histopathological examination of the resected tumor specimen showed direct invasion of the mesocolon and rectus abdominis muscle. The patient was postoperatively diagnosed with L Gre-Ant type5 T4b (SI: rectus abdominis muscle) N2 PM0 DM0 Stage IIIA R0 Grade 2a gastric cancer based on histopathological findings and received S-1 as adjuvant chemotherapy, 2 months postoperatively. No recurrence was detected 6 months postoperatively. Conclusions We report a case of advanced gastric cancer with extensive abdominal wall invasion that was successfully treated with gastrectomy combined with resection of adjacent organs showing tumor invasion after effective systemic chemotherapy. A therapeutic approach comprising curative surgery combined with perioperative chemotherapy is useful in patients with T4b gastric cancer.
Published: 2021
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4. Protocol for enhanced proliferation of human pluripotent stem cells in tryptophan-fortified media

Author: Kotaro Kameda, Shota Someya, Jun Fujita, Keiichi Fukuda, and Shugo Tohyama
Subjects: Cell culture, Metabolism, Stem Cells, Science (General), Q1-390
Abstract: Summary: We describe a protocol for the efficient culture of human pluripotent stem cells (hPSCs) by supplementing conventional culture medium with L-tryptophan (TRP). TRP is an essential amino acid that is widely available at an affordable cost, thereby allowing cost-effective proliferation of hPSCs compared to using a conventional medium alone. Here, we describe the steps for enhanced proliferation of hPSCs from dermal fibroblasts or peripheral blood cells, but the protocol can be applied to any hPSCs.For complete details on the use and execution of this protocol, please refer to Someya et al. (2021).
Published: 2022
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5. Purification of cardiomyocytes and neurons derived from human pluripotent stem cells by inhibition of de novo fatty acid synthesis

Author: Sho Tanosaki, Tomohiko Akiyama, Sayaka Kanaami, Jun Fujita, Minoru S.H. Ko, Keiichi Fukuda, and Shugo Tohyama
Subjects: Cell culture, Cell isolation, Stem Cells, Cell Differentiation, Science (General), Q1-390
Abstract: Summary: Here we describe a protocol to obtain highly pure cardiomyocytes and neurons from human induced pluripotent stem cells (hiPSCs) via metabolic selection processes. Compared to conventional purification protocols, this approach is easier to perform and scale up and more cost-efficient. The protocol can be applied to hiPSCs and human embryonic stem cells.For complete details on the use and execution of this protocol, please refer to Tohyama et al. (2016) and Tanosaki et al. (2020).
Published: 2022
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6. Early gastric mixed neuroendocrine‐non‐neuroendocrine neoplasm with early poor prognosis after endoscopic submucosal dissection: A case report

Author: Yusuke Tomita, Hideyuki Seki, Emi Matsuzono, Yoshimitsu Kobayashi, Susumu Sogabe, Nozomu Sugai, Jun Fujita, and Akira Suzuki
Subjects: cancerization, early gastric cancer, ESD, MANEC, MiNENs, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: Abstract Early gastric mixed neuroendocrine‐non‐neuroendocrine neoplasms (MiNENs) are rare diseases, with no data on their incidence and prognosis. We report the case of intramucosal gastric MiNENs for endoscopic submucosal dissection (ESD) treatment. An 80‐year‐old male underwent esophagogastroduodenoscopy for screening and was suspected of early gastric cancer type 0‐IIa+IIc on the lesser curvature of the antrum, for which ESD treatment was performed. Histopathologically, the diagnosis was MiNENs. Synaptophysin‐positive adenoductal structures were observed in the adenocarcinoma component, suggesting that adenocarcinoma had dedifferentiated into neuroendocrine carcinoma. The tumor was located within the mucosal layer, with lympho‐vascular invasion. The patient was kept under observation; however, 6 months after the ESD, computed tomography scan revealed prominent ascites, enlarged lymph nodes, and liver metastases, and MiNENs were suspected to have poor prognosis. If MiNENs diagnosis is made preoperatively or postoperatively, surgical resection may be considered as treatment regardless of the tumor depth or lympho‐vascular invasion.
Published: 2022
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7. Metabolism of human pluripotent stem cells and differentiated cells for regenerative therapy: a focus on cardiomyocytes

Author: Sho Tanosaki, Shugo Tohyama, Yoshikazu Kishino, Jun Fujita, and Keiichi Fukuda
Subjects: Metabolism, Pluripotent stem cells, Cardiomyocytes, Regenerative therapy, Pathology, RB1-214
Abstract: Abstract Pluripotent stem cells (PSCs) exhibit promising application in regenerative therapy, drug discovery, and disease modeling. While several protocols for differentiating somatic cells from PSCs exist, their use is limited by contamination of residual undifferentiated PSCs and immaturity of differentiated somatic cells. The metabolism of PSCs differs greatly from that of somatic cells, and a distinct feature is required to sustain the distinct properties of PSCs. To date, several studies have reported on the importance of metabolism in PSCs and their derivative cells. Here, we detail advancements in the field, with a focus on cardiac regenerative therapy.
Published: 2021
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8. Predictive factors for developing acute cholangitis and/or cholecystitis in patients undergoing delayed cholecystectomy: A retrospective study

Author: Takashi Miyata, Daisuke Matsui, Yuta Fujiwara, Hiroto Saito, Yoshinao Ohbatake, Koji Nishijima, Tomoharu Miyashita, Fumio Futagami, Takashi Nakamura, Jun Fujita, Daisuke Kaida, Yasuto Tomita, Naohiko Nakamura, Hideto Fujita, Nobuhiko Ueda, and Hiroyuki Takamura
Subjects: Acute cholangitis, Acute cholecystitis, Cholecystectomy, Elective surgical procedure, Surgery, RD1-811
Abstract: Background: /Objective: We evaluated the risk of acute cholangitis and/or cholecystitis while waiting for cholecystectomy for gallstones. Methods: We retrospectively enrolled 168 patients who underwent cholecystectomy for gallstones after conservative therapy. We compared clinical data of 20 patients who developed acute cholangitis and/or cholecystitis while waiting for cholecystectomy (group A) with 148 patients who did not develop (group B). We investigated surgical outcomes and risk factors for developing acute cholangitis and/or cholecystitis. Results: Preoperatively, significant numbers of patients with previous history of acute grade II or III cholecystitis (55.0% vs 10.8%; p
Published: 2021
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9. A Case of Advanced Gastroesophageal Junction Cancer with Bulky Lymph Node Metastases Treated with Nivolumab

Author: Naohiko Nakamura, Shinichi Kinami, Jun Fujita, Daisuke Kaida, Yasuto Tomita, Takashi Miyata, Hideto Fujita, Nobuhiko Ueda, Hiroyuki Takamura, and Takeo Kosaka
Subjects: gastroesophageal junction cancer, nivolumab, adenocarcinoma, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: A 71-year-old woman was diagnosed with advanced gastroesophageal junction cancer with bulky lymph nodes along the cardiac region and the lower mediastinum (GE-Circ type 3 T3 N3 M0 H0 stage III) and received treatment with S-1 and oxaliplatin (SOX) as first-line chemotherapy. After 3 cycles of SOX, severe anorexia and diarrhea were observed. We converted from this regimen of systemic chemotherapy to ramucirumab (RAM) monotherapy as second-line chemotherapy. This treatment resulted in a reduction in size of the metastatic lymph nodes along the cardiac region and the lower mediastinum. However, progression of lymph node metastasis and the primary tumor was observed following 7 months of RAM monotherapy. Therefore, nivolumab was initiated as third-line chemotherapy 14 months after the initial treatment. After 3 months of nivolumab administration, a 47% reduction in metastatic lymph nodes was achieved and a regression of the primary gastric tumor as seen on an enhanced computed tomography scan. After 7 months of nivolumab monotherapy, the diameter of the target lymph nodes had reduced by 81% from baseline, and there was no evidence of malignancy upon pathological assessment of the primary tumor site biopsy. The patient survived with nivolumab monotherapy for approximately 2 years after her first visit, without any adverse reaction to nivolumab.
Published: 2020
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10. Toward the realization of cardiac regenerative medicine using pluripotent stem cells

Author: Yoshikazu Kishino, Jun Fujita, Shugo Tohyama, Marina Okada, Sho Tanosaki, Shota Someya, and Keiichi Fukuda
Subjects: Regenerative medicine, Induced pluripotent stem cell, Cardiomyocyte, Pathology, RB1-214
Abstract: Abstract Heart transplantation (HT) is the only radical treatment available for patients with end-stage heart failure that is refractory to optimal medical treatment and device therapies. However, HT as a therapeutic option is limited by marked donor shortage. To overcome this difficulty, regenerative medicine using human-induced pluripotent stem cells (hiPSCs) has drawn increasing attention as an alternative to HT. Several issues including the preparation of clinical-grade hiPSCs, methods for large-scale culture and production of hiPSCs and cardiomyocytes, prevention of tumorigenesis secondary to contamination of undifferentiated stem cells and non-cardiomyocytes, and establishment of an effective transplantation strategy need to be addressed to fulfill this unmet medical need. The ongoing rapid technological advances in hiPSC research have been directed toward the clinical application of this technology, and currently, most issues have been satisfactorily addressed. Cell therapy using hiPSC-derived cardiomyocytes is expected to serve as an integral component of realistic medicine in the near future and is being potentially viewed as a treatment that would revolutionize the management of patients with severe heart failure.
Published: 2020
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11. The neutrophil/lymphocyte ratio as a predictor of peritoneal metastasis during staging laparoscopy for advanced gastric cancer: a retrospective cohort analysis

Author: Naohiko Nakamura, Shinichi Kinami, Yoritaka Fujii, Seiko Miura, Jun Fujita, Daisuke Kaida, Yasuto Tomita, Takashi Miyata, Hideto Fujita, Nobuhiko Ueda, Yasuo Iida, and Takeo Kosaka
Subjects: Gastric cancer, Staging laparoscopy, Neutrophil/lymphocyte ratio, Surgery, RD1-811, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background The use of staging laparoscopy (SL) has become widespread in patients with advanced gastric cancer (GC). This study aimed to evaluate the predictive value of the neutrophil/lymphocyte ratio (NLR) for the presence of peritoneal metastasis during staging laparoscopy in patients with advanced GC. Methods This retrospective analysis was performed in 35 patients with advanced GC who underwent SL at Kanazawa Medical University Hospital between January 2009 and December 2017. Clinicopathological characteristics were examined and multivariate analyses were performed to identify preoperative laboratory parameters that were independently associated with the presence of peritoneal metastasis or cytological malignancy (P/CY positive) during SL. Results A P/CY-positive result was confirmed during SL in 16 patients (45.7%). Patients with type 4 or diffuse type 3 tumors showed a significantly higher P/CY-positive rate than those with other tumor types (58.3% vs. 18.2%, P = 0.02). In the univariate analysis for preoperative laboratory parameters, NLR (P 3.5) was associated with a significantly higher P/CY-positive rate than a low NLR (≤ 3.5) (83.3% vs. 33.3%, P = 0.01). Moreover, in patients without type 4 or diffuse type 3 tumors, the P/CY-positive rates were 100% and 0% in patients with NLR > 3.5 and NLR ≤ 3.5, respectively. Conclusions The preoperative NLR was a significant independent predictor of the presence of peritoneal metastasis during SL. Regardless of tumor type, patients with a high NLR could be reasonable candidates for SL. On the other hand, non-diffuse type tumor accompanied by a low NLR may not need to undergo SL.
Published: 2019
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12. A remarkable clinical response in advanced gastric cancer treated with trastuzumab plus capecitabine combination chemotherapy: A report of two cases

Author: Naohiko Nakamura, Shinichi Kinami, Yoritaka Fujii, Seiko Miura, Jun Fujita, Daisuke Kaida, Yasuto Tomita, Takashi Miyata, Hideto Fujita, Nobuhiko Ueda, and Takeo Kosaka
Subjects: capecitabine, gastric cancer, trastuzumab, Medicine, Medicine (General), R5-920
Abstract: Key Clinical Message When trastuzumab + capecitabine and cisplatin chemotherapy could not be conducted continuously because of severe adverse reactions to cisplatin, trastuzumab + capecitabine could be an alternative systemic chemotherapy options for metastatic or recurrent gastric cancer patients.
Published: 2019
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13. Tryptophan Metabolism Regulates Proliferative Capacity of Human Pluripotent Stem Cells

Author: Shota Someya, Shugo Tohyama, Kotaro Kameda, Sho Tanosaki, Yuika Morita, Kazunori Sasaki, Moon-Il Kang, Yoshikazu Kishino, Marina Okada, Hidenori Tani, Yusuke Soma, Kazuaki Nakajima, Tomohiko Umei, Otoya Sekine, Taijun Moriwaki, Hideaki Kanazawa, Eiji Kobayashi, Jun Fujita, and Keiichi Fukuda
Subjects: Cell Biology, Metabolomics, Stem Cell Research, Science
Abstract: Summary: Human pluripotent stem cells (hPSCs) have a unique metabolic signature for maintenance of pluripotency, self-renewal, and survival. Although hPSCs could be potentially used in regenerative medicine, the prohibitive cost associated with large-scale cell culture presents a major barrier to the clinical application of hPSC. Moreover, without a fully characterized metabolic signature, hPSC culture conditions are not optimized. Here, we performed detailed amino acid profiling and found that tryptophan (TRP) plays a key role in the proliferation with maintenance of pluripotency. In addition, metabolome analyses revealed that intra- and extracellular kynurenine (KYN) is decreased under TRP-supplemented conditions, whereas N-formylkynurenine (NFK), the upstream metabolite of KYN, is increased thereby contributing to proliferation promotion. Taken together, we demonstrate that TRP is indispensable for survival and proliferation of hPSCs. A deeper understanding of TRP metabolism will enable cost-effective large-scale production of hPSCs, leading to advances in regenerative medicine.
Published: 2021
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14. Fatty Acid Synthesis Is Indispensable for Survival of Human Pluripotent Stem Cells

Author: Sho Tanosaki, Shugo Tohyama, Jun Fujita, Shota Someya, Takako Hishiki, Tomomi Matsuura, Hiroki Nakanishi, Takayo Ohto-Nakanishi, Tomohiko Akiyama, Yuika Morita, Yoshikazu Kishino, Marina Okada, Hidenori Tani, Yusuke Soma, Kazuaki Nakajima, Hideaki Kanazawa, Masahiro Sugimoto, Minoru S.H. Ko, Makoto Suematsu, and Keiichi Fukuda
Subjects: Biological Sciences, Cell Biology, Stem Cells Research, Proteomics, Metabolomics, Metabolic Flux Analysis, Science
Abstract: Summary: The role of lipid metabolism in human pluripotent stem cells (hPSCs) is poorly understood. We have used large-scale targeted proteomics to demonstrate that undifferentiated hPSCs express different fatty acid (FA) biosynthesis-related enzymes, including ATP citrate lyase and FA synthase (FASN), than those expressed in hPSC-derived cardiomyocytes (hPSC-CMs). Detailed lipid profiling revealed that inhibition of FASN resulted in significant reduction of sphingolipids and phosphatidylcholine (PC); moreover, we found that PC was the key metabolite for cell survival in hPSCs. Inhibition of FASN induced cell death in undifferentiated hPSCs via mitochondria-mediated apoptosis; however, it did not affect cell survival in hPSC-CMs, neurons, or hepatocytes as there was no significant reduction of PC. Furthermore, we did not observe tumor formation following transplantation of FASN inhibitor-treated cells. Our findings demonstrate the importance of de novo FA synthesis in the survival of undifferentiated hPSCs and suggest applications for FASN inhibition in regenerative medicine.
Published: 2020
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15. Consistent map building in petrochemical complexes for firefighter robots using SLAM based on GPS and LIDAR

Author: Abu Ubaidah Shamsudin, Kazunori Ohno, Ryunosuke Hamada, Shotaro Kojima, Thomas Westfechtel, Takahiro Suzuki, Yoshito Okada, Satoshi Tadokoro, Jun Fujita, and Hisanori Amano
Subjects: Disaster robotic, SLAM, Mapping, Technology, Mechanical engineering and machinery, TJ1-1570, Control engineering systems. Automatic machinery (General), TJ212-225, Machine design and drawing, TJ227-240, Technology (General), T1-995, Industrial engineering. Management engineering, T55.4-60.8, Automation, T59.5, Information technology, T58.5-58.64
Abstract: Abstract The objective of this study was to achieve simultaneous localization and mapping (SLAM) of firefighter robots for petrochemical complexes. Consistency of the SLAM map is important because human operators compare the map with aerial images and identify target positions on the map. The global positioning system (GPS) enables increased consistency. Therefore, this paper describes two Rao-Blackwellized particle filters (RBPFs) based on GPS and light detection and ranging (LIDAR) as SLAM solutions. Fast-SLAM 1.0 and Fast-SLAM 2.0 were used in grid maps for RBPFs in this study. We herein propose the use of Fast-SLAM to combine GPS and LIDAR. The difference between the original Fast-SLAM and the proposed method is the use of the log-likelihood function of GPS; the proposed combination method is implemented using a probabilistic mathematics formulation. The proposed methods were evaluated using sensor data measured in a real petrochemical complex in Japan ranging in size from 550–380 m. RTK-GPS data was used for the GPS measurement and had an availability of 56%. Our results showed that Fast-SLAM 2.0 based on GPS and LIDAR in a dense grid map produced the best results. There was significant improvement in alignment to aerial data, and the mean square root error was 0.65 m. To evaluate the mapping consistency, accurate 3D point cloud data measured by Faro Focus 3D (± 3 mm) was used as the ground truth. Building sizes were compared; the minimum mean errors were 0.17 and 0.08 m for the oil refinery and management building area and the area of a sparse building layout with large oil tanks, respectively. Consequently, a consistent map, which was also consistent with an aerial map (from Google Maps), was built by Fast-SLAM 1.0 and 2.0 based on GPS and LIDAR. Our method reproduced map consistency results for ten runs with a variance of ± 0.3 m. Our method reproduced map consistency results with a global accuracy of 0.52 m in a low RTK-Fix-GPS environment, which was a factory with a building layout similar to petrochemical complexes with 20.9% of RTK-Fix-GPS data availability.
Published: 2018
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16. Duct Attachment on Improving Breaking Wave Zone Energy Extractor Device Performance

Author: Krisna Adi Pawitan, Hideki Takebe, Hanley Andrean, Shuji Misumi, Jun Fujita, and Tsumoru Shintake
Subjects: wave energy converter, coastal engineering, renewable energy, structural response, Technology
Abstract: A challenging wave energy converter design that utilized the denser energy part of the nearshore breaking wave zone to generate electricity was introduced in 2016 by Shintake. The Okinawa Institute of Science and Technology Graduate University’s project aims to take advantage of breaking wave energy to harness electricity. The 2016 version of the device consisted only of a bare turbine and power generator. Early exploration of the design recorded short periods and high impact wave pressures were experienced by the structure, with the turbine unable to harvest energy effectively. Additional structure to not only reduce incoming impact pressure but also increase the duration of water flow through the turbine was needed. These are the main reasons behind incorporating the duct attachment into the design. This paper show that the duct is capable of halving the impact pressure experienced by the turbine and can increase the energy exposure by up to 1.6 times the bare turbine configuration. Furthermore, it is also said that wave angle (β) = 40° is the critical angle, although the duct still increases wave energy exposure to the power take-off up to β = 60°.
Published: 2021
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17. Efficient Large-Scale 2D Culture System for Human Induced Pluripotent Stem Cells and Differentiated Cardiomyocytes

Author: Shugo Tohyama, Jun Fujita, Chihana Fujita, Miho Yamaguchi, Sayaka Kanaami, Rei Ohno, Kazuho Sakamoto, Masami Kodama, Junko Kurokawa, Hideaki Kanazawa, Tomohisa Seki, Yoshikazu Kishino, Marina Okada, Kazuaki Nakajima, Sho Tanosaki, Shota Someya, Akinori Hirano, Shinji Kawaguchi, Eiji Kobayashi, and Keiichi Fukuda
Subjects: Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract: Summary: Cardiac regenerative therapies utilizing human induced pluripotent stem cells (hiPSCs) are hampered by ineffective large-scale culture. hiPSCs were cultured in multilayer culture plates (CPs) with active gas ventilation (AGV), resulting in stable proliferation and pluripotency. Seeding of 1 × 106 hiPSCs per layer yielded 7.2 × 108 hiPSCs in 4-layer CPs and 1.7 × 109 hiPSCs in 10-layer CPs with pluripotency. hiPSCs were sequentially differentiated into cardiomyocytes (CMs) in a two-dimensional (2D) differentiation protocol. The efficiency of cardiac differentiation using 10-layer CPs with AGV was 66%–87%. Approximately 6.2–7.0 × 108 cells (4-layer) and 1.5–2.8 × 109 cells (10-layer) were obtained with AGV. After metabolic purification with glucose- and glutamine-depleted and lactate-supplemented media, a massive amount of purified CMs was prepared. Here, we present a scalable 2D culture system using multilayer CPs with AGV for hiPSC-derived CMs, which will facilitate clinical applications for severe heart failure in the near future. : In this article, Fujita and colleagues show that human induced pluripotent stem cells (hiPSCs) and hiPSC-derived cardiomyocytes (hiPSC-CMs) are stably and efficiently produced using multilayer culture plates with an active gas ventilation system because of stable CO2 and O2 concentration in culture media. Large numbers of obtained hiPSC-CMs are metabolically purified under glucose- and glutamine-depleted and lactate-supplemented conditions. Keywords: iPSCs, regenerative medicine, cardiomyocytes, purification, large scale, 2D culture
Published: 2017
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18. Ronin Governs Early Heart Development by Controlling Core Gene Expression Programs

Author: Jun Fujita, Pablo Freire, Cristian Coarfa, Ashley L. Benham, Preethi Gunaratne, Michael D. Schneider, Marion Dejosez, and Thomas P. Zwaka
Subjects: Biology (General), QH301-705.5
Abstract: Summary: Ronin (THAP11), a DNA-binding protein that evolved from a primordial DNA transposon by molecular domestication, recognizes a hyperconserved promoter sequence to control developmentally and metabolically essential genes in pluripotent stem cells. However, it remains unclear whether Ronin or related THAP proteins perform similar functions in development. Here, we present evidence that Ronin functions within the nascent heart as it arises from the mesoderm and forms a four-chambered organ. We show that Ronin is vital for cardiogenesis during midgestation by controlling a set of critical genes. The activity of Ronin coincided with the recruitment of its cofactor, Hcf-1, and the elevation of H3K4me3 levels at specific target genes, suggesting the involvement of an epigenetic mechanism. On the strength of these findings, we propose that Ronin activity during cardiogenesis offers a template to understand how important gene programs are sustained across different cell types within a developing organ such as the heart. : Fujita et al. find that the transcriptional regulator Ronin (Thap11) appears to control embryonic heart development. Early heart-specific knockout of Ronin leads to growth defects in the developing heart and embryonic lethality, whereas slightly later Ronin loss results in severe dilated cardiomyopathy in the adult. Keywords: transcriptional control, heart development, organ growth, heart disease, dilative cardiomyopathy
Published: 2017
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19. TRPV4-dependent induction of a novel mammalian cold-inducible protein SRSF5 as well as CIRP and RBM3

Author: Takanori Fujita, Hiroaki Higashitsuji, Hisako Higashitsuji, Yu Liu, Katsuhiko Itoh, Toshiharu Sakurai, Takahiro Kojima, Shuya Kandori, Hiroyuki Nishiyama, Motoi Fukumoto, Manabu Fukumoto, Koji Shibasaki, and Jun Fujita
Subjects: Medicine, Science
Abstract: Abstract Cold-inducible RNA-binding protein (CIRP) and RNA-binding motif protein 3 (RBM3) are two evolutionarily conserved RNA-binding proteins that are structurally related to hnRNPs and upregulated in response to moderately low temperatures in mammalian cells. Although contributions of splicing efficiency, the gene promoters activated upon mild hypothermia and the transcription factor Sp1 to induction of CIRP have been reported, precise mechanisms by which hypothermia and other stresses induce the expression of mammalian cold-inducible proteins (CIPs) are poorly understood. By screening the serine/arginine-rich splicing factors (SRSFs), we report that the transcript and protein levels of SRSF5 were increased in mammalian cells cultured at 32 °C. Expression of SRSF5 as well as CIRP and RBM3 were also induced by DNA damage, hypoxia, cycloheximide and hypotonicity. Immunohistochemical studies demonstrated that SRSF5 was constitutively expressed in male germ cells and the level was decreased in human testicular germ cell tumors. SRSF5 facilitated production of p19 H-RAS, and increased sensitivity to doxorubicin in human U-2 OS cells. Induction of CIPs was dependent on transient receptor potential vanilloid 4 (TRPV4) channel protein, but seemed independent of its ion channel activity. These findings indicate a previously unappreciated role for the TRP protein in linking environmental stress to splicing.
Published: 2017
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20. Turbine Characteristics of Wave Energy Conversion Device for Extraction Power Using Breaking Waves

Author: Paresh Halder, Hideki Takebe, Krisna Pawitan, Jun Fujita, Shuji Misumi, and Tsumoru Shintake
Subjects: wave energy conversion device, breaking wave, computational fluid dynamics, turbine and generator characteristics, Technology
Abstract: A new type of wave energy converter which harnesses electricity from onshore breaking waves has been studied at Okinawa Institute of Science and Technology Graduate University (OIST) since 2014. This concept has been demonstrated at a coral beach on the Maldives since 2018. Wave energy conversion is possible when waves approaching the shore steepen due to decreased water depth resulting in wave breaks near the surface. A steepened wave reaches the critical velocity of 4~6 m/sec shoreward before it breaks. A rotating blade takes advantage of this breaking phenomenon to convert the wave energy into electricity. The work presented here includes an experimental and numerical investigation of a prototype model of the wave energy converter. The turbine having five blades of variable chord lengths, twist angles, and constant thickness profile from hub to tip was simulated under similar flow as well as testing conditions, to predict the turbine performance. A commercial computational fluid dynamic tool SolidWorks Flow Simulation 2018 was used for the simulations at various rotation speeds with a uniform inlet velocity. The modified k-ε with a two-scale wall function turbulence closure model was selected. The validation performed for different test cases showed that the present computational results match in good agreement with the experimental results. Additionally, details performance of the turbine running, and generator characteristics have been reported in this paper.
Published: 2020
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21. Future Prospects for Regenerated Heart Using Induced Pluripotent Stem Cells

Author: Jun Fujita and Keiichi Fukuda
Subjects: Therapeutics. Pharmacology, RM1-950
Abstract: Abstract.: Induced pluripotent stem cell (iPSC) generation is an epoch-making technology. The potential applications for iPSCs are wide-ranging from in vitro disease models to drug discovery. For regenerative medicine in particular, the technology provides great hope for patients with incurable diseases or potentially fatal disorders such as heart failure (HF). However, the true realization of that promise for HF remains uncertain and moving toward the clinical application of iPSCs needs to be stepwise and careful. The establishment of “safe” iPSCs must be a major premise, while genome integration-free and oncogene-free reprogramming is also necessary. Teratoma formation also remains a risk with undifferentiated iPSCs, but it must not happen in patients’ bodies. Thus, regardless of the target organ, the differentiated cells from iPSCs must be purified to exclude any possibility of tumorigenicity. The transplantation strategies used for iPSC-derived cells are very important for the recovery of lost cardiac function. Longer engraftment of transplanted iPSCs-derived cardiomyocytes is essential particularly because their survival could be hampered by ischemia, inflammation, apoptosis, immunological rejection, and other cardiac phenomena. Providing these multistep solutions will open the new frontier of regenerative therapies with iPSCs for patients with severe HF. Keywords:: induced pluripotent stem cell, cardiomyocyte, regenerative medicine, cell transplantation, cell survival
Published: 2014
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22. A variant of Runx2 that differs from the bone isoform in its splicing is expressed in spermatogenic cells

Author: Satoru Kanto, Marcin Grynberg, Yoshiyuki Kaneko, Jun Fujita, and Masanobu Satake
Subjects: Alternative splicing, Cell differentiation, Spermatogenesis, Runx transcription factor, Medicine, Biology (General), QH301-705.5
Abstract: Background. Members of the Runx gene family encode transcription factors that bind to DNA in a sequence-specific manner. Among the three Runx proteins, Runx2 comprises 607 amino acid (aa) residues, is expressed in bone, and plays crucial roles in osteoblast differentiation and bone development. We examined whether the Runx2 gene is also expressed in testes. Methods. Murine testes from 1-, 2-, 3-, 4-, and 10-week-old male mice of the C57BL/6J strain and W∕Wv strain were used throughout the study. Northern Blot Analyses were performed using extracts form the murine testes. Sequencing of cDNA clones and 5′-rapid amplification of cDNA ends were performed to determine the full length of the transcripts, which revealed that the testicular Runx2 comprises 106 aa residues coding novel protein. Generating an antiserum using the amino-terminal 15 aa of Runx2 (Met1 to Gly15) as an antigen, immunoblot analyses were performed to detect the predicted polypeptide of 106 aa residues with the initiating Met1. With the affinity-purified anti-Runx2 antibody, immunohistochemical analyses were performed to elucidate the localization of the protein. Furthermore, bioinformatic analyses were performed to predict the function of the protein. Results. A Runx2 transcript was detected in testes and was specifically expressed in germ cells. Determination of the transcript structure indicated that the testicular Runx2 is a splice isoform. The predicted testicular Runx2 polypeptide is composed of only 106 aa residues, lacks a Runt domain, and appears to be a basic protein with a predominantly alpha-helical conformation. Immunoblot analyses with an anti-Runx2 antibody revealed that Met1 in the deduced open reading frame of Runx2 is used as the initiation codon to express an 11 kDa protein. Furthermore, immunohistochemical analyses revealed that the Runx2 polypeptide was located in the nuclei, and was detected in spermatocytes at the stages of late pachytene, diplotene and second meiotic cells as well as in round spermatids. Bioinformatic analyses suggested that the testicular Runx2 is a histone-like protein. Discussion. A variant of Runx2 that differs from the bone isoform in its splicing is expressed in pachytene spermatocytes and round spermatids in testes, and encodes a histone-like, nuclear protein of 106 aa residues. Considering its nuclear localization and differentiation stage-dependent expression, Runx2 may function as a chromatin-remodeling factor during spermatogenesis. We thus conclude that a single Runx2 gene can encode two different types of nuclear proteins, a previously defined transcription factor in bone and cartilage and a short testicular variant that lacks a Runt domain.
Published: 2016
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23. Correction to: Consistent map building in petrochemical complexes for firefighter robots using SLAM based on GPS and LIDAR

Author: Abu Ubaidah Shamsudin, Kazunori Ohno, Ryunosuke Hamada, Shotaro Kojima, Thomas Westfechtel, Takahiro Suzuki, Yoshito Okada, Satoshi Tadokoro, Jun Fujita, and Hisanori Amano
Subjects: Technology, Mechanical engineering and machinery, TJ1-1570, Control engineering systems. Automatic machinery (General), TJ212-225, Machine design and drawing, TJ227-240, Technology (General), T1-995, Industrial engineering. Management engineering, T55.4-60.8, Automation, T59.5, Information technology, T58.5-58.64
Abstract: Following publication of the original article [1], the authors reported that one of the authors’ name is spelled incorrectly. In this Correction the incorrect and correct author name are shown. The original publication of this article has been corrected.
Published: 2018
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24. Gelatin Hydrogel Enhances the Engraftment of Transplanted Cardiomyocytes and Angiogenesis to Ameliorate Cardiac Function after Myocardial Infarction.

Author: Kazuaki Nakajima, Jun Fujita, Makoto Matsui, Shugo Tohyama, Noriko Tamura, Hideaki Kanazawa, Tomohisa Seki, Yoshikazu Kishino, Akinori Hirano, Marina Okada, Ryota Tabei, Motoaki Sano, Shinya Goto, Yasuhiko Tabata, and Keiichi Fukuda
Subjects: Medicine, Science
Abstract: Cell transplantation therapy will mean a breakthrough in resolving the donor shortage in cardiac transplantation. Cardiomyocyte (CM) transplantation, however, has been relatively inefficient in restoring cardiac function after myocardial infarction (MI) due to low engraftment of transplanted CM. In order to ameliorate engraftment of CM, the novel transplantation strategy must be invented. Gelatin hydrogel (GH) is a biodegradable water-soluble polymer gel. Gelatin is made of collagen. Although we observed that collagen strongly induced the aggregation of platelets to potentially cause coronary microembolization, GH did not enhance thrombogenicity. Therefore, GH is a suitable biomaterial in the cell therapy after heart failure. To assess the effect of GH on the improvement of cardiac function, fetal rat CM (5×10(6) or 1x10(6) cells) were transplanted with GH (10 mg/ml) to infarcted hearts. We compared this group with sham operated rats, CM in phosphate buffered saline (PBS), only PBS, and only GH-transplanted groups. Three weeks after transplantation, cardiac function was evaluated by echocardiography. The echocardiography confirmed that transplantation of 5×10(6) CM with GH significantly improved cardiac systolic function, compared with the CM+PBS group (fractional area change: 75.1±3.4% vs. 60.7±5.9%, p
Published: 2015
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25. The Prevalence of Clinically Significant Ischemia in Patients Undergoing Percutaneous Coronary Intervention: A Report from the Multicenter Registry.

Author: Jun Fujita, Shun Kohsaka, Ikuko Ueda, Taku Inohara, Yuichiro Maekawa, Akio Kawamura, Hideaki Kanazawa, Kentaro Hayashida, Ryota Tabei, Shugo Tohyama, Tomohisa Seki, Masahiro Suzuki, Motoaki Sano, and Keiichi Fukuda
Subjects: Medicine, Science
Abstract: Myocardial perfusion scintigraphy (MPS) plays an important role in the evaluation and quantification of myocardial ischemia, and those with significant ischemia (SI) benefit most from revascularization procedures. This study aimed to identify the clinical factors and anatomical features associated with SI in patients with stable ischemic heart disease (SIHD).Data were analyzed from 4197 SIHD patients undergoing percutaneous coronary intervention (PCI). Ischemia was based on MPS findings prior to PCI, with SI defined as an ischemic region of more than 10% of the total left ventricular area. Logistic regression analysis was performed to identify any clinical factors associated with SI. MPS was used to evaluate 1070 (25.5%) patients pre-procedurally. Patients with a history of heart failure, stroke, or anginal symptoms with Canadian Cardiovascular Society class 2 or more were more likely to have SI (odds ratio [OR] 1.63, p = 0.025, OR: 1.85, p = 0.009, and OR: 1.49, p = 0.003, respectively). When angiographic variables were considered, a proximal left anterior descending artery (pLAD) lesion was the sole factor associated with SI (OR: 1.45, p = 0.012). Importantly, those with SI had more in-hospital complications (p = 0.006), most notably post-PCI infarcts (p = 0.008).Patients' background data, such as stronger anginal symptoms or a pLAD lesion, were associated with SI. Patients with SI must be treated with PCI to improve their long-term prognosis; however, procedure-related complications happen more frequently in SI patients than in non-SI patients. Physicians must give their full attention when performing the PCI procedure in SI patients to minimize their complication rate.
Published: 2015
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26. Derivation of transgene-free human induced pluripotent stem cells from human peripheral T cells in defined culture conditions.

Author: Yoshikazu Kishino, Tomohisa Seki, Jun Fujita, Shinsuke Yuasa, Shugo Tohyama, Akira Kunitomi, Ryota Tabei, Kazuaki Nakajima, Marina Okada, Akinori Hirano, Hideaki Kanazawa, and Keiichi Fukuda
Subjects: Medicine, Science
Abstract: Recently, induced pluripotent stem cells (iPSCs) were established as promising cell sources for revolutionary regenerative therapies. The initial culture system used for iPSC generation needed fetal calf serum in the culture medium and mouse embryonic fibroblast as a feeder layer, both of which could possibly transfer unknown exogenous antigens and pathogens into the iPSC population. Therefore, the development of culture systems designed to minimize such potential risks has become increasingly vital for future applications of iPSCs for clinical use. On another front, although donor cell types for generating iPSCs are wide-ranging, T cells have attracted attention as unique cell sources for iPSCs generation because T cell-derived iPSCs (TiPSCs) have a unique monoclonal T cell receptor genomic rearrangement that enables their differentiation into antigen-specific T cells, which can be applied to novel immunotherapies. In the present study, we generated transgene-free human TiPSCs using a combination of activated human T cells and Sendai virus under defined culture conditions. These TiPSCs expressed pluripotent markers by quantitative PCR and immunostaining, had a normal karyotype, and were capable of differentiating into cells from all three germ layers. This method of TiPSCs generation is more suitable for the therapeutic application of iPSC technology because it lowers the risks associated with the presence of undefined, animal-derived feeder cells and serum. Therefore this work will lead to establishment of safer iPSCs and extended clinical application.
Published: 2014
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27. Generation and characterization of functional cardiomyocytes derived from human T cell-derived induced pluripotent stem cells.

Author: Tomohisa Seki, Shinsuke Yuasa, Dai Kusumoto, Akira Kunitomi, Yuki Saito, Shugo Tohyama, Kojiro Yae, Yoshikazu Kishino, Marina Okada, Hisayuki Hashimoto, Makoto Takei, Toru Egashira, Masaki Kodaira, Yusuke Kuroda, Atsushi Tanaka, Shinichiro Okata, Tomoyuki Suzuki, Mitsushige Murata, Jun Fujita, and Keiichi Fukuda
Subjects: Medicine, Science
Abstract: Induced pluripotent stem cells (iPSCs) have been proposed as novel cell sources for genetic disease models and revolutionary clinical therapies. Accordingly, human iPSC-derived cardiomyocytes are potential cell sources for cardiomyocyte transplantation therapy. We previously developed a novel generation method for human peripheral T cell-derived iPSCs (TiPSCs) that uses a minimally invasive approach to obtain patient cells. However, it remained unknown whether TiPSCs with genomic rearrangements in the T cell receptor (TCR) gene could differentiate into functional cardiomyocyte in vitro. To address this issue, we investigated the morphology, gene expression pattern, and electrophysiological properties of TiPSC-derived cardiomyocytes differentiated by floating culture. RT-PCR analysis and immunohistochemistry showed that the TiPSC-derived cardiomyocytes properly express cardiomyocyte markers and ion channels, and show the typical cardiomyocyte morphology. Multiple electrode arrays with application of ion channel inhibitors also revealed normal electrophysiological responses in the TiPSC-derived cardiomyocytes in terms of beating rate and the field potential waveform. In this report, we showed that TiPSCs successfully differentiated into cardiomyocytes with morphology, gene expression patterns, and electrophysiological features typical of native cardiomyocytes. TiPSCs-derived cardiomyocytes obtained from patients by a minimally invasive technique could therefore become disease models for understanding the mechanisms of cardiac disease and cell sources for revolutionary cardiomyocyte therapies.
Published: 2014
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28. Human pentraxin 3 (PTX3) as a novel biomarker for the diagnosis of pulmonary arterial hypertension.

Author: Yuichi Tamura, Tomohiko Ono, Masataka Kuwana, Kenji Inoue, Makoto Takei, Tsunehisa Yamamoto, Takashi Kawakami, Jun Fujita, Masaharu Kataoka, Kensuke Kimura, Motoaki Sano, Hiroyuki Daida, Toru Satoh, and Keiichi Fukuda
Subjects: Medicine, Science
Abstract: BACKGROUND: Although inflammation is an important feature of pulmonary arterial hypertension (PAH), the usefulness of local inflammatory markers as biomarkers for PAH is unknown. In this study, we tested whether plasma concentrations of human pentraxin 3 (PTX3), a local inflammatory marker, would be a useful biomarker for detecting PAH. METHODS: Plasma PTX3 concentrations were evaluated in 50 PAH patients (27 with idiopathic PAH, 17 with PAH associated with connective tissue disease (CTD-PAH), and six with congenital heart disease), 100 age and sex-matched healthy controls, and 34 disease-matched CTD patients without PAH. Plasma concentrations of B-type natriuretic peptide (BNP) and C-reactive protein (CRP) were also determined. RESULTS: Mean PTX3 levels were significantly higher in all PAH patients than in the healthy controls (4.40±0.37 vs. 1.94±0.09 ng/mL, respectively; P
Published: 2012
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29. Development of a Robust Tracking Target Against Disturbance Noise for Tracking Control of Fire Fighting Robots.

Author: Jun Fujita, Hisanori Amano, Kazunori Ohno, and Satoshi Tadokoro
Published: 2023
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30. Consideration of the contribution of operating a firefighting robot system for large fires to prevent COVID-19 infection among firefighters.

Author: Jun Fujita, Hisanori Amano, Kazunori Ohno, and Satoshi Tadokoro
Published: 2023
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31. Enhanced path smoothing based on conjugate gradient descent for firefighting robots in petrochemical complexes.

Author: Naoki Mizuno, Kazunori Ohno, Ryunosuke Hamada, Hiroyoshi Kojima, Jun Fujita, Hisanori Amano, Thomas Westfechtel, Takahiro Suzuki, and Satoshi Tadokoro
Published: 2019
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32. Evaluation of LIDAR and GPS based SLAM on fire disaster in petrochemical complexes.

Author: Abu Ubaidah bin Shamsudin, Naoki Mizuno, Jun Fujita, Kazunori Ohno, Ryunosuke Hamada, Thomas Westfechtel, Satoshi Tadokoro, and Hisanori Amano
Published: 2017
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33. Two-stage Hybrid A* path-planning in large petrochemical complexes.

Author: Abu Ubaidah Shamsudin, Kazunori Ohno, Ryunosuke Hamada, Shotaro Kojima, Naoki Mizuno, Thomas Westfechtel, Takahiro Suzuki, Satoshi Tadokoro, Jun Fujita, and Hisanori Amano
Published: 2017
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34. Consideration of the contribution of operating a firefighting robot system for large fires to prevent COVID-19 infection among firefighters

Author: Jun Fujita, Hisanori Amano, Kazunori Ohno, and Satoshi Tadokoro
Subjects: Human-Computer Interaction, Hardware and Architecture, Control and Systems Engineering, Software, Computer Science Applications
Published: 2022

35. Enhancing the multi-encoder-based cutting force estimation along the stationary axis of a machine tool with multiple inertia dynamics

Author: Keisuke Yamamoto, Aya Kamba, Kazuhiro Takeuchi, Jun Fujita, Yusuke Fujimagari, and Yasuhiro Kakinuma
Subjects: Control and Systems Engineering, Mechanical Engineering, Industrial and Manufacturing Engineering, Software, Computer Science Applications
Abstract: Wideband cutting force sensing is a key technology for process monitoring. Sensorless cutting force estimation using the internal servo information of a machine tool with ball-screw-driven stages has been studied owing to its high maintainability and ease of introduction. In the motor current-based method, the cutting force estimation along the stationary axis is challenging, and the estimation bandwidth is significantly limited owing to the low sensitivity of the motor current in the high-frequency range. The dual-inertia model-based load-side disturbance observer (LDOB) can estimate the cutting force along the stationary axis using the relative position obtained from the rotary encoder and linear encoder, which is installed relatively near the cutting point and has a high sensitivity in the high-frequency range. However, this approach is not applicable to machine tools with complicated structural dynamics. To address this challenge, we propose a cutting force estimation method along the stationary axis using the Kalman filter (KF) based on a multiple inertia model derived solely from the relative position signal. The dynamics, depending on the stage position of the feed drive, were modeled using linear interpolation. Through end milling tests, we confirmed that the cutting force estimation accuracy along the stationary axis of a machine tool with multiple inertia dynamics was significantly improved by the proposed method compared to the current and LDOB-based methods. Additionally, the wideband cutting force could be estimated using the proposed method for bandwidths up to 1000 Hz.
Published: 2022

36. Le Ciné-capital : D'Hitchcock à Ozu

Author: Jun FUJITA and Jun FUJITA
Published: 2018

37. Supplementary Figure S2 from Stress Response Protein Cirp Links Inflammation and Tumorigenesis in Colitis-Associated Cancer

Author: Masatoshi Kudo, Jun Fujita, Hiroaki Higashitsuji, Naoshi Nishida, Hideki Iijima, Tsunekazu Mizushima, Satoru Hagiwara, Tomohiro Watanabe, Hiroshi Kashida, and Toshiharu Sakurai
Abstract: Figure S2. Association between Cirp and IL-17, Bcl-2, Bcl-xL or Sox2 in the colonic mucosa of patients with Crohn's disease (CD). Scatter plot of relative mRNA levels of Cirp and respective genes in human colonic mucosa.
Published: 2023

38. Supplementary Figure Legends from Stress Response Protein Cirp Links Inflammation and Tumorigenesis in Colitis-Associated Cancer

Author: Masatoshi Kudo, Jun Fujita, Hiroaki Higashitsuji, Naoshi Nishida, Hideki Iijima, Tsunekazu Mizushima, Satoru Hagiwara, Tomohiro Watanabe, Hiroshi Kashida, and Toshiharu Sakurai
Abstract: Supplementary Figure Legends
Published: 2023

39. Internal Translation of p53 Oncoproteins During Integrated Stress Response Confers Survival Advantage on Cancer Cells

Author: Maria José López-Iniesta, Rafaela Lacerda, Ana Catarina Ramalho, Shrutee N. Parkar, Ana Marques-Ramos, Bruna Pereira, Lina Miyawaki, Jun Fujita, Roman Hrstka, Luísa Romão, and Marco M Candeias
Abstract: p53is the most known and studied tumour suppressor gene. Yet we have recently shown thatp53is also a proto-oncogene, as it encodes the Δ160p53 oncoprotein. Integrated stress response (ISR) is a survival pathway frequently activated in cancers, marked by the phosphorylation of eukaryotic initiation factor 2alpha (eIF2α) and a defined reprogramming in mRNA translation. Here we identified ISR as a powerful trigger of p53 oncogene, leading to the induction of not only Δ160p53 but also Δ133p53, another protein variant of thep53gene. Upon ISR the two isoforms were translated internally from p53 full-length (FL) transcript through an internal regulator of expression site (IRES) located in the vicinity of codon 160. Frameshift mutations upstream of codons 133 and 160 demonstrated that FLp53 protein synthesis is not required for making Δ133p53 and Δ160p53. Instead, targeting IRES(160) with an antisense oligo was sufficient to efficiently and specifically impair the expression of these isoforms without affecting FLp53 levels. This in turn averted ISR’s protective program culminating in cancer cell cycle arrest and death. Mechanistically, FLp53 showed 3 times more affinity to Δ160p53 than to other isoforms, Δ40p53 or Δ133p53. During ISR Δ160p53 localized to the nucleus and strongly inhibited FLp53-mediated activation of pro-apoptotic genep53 upregulated modulator of apoptosis(PUMA). Our results uncover a new branch of the ISR network essential for cancer cell survival and growth and establish the proof of concept for a new strategy to target cancer.
Published: 2023

40. The role of torsional stress in the development of subchondral insufficiency fracture of the femoral head: A finite element model analysis

Author: Jun Fujita, Koichi Kinoshita, Tetsuya Sakamoto, Hajime Seo, Kenichiro Doi, and Takuaki Yamamoto
Subjects: Orthopedics and Sports Medicine, Surgery
Published: 2023

41. Nuclear Ceramide Is Associated with Ataxia Telangiectasia Mutated Activation in the Neocarzinostatin-Induced Apoptosis of Lymphoblastoid Cells

Author: Jun Fujita, Makoto Taniguchi, Chieko Hashizume, Yoshibumi Ueda, Shota Sakai, Tadakazu Kondo, Mayumi Hashimoto-Nishimura, Kentaro Hanada, Takeo Kosaka, and Toshiro Okazaki
Subjects: Pharmacology, DNA Repair, Tumor Suppressor Proteins, Apoptosis, Cell Cycle Proteins, Ataxia Telangiectasia Mutated Proteins, Protein Serine-Threonine Kinases, Ceramides, DNA-Binding Proteins, Ataxia Telangiectasia, Sphingomyelin Phosphodiesterase, Zinostatin, Humans, Molecular Medicine
Abstract: Ceramide is a bioactive sphingolipid that mediates ionizing radiation- and chemotherapy-induced apoptosis. Neocarzinostatin (NCS) is a genotoxic anti-cancer drug that induces apoptosis in response to DNA double-strand breaks (DSBs) through ataxia telangiectasia mutated (ATM) activation. However, the involvement of ceramide in NCS-evoked nuclear events such as DSB-activated ATM has not been clarified. Here, we found that nuclear ceramide increased by NCS-mediated apoptosis through the enhanced assembly of ATM and the meiotic recombination 11/double-strand break repair/Nijmengen breakage syndrome 1 (MRN) complex proteins in human lymphoblastoid L-39 cells. NCS induced an increase of ceramide production through activation of neutral sphingomyelinase (nSMase) and suppression of sphingomyelin synthase (SMS) upstream of DSB-mediated ATM activation. In ATM-deficient lymphoblastoid AT-59 cells compared with L-39 cells, NCS treatment showed a decrease of apoptosis even though ceramide increase and DSBs were observed. Expression of wild-type ATM, but not the kinase-dead mutant ATM, in AT-59 cells increased NCS-induced apoptosis despite similar ceramide accumulation. Interestingly, NCS increased ceramide content in the nucleus through nSMase activation and SMS suppression and promoted colocalization of ceramide with phosphorylated ATM and foci of MRN complex. Inhibition of ceramide generation by the overexpression of SMS suppressed NCS-induced apoptosis through the inhibition of ATM activation and assembly of the MRN complex. In addition, inhibition of ceramide increased by the nSMase inhibitor GW4869 prevented NCS-mediated activation of the ATM. Therefore, our findings suggest the involvement of the nuclear ceramide with ATM activation in NCS-mediated apoptosis. SIGNIFICANCE STATEMENT: This study demonstrates that regulation of ceramide with neutral sphingomyelinase and sphingomyelin synthase in the nucleus in double-strand break-mimetic agent neocarzinostatin (NCS)-induced apoptosis. This study also showed that ceramide increase in the nucleus plays a role in NCS-induced apoptosis through activation of the ataxia telangiectasia mutated/meiotic recombination 11/double-strand break repair/Nijmengen breakage syndrome 1 complex in human lymphoblastoid cells.
Published: 2022

42. Pulmonary tumor thrombotic microangiopathy caused by metastatic ovarian high-grade serous carcinoma: a case report and literature review

Author: Jun Fujita, Kelsey Hummel, and Ya Xu
Subjects: General Medicine, Cardiology and Cardiovascular Medicine, Pathology and Forensic Medicine
Published: 2023

43. Clinical characteristics of immunoglobulin IgG4-related sclerosing cholangitis: Comparison of cases with and without autoimmune pancreatitis in a large cohort

Author: Itaru Naitoh, Terumi Kamisawa, Atsushi Tanaka, Takahiro Nakazawa, Kensuke Kubota, Hajime Takikawa, Michiaki Unno, Atsushi Masamune, Shigeyuki Kawa, Seiji Nakamura, Kazuichi Okazaki, Keisuke Furumatsu, Shigeaki Sawai, Takuma Goto, Toshikatsu Okumura, Daisuke Suzuki, Masayuki Otsuka, Ikuhiro Kobori, Masaya Tamano, Mitsuhito Koizumi, Yoichi Hiasa, Naoto Kawabe, Yoshiki Hirooka, Satoshi Yamamoto, Yukio Asano, Kazuo Inui, Akihiko Horiguchi, Hiroyuki Watanabe, Daishu Toya, Katsuko Hatayama, Toshiharu Ueki, Norikatsu Kinoshita, Mitsuru Sugimoto, Hiromasa Ohira, Tsuyoshi Mukai, Eiichi Tomita, Keisuke Iwata, Shogo Shimizu, Jun Suetsugu, Masahito Shimizu, Keiji Tsuji, Ryoko Ishida, Masanori Ito, Ryutaro Furukawa, Naoya Sakamoto, Masahiro Araki, Satoshi Tanno, Yasunari Sakamoto, Tetsuhide Ito, Satoshi Takai, Shinichi Ikeya, Takanori Yamada, Norihiko Kudara, Akinori Shimizu, Keiji Hanada, Yasunori Ichiki, Hideki Kitada, Michio Hifumi, Hiroyuki Kimura, Masayuki Kurosaki, Namiki Izumi, Hajime Sumi, Jun-ichi Haruta, Katsumi Hayashi, Ryo Harada, Masafumi Inoue, Shinichiro Nakamura, Tetsuya Ito, Ko Tomishima, Hiroyuki Isayama, Kyoko Oura, Tsutomu Masaki, Naoto Shimokawahara, Shirou Tanoue, Kousei Maemura, Akio Ido, Ichiro Mizushima, Mitsuhiro Kawano, Katsunori Yoshida, Makoto Naganuma, Miki Murata, Akiyoshi Nishio, Yuji Fujita, Takuma Teratani, Shohei Matsubara, Hironao Tamai, Yuu Yoshida, Ryousaku Azemoto, Ken Kamata, Tomohiro Watanabe, Takahiro Kurosu, Wasaburou Koizumi, Jun Fujita, Hideyuki Seki, Yasuhiro Ueda, Takumi Fukumoto, Takuhiro Kousaki, Kazushige Uchida, Toshimasa Ochiai, Takeshi Kawasaki, Motohiko Tanaka, Etsuji Ishida, Kenji Notohara, Hideaki Mori, Toshiyuki Mori, Hideaki Kawabata, Masatoshi Miyata, Junichi Sakagami, Yoshito Itoh, Masahiro Shiokawa, Hiroshi Seno, Noriko Watanabe, Hiromi Kataoka, Toshinori Aoki, Mitsuhiro Fujishiro, Toru Niihara, Hiroto Nishimata, Akira Mitoro, Hitoshi Yoshiji, Motoyuki Yoshida, Masafumi Ikeda, Kengo Tomita, Ryota Hokari, Kenji Hayasaka, Yuji Amano, Kazuhiko Shioji, Kazunao Hayashi, Shuji Terai, Michiko Nakajima, Junya Yamahana, Ryusuke Matsumoto, Hideaki Kikuchi, Akira Kanamori, Seiki Kiriyama, Shinichi Iwatsu, Yuji Kato, Shigeru Horiguchi, Takahito Yagi, Hiroyuki Okada, Kazuyoshi Ohkawa, Motohiro Hirao, Naoki Hiramatsu, Noriko Oza, Haruo Imamura, Takeshi Baba, Shigeru Nakano, Tetsuya Shinobi, Shomei Ryozawa, Masayo Motoya, Hiroshi Nakase, Noboru Kinoshita, Kei Ito, Tatsuya Miyake, Naruaki Kohge, Hiroshi Tobita, Satoru Joshita, Takeji Umemura, Shinya Kawaguchi, Kazuya Ohno, Koichi Sonobe, Akihiko Satoh, Tooru Shimosegawa, Fumihiko Miura, Minami Yagi, Keiji Sano, Toshifumi Kin, Akio Katanuma, Kazuhiko Koike, Shin Miura, Youhei Kawashima, Tatehiro Kagawa, Seishin Azuma, Mamoru Watanabe, Mitsuyoshi Honjyo, Takao Itoi, Akira Honda, Katsumasa Kobayashi, Toru Asano, Suguru Mizuno, Takayoshi Nishino, Hideaki Taniguchi, Kazuto Tajiri, Ichiro Yasuda, Yoshiya Tanaka, Shinji Oe, Masaru Harada, Masanao Kurata, Mituharu Fukasawa, Nobuyuki Enomoto, Yuki Kawaji, Masayuki Kitano, Yuko Nishise, Hidetoshi Hirakawa, Tetsuya Ishizawa, Yoshiyuki Ueno, Miyuki Kaino, Yuko Fujimoto, and Isao Sakaida
Subjects: Male, medicine.medical_specialty, Autoimmune Pancreatitis, Cholangitis, Sclerosing, Gastroenterology, Primary sclerosing cholangitis, Serology, 03 medical and health sciences, 0302 clinical medicine, Japan, Surveys and Questionnaires, Internal medicine, Humans, Medicine, Retrospective Studies, Autoimmune pancreatitis, Hepatology, medicine.diagnostic_test, business.industry, Bile duct, Ultrasound, Magnetic resonance imaging, Histology, medicine.disease, medicine.anatomical_structure, Immunoglobulin G, 030220 oncology & carcinogenesis, Female, 030211 gastroenterology & hepatology, IgG4-related disease, Bile Ducts, Immunoglobulin G4-Related Disease, business, Cholangiography
Abstract: Background The clinical characteristics of IgG4-related sclerosing cholangitis (IgG4-SC) especially without autoimmune pancreatitis (AIP) have not been investigated in a large cohort. Aims To clarify the clinical characteristics of IgG4-SC and IgG4-SC without AIP. Methods We retrospectively reviewed imaging, serology, other organ involvement (OOI) and histology of 872 patients with IgG4-SC who participated in a Japanese nationwide survey in 2019, and compared these items between IgG4-SC with and without AIP. Results AIP was present in 83.7% (730/872) of IgG4-SC. In IgG4-SC, bile duct wall thickening was observed on ultrasound (528/650; 81.2%), computed tomography (375/525; 71.4%) and magnetic resonance imaging or cholangiopancreatography (290/440; 65.9%). An elevated serum IgG4 level (≥ 135 mg/dL) was found in 88.0% (322/366). IgG4-related OOI other than AIP was observed in 25.2% (211/836). The proportion of females was significantly higher in IgG4-SC without AIP (28.9% vs. 20.1%; p = 0.025). Hilar stricture was the most common cholangiographic type in IgG4-SC without AIP (39/107; 36.4%).There were no significant differences between IgG4-SC with and without AIP in the rates of bile duct wall thickening, elevated serum IgG4 level, or IgG4-related OOI. Conclusions The clinical characteristics of IgG4-SC was similar between IgG4-SC with and without AIP in a large cohort.
Published: 2021

44. Onecut1partially contributes to the liver progenitor cell transition and acquisition of metastatic potential in hepatocellular carcinoma

Author: Yu Liu, Hiroaki Higashitsuji, Katsuhiko Itoh, Kanji Yamaguchi, Atsushi Umemura, Yoshito Itoh, and Jun Fujita
Abstract: Metastasis-initiating cells are considered to originate from stem cell-like cancer cells. In hepatocellular carcinoma, liver progenitor-like cells are reported to be derived from hepatocytes, indicating the possible acquisition of metastatic potential during hepatocyte-to-cholangiocyte transdifferentiation. Consistent with the expression pattern observed during ductal plate formation, we revealed an LPC transition withOnecut1accumulation both during hepatocyte-to-cholangiocyte transdifferentiation and in a cell model. This event may be associated with transient acquisition of metastatic potential.
Published: 2022

45. Heart-derived collagen promotes maturation of engineered heart tissue

Author: Hidenori Tani, Eiji Kobayashi, Shinomi Yagi, Keisuke Tanaka, Kotaro Kameda-Haga, Shinsuke Shibata, Nobuko Moritoki, Kaworu Takatsuna, Taijun Moriwaki, Otoya Sekine, Tomohiko Umei, Yuika Morita, Yusuke Soma, Yoshikazu Kishino, Hideaki Kanazawa, Jun Fujita, Shunji Hattori, Keiichi Fukuda, and Shugo Tohyama
Subjects: Biomaterials, Mechanics of Materials, Biophysics, Ceramics and Composites, Bioengineering
Published: 2023

46. Initial Invasive or Conservative Strategy for Stable Coronary Disease

Author: Maron D. J., Hochman J. S., Reynolds H. R., Bangalore S., O'Brien S. M., Boden W. E., Chaitman B. R., Senior R., Lopez-Sendon J., Alexander K. P., Lopes R. D., Shaw L. J., Berger J. S., Newman J. D., Sidhu M. S., Goodman S. G., Ruzyllo W., Gosselin G., Maggioni A. P., White H. D., Bhargava B., Min J. K., John Mancini G. B., Berman D. S., Picard M. H., Kwong R. Y., Ali Z. A., Mark D. B., Spertus J. A., Krishnan M. N., Elghamaz A., Moorthy N., Hueb W. A., Demkow M., Mavromatis K., Bockeria O., Peteiro J., Miller T. D., Szwed H., Doerr R., Keltai M., Selvanayagam J. B., Gabriel Steg P., Held C., Kohsaka S., Mavromichalis S., Kirby R., Jeffries N. O., Harrell F. E., Rockhold F. W., Broderick S., Bruce Ferguson T., Williams D. O., Harrington R. A., Stone G. W., Rosenberg Y, ISCHEMIA Research Group: Joseph Ricci, A Tello Montoliu, A I Robero Aniorte, Abbey Mulder, Abhay A Laddu, Abhinav Goyal, Abhishek Dubey, Abhishek Goyal, Abigail Knighton, Abraham Oomman, Adam J Jaskowiak, Adam Kolodziej, Adam Witkowski, Adnan Hameed, Adriana Anesini, Afshan Hussain, Agne Juceviciene, Agne Urboniene, Agnes Jakal, Agnieszka Szramowska, Ahmad Khairuddin, Ahmed Abdel-Latif, Ahmed Adel, Ahmed Aljzeeri, Ahmed Kamal, Ahmed Talaat, Aimee Mann, Aira Contreras, Ajit Kumar, V K Kumar, Akemi Furukawa, Akshay Bagai, Akvile Smigelskaite, Alain Furber, Alain Rheault, Alaine Melanie Loehr, Alan Rosen, Albert Varga, Albertina Qelaj, Alberto Barioli, Aldo Russo, Alec Moorman, Alejandro Gisbert, Aleksandra Fratczak, Aleksandras Laucevicius, Alena Kuleshova, Alessandro Sionis, Alexander A Sirker, Alexander M Chernyavskiy, Alexandra Craft, Alexandra Vazquez, Alexandre Ciappina Hueb, Alexandre S Colafranseschi, Alexandre Schaan de Quadros, Alexandre Tognon, Ali Alghamdi, Alice Manica Muller, Aline Nogueira Rabaça, Aline Peixoto Deiro, Alison Hallam, Allegra Stone, Allison Schley, Almudena Castro, Alvaro Rabelo Ales, Amanda Germann, Amanda O'Malley, Amar Uxa, Amarachi Ojajuni, Amarino C Oliveira Jr, Amber B Hull, Ambuj Roy, Amer Zarka, Amir Janmohamed, Ammani Brown, Ammy Malinay, Amparo Martinez Monzonis, Amy J Richards, Amy Iskandrian, Amy Ollinger, Ana D Djordjevic-Dikic, Ana Fernández Martínez, Ana Gomes Almeida, Ana Paula Batista, Ana Rita Francisco, Ana S Mladenovic, Ana Santana, Anam Siddiqui, Anastasia M Kuzmina-Krutetskaya, Andras Vertes, Andre S Sousa, Andre Gabriel, André Schmidt, Andrea M Lundeen, Andrea Bartykowszki, Andrea Lorimer, Andrea Mortara, Andrea Pascual, Andreia Coelho, Andreia Rocha, Andrés García-Rincón, Andrew G Howarth, Andrew J Moriarty, Andrew Docherty, Andrew Starovoytov, Andrew Zurick, Andrzej Łabyk, Andrzej Swiatkowski, Andy Lam, Anelise Kawakami, Angela Hoye, Angela Kim, Angelique Smit, Angelo Nobre, Anil V Shah, Anja Ljubez, Anjali Anand, Ankush Sachdeva, Ann Greenberg, Ann Luyten, Ann Ostrander, Anna Di Donato, Anna Cichocka-Radwan, Anna Fojt, Anna Plachcinska, Anna Proietti, Anna Teresinska, Anne Marie Webb, Anne Cartwright, Anne Heath, Anne Mackin, Anong Amaritakomol, Anong Chaiyasri, Anoop Chauhan, Anoop Mathew, Anthony Gemignani, Anto Luigi Andres, Antonia Vega, Antonietta Hansen, Antonino Ginel Iglesias, Antonio Carlos Carvalho, Antonio Di Chiara, Antonio Serra Peñaranda, Antonio Carvalho, Antonio Colombo, Antonio Fiarresga, Anupama Rao, Aquiles Valdespino-Estrada, Araceli Boan, Areef Ishani, Ariel Diaz, Arijit Ghosh, Arintaya Prommintikul, Arline Roberts, Arnold H Seto, Arnold P Good, Arshed Quyyumi, Arthur J Labovitz, Arthur Kerner, Arturo S Campos-Santaolalla, Arunima Misra, Ashok Mukherjee, Ashok Seth, Ashraf Seedhom, Asim N Cheema, Asker Ahmed, Atul Mathur, Atul Verma, Audrey W Leong, Axel Åkerblom, Axelle Fuentes, Aynun Naher, Badhma Valaiyapathi, Baljeet Kaur, Bandula Guruge, Barbara Brzezińska, Barbara Nardi, Bartosz Czarniak, Bebek Singh, Begoña Igual, Bela Merkely, Belen Cid Alvarez, Benjamin J Spooner, Benjamin J W Chow, Benjamin Cheong, Benoy N Shah, Bernard de Bruyne, Bernardas Valecka, Bernhard Jäger, Beth A Archer, Beth Abramson, Beth Jorgenson, Bethany Harvey, Betsy O'Neal, Bev Atkinson, Bev Bozek, Bevin Lang, Bijulal Sasidharan, Bin Yang, Bin Zhang, Binoy Mannekkattukudy Kurian, Bjoern Goebel, Bob Hu, Bogdan A Popescu, Bogdan Crnokrak, Bolin Zhu, Bonnie J Kirby, Brandi D Zimbelman, Brandy Starks, Branko D Beleslin, Brenda Hart, Brian P Shapiro, Brian McCandless, Brianna Wisniewski, Brigham R Smith, Brooks Mirrer, Bruce McManus, Bruce Rutkin, Bruna Edilena Paulino, Bruna Maria Ascoli, Bryn Smith, Byron J Allen, C Michael Gibson, C Noel Bairey Merz, Calin Pop, Cameron Hague, Camila Thais de Ormundo, Candace Gopaul, Candice P Edillo, Carísi A Polanczyk, Carita Krannila, Carla Vicente, Carl-Éric Gagné, Carlo Briguori, Carlos Peña Gil, Carlos Alvarez, Carly Ohmart, Carmen C Beladan, Carmen Ginghina, Carol M Kartje, Caroline Alsweiler, Caroline Brown, Caroline Callison, Caroline Pinheiro, Caroline Rodgers, Caroline Spindler, Carolyn Corbett, Carrie Drum, Casey Riedberger, Catherine Bone, Catherine Fleming, Catherine Gordon, Catherine Jahrsdorfer, Catherine Lemay, Catherine Weick, Cathrine Patten, Cecilia Goletto, Cezary Kepka, Chandini Suvarna, Chang Xu, Chantale Mercure, Charle A Viljoen, Charlene Wiyarand, Charles Jia-Yin Hou, Charles Y Lui, Charles Cannan, Charles Cornet, Charlotte Pirro, Chataroon Rimsukcharoenchai, Chen Wang, Cheng-Ting Tsai, Chen-Yen Chien, Cheryl A Allardyce, Chester M Hedgepeth, Chetan Patel, Chiara Attanasio, Chih-Hsuan Yen, Chi-Ming Chow, Ching Min Er, Ching-Ching Ong, Cholenahally Nanjappa Manjunath, Chris Beck, Chris Buller, Christel Vassaliere, Christian Hamm, Christiano Caldeira, Christie Ballantyne, Christina Björklund, Christine R Hinton, Christine Bergeron, Christine Masson, Christine Roraff, Christine Shelley, Christophe Laure, Christophe Thuaire, Christopher Kinsey, Christopher McFarren, Christopher Spizzieri, Christopher Travill, Chun-Chieh Liu, Chung-Lieh Hung, Chunguang Li, Chun-Ho Yun, Chunli Xia, Ciarra Heard, Cidney Schultz, Clare Venn-Edmonds, Claudia P Hochberg, Claudia Wegmayr, Claudia Cortés, Claudia Escobar, Cláudia Freixo, Claudio T Mesquita, Clemens T Kadalie, Colin Berry, Constance Philander, Corine Thobois, Costantino Costantini, Courtney Page, Craig Atkinson, Craig Barr, Craig Paterson, Cristina Bare, Cynthia Baumann, Cynthia Burman, Dalisa Espinosa, Damien Collison, Dan Deleanu, Dan Elian, Dan Gao, Dana Oliver, Daniel P Vezina, Daniel O'Rourke, Daniele Komar, Danielle Schade, Darrel P Francis, Dastan Malaev, David A Bull, David E Winchester, David P Faxon, David Booth, David Cohen, David DeMets, David Foo, David Schlichting, David Taggart, David Waters, David Wohns, Davis Vo, Dawid Teodorczyk, Dawn Shelstad, Dawn Turnbull, Dayuan Li, Dean Kereiakes, Deborah O'Neill, Deborah Yip, Debra K Johnson, Debra Dees, Deepak L Bhatt, Deepika Gopal, Deepti Kumar, Deirdre Mattina, Deirdre Murphy, Delano R Small, Delsa K Rose, Dengke Jiang, Denis Carl Phaneuf, Denise Braganza, Denise Fine, Derek Cyr, Desiree Tobin, Diana Cukali, Diana Parra, Diane Camara, Diane Minshall Liu, Diego Adrián Vences, Diego Franca de Cunha, Dimitrios Stournaras, Dipti Patel, Dongze Li, Donna Exley, Dorit Grahl, Dragana Stanojevic, Duarte Cacela, Dwayne S G Conway, E Pinar Bermudez, Eapen Punnoose, Edgar L Tay, Edgar Karanjah, Edoardo Verna, Eduardo Hernandez-Rangel, Edward D Nicol, Edward O McFalls, Edward T Martin, Edyta Kaczmarska, Ekaterina I Lubinskaya, Elena A Demchenko, Elena Refoyo Salicio, Eli Feen, Elihú Durán-Cortés, Elisabeth M Janzen, Elise L Hannemann, Elise van Dongen, Elissa Restelli Piloto, Eliza Kaplan, Elizabeta Srbinovska Kostovska, Elizabeth Capasso-Gulve, Elizabeth Congdon, Elizabeth Ferguson, Elizaveta V Zbyshevskaya, Ellen Magedanz, Ellie Fridell, Ellis W Lader, Elvin Kedhi, Emanuela Racca, Emilie Tachot, Emily DeRosa, Encarnación Alonso-Álvarez, Eric Nicollet, Eric Peterson, Erick Alexánderson Rosas, Erick Donato Morales, Erin Orvis, Ermina Moga, Estelle Montpetit, Estevao Figueiredo, Eugene Passamani, Eugenia Nikolsky, Eunice Yeoh, Evgeniy I Kretov, Ewa Szczerba, Ewelina Wojtala, Expedito Eustáquio Ribeiro Silva, F Marin Ortuño, Fabio R Farias, Fabio Fimiani, Fabrizio Rolfo, Fa-Chang Yu, Fadi Hage, Fadi Matar, Fahim Haider Jafary, Fang Feng, Fang Liu, Fatima Ranjbaran, Fatima Rodriguez, Fausto J Pinto, Fauzia Rashid, Federica Ramani, Fei Wang, Fernanda Igansi, Filipa Silva, Filippo Ottani, Fiona Haines, Firas Al Solaiman, Flávia Egydio, Flavio Lyra, Florian Egger, Fran Farquharson, Frances Laube, Francesc Carreras Costa, Francesca de Micco, Francesca Bianchini, Francesca Pezzetta, Francesca Pietrucci, Francesco Orso, Francesco Pisano, Francis Burt, Francisca Patuleia Figueiras, Francisco Fernandez-Aviles, Francois Pierre Mongeon, Frans Van de Werf, Franziska Guenther, Fraser N Witherow, Fred Mohr, Frederico Dall'Orto, Fumiyuki Otsuka, G De La Morena, G Karthikeyan, Gabor Dekany, Gabor Kerecsen, Gabriel Galeote, Gabriel Grossmann, Gabriel Vorobiof, Gabriela Sanchez de Souza, Gabriela Guzman, Gabriela Zeballos, Gabriele Gabrielli, Gabriele Jakl-Kotauschek, Gail A Shammas, Gail Brandt, Gang Chen, Gary E Lane, Gary J Luckasen, Gautam Sharma, Gelmina Mikolaitiene, Gennie Yee, Georg Nickenig, George E Revtyak, George J Juang, Gerald Fletcher, Gerald Leonard, Gerard Patrick Devlin, Gerard Esposito, Gergely Ágoston, Gervasio Lamas, Geza Fontos, Ghada Mikhail, Gia Cobb, Gian Piero Perna, Gianpiero Leone, Giles Roditi, Gilles Barone-Rochette, Girish Mishra, Giuseppe Tarantini, Glenda Wong, Glenn S Hamroff, Glenn Rayos, Gong Cheng, Gonzalo Barge-Caballero, Goran Davidović, Goran Stankovic, Gordana Stevanovic, Grace Jingyan Wang, Grace M Young, Graceanne Wayser, Graciela Scaro, Graham S Hillis, Graham Wong, Grazyna Anna Szulczyk, Gregor Simonis, Gregory Kumkumian, Gretchen Ann Peichel, Grzegorz Gajos, Gudrun Steinmaurer, Guilherme G Rucatti, Guilherme Portugal, Guilhermina Cantinho Lopes, Guillem Pons Lladó, Gunnar Frostfelt, Gurpreet S Wander, Gurpreet Gulati, Gustavo Pucci, Hafidz Abd Hadi, Haibo Zhang, Haitao Wang, Halina Marciniak, Han Chen, Hanan Kerr, Hani Najm, Hanna Douglas, Hannah Phillips, Hao Dai, Haojian Dong, Haqeel Jamil, Harikrishnan Sivadasanpillai, Harry Suryapranata, Hassan Reda, Hayley Pomeroy, Heather Barrentine, Heather Golden, Heather Hurlburt, Heidi Wilson, Helen C Tucker, Helene Abergel, Hemalata Siddaram, Hermine Osseni, Herwig Schuchlenz, Hesong Zeng, Hicham Skali, Hilda Solomon, Hollie Horton, Holly Hetrick, Holly Little, Holly Park, Hongjie Chi, Hossam Mahrous, Howard A Levite, Hristo Pejkov, Huajun Li, Hugo Bloise-Adames, Hugo Marques, Hui Zhong, Hui-Min Zhang, Humayrah Hashim, Hung-I Yeh, Hussien El Fishawy, Ian Webb, Iftikhar Kullo, Igor O Grazhdankin, Ihab Hamzeh, Ikraam Hassan, Ikuko Ueda, Ileana L Pina, Ilona Tamasauskiene, Ilse Bouwhuis, Imran Arif, Ina Wenzelburger, Inês Zimbarra Cabrita, Ines Rodrigues, Inga H Robbins, Inga Soveri, Ingela Schnittger, Iqbal Karimullah, Ira M Dauber, Iram Rehman, Irena Peovska Mitevska, Irene Marthe Lang, Irina Subbotina, Irma Kalibataite-Rutkauskiene, Irni Yusnida, Isabel Estela Carvajal, Isabella C Palazzo, Isabelle Hogan, Isabelle Roy, Ishba Syed, Ishita Tejani, Ivan A Naryshkin, Ivana Jankovic, Iwona Niedzwiecka, J David Knight, Jacek Kusmierek, Jackie M White, Jackie Chow, Jacob Udell, Jacqueline E Tamis-Holland, Jacqueline Fannon, Jacquelyn A Quin, Jacquelyn Do, Jaekyeong Heo, Jakub Maksym, James E Davies, James H O'Keefe Jr, James J Jang, James Cha, James Harrison, James Hirsch, James Stafford, James Tatoulis, Jamie Rankin, Jan Henzel, Jan Orga, Jana Tancredi, Janaina Oliveira, Jane Burton, Jane Eckstein, Jane Marucci, Janet P Knight, Janet Blount, Janet Halliday, Janetta Kourzenkova, Janitha Raj, Jan-Malte Sinning, Jaqueline Pozzibon, Jaroslaw Drozdz, Jaroslaw Karwowski, Jason D Glover, Jason Loh Kwok, Jason T Call, Jason Linefsky, Jassira Gomes, Jati Anumpa, Javier J Garcia, Javier Courtis, Jay Meisner, K Jayakumar, Jayne Scales, Jean E Denaro, Jean Michel Juliard, Jean Ho, Jeanette K Stansborough, Jean-Michel Juliard, Jeanne Russo, Jeannette J M Schoep, Jeet Thambyrajah, Jeff Leimberger, Jeffery A Breall, Jeffrey A Kohn, Jeffrey C Milliken, Jeffrey Anderson, Jeffrey Blume, Jeffrey Kanters, Jeffrey Lorin, Jeffrey Moses, Jelena J Stepanovic, Jelena Celutkiene, Jelena Djokic, Jelena Stojkovic, Jenne M Jose, Jenne Manchery, Jennifer A Mull, Jennifer H Czerniak, Jennifer L Stanford, Jennifer Gillis, Jennifer Horst, Jennifer Isaacs, Jennifer Langdon, Jennifer Thomson, Jennifer Tomfohr, Jennifer White, Jen-Yuan Kuo, Jeremy Rautureau, Jerome Fleg, Jessica Berg, Jessica Rodriguez, Jessica Waldron, Jhina Patro, Jia Li, Jiajia Mao, Jiamin Liu, Jian'an Wang, Jianhua Li, Jianxin Zhang, Jie Qi, Jihyun Lyo, Jill Marcus, Jim Blankenship, Jing Zhang, Jingjing Liu, Jing-Yao Fan, Jiun-Yi Li, Jiwan Pradhan, Jiyan Chen, J M Rivera Caravaca, Jo Evans, Joan Garcia Picart, Joan Hecht, Joanna Jaroch, Joanna Zalewska, Joanne Kelly, Joanne Taaffe, João Reynaldo Abbud, João V Vitola, Joaquín V Peñafiel, Jocelyne Benatar, Jody Bindeman, Joe Sabik, Joel Klitch, Johann Christopher, Johannes Aspberg, John D Friedman, John F Beltrame, John F Heitner, John Joseph Graham, John R Davies, John Doan, John Kotter, John Kurian, John Mukai, John Pownall, Jolanta Sobolewska, Jon Kobashigawa, Jonathan L Goldberg, Jonathan W Bazeley, Jonathan Byrne, Jonathan Himmelfarb, Jonathan Leipsic, Jonean Thorsen, Jorge F Trejo Gutierrez, Jorge Escobedo, Jorik Timmer, José A Ortega-Ramírez, José Antonio Marin-Neto, Jose D Salas, Jose Enrique Castillo, Jose Francisco Saraiva, José J Cuenca-Castillo, Jose L Diez, José Luis Narro Villanueva, José Luiz da Vieira, José M Flores-Palacios, Jose Ramon Gonzalez, Jose Seijas Amigo, Jose Fragata, Josep Maria Padró, Josheph F X McGarvey Jr, Joseph Hannan, Joseph Sacco, Joseph Sweeny, Joseph Wiesel, Josephine D Abraham, Joshua P Loh, Joy Burkhardt, Joyce R White, Joyce Riestenberg-Smith, Judit Sebo, Judith L Meadows, Judith Wright, Judy Mae Foltz, Judy Hung, Judy Otis, Juergen Stumpf, Jui-Peng Tsai, Julia S Dionne, Julia de Aveiro Morata, Julie Bunke, Julie Morrow, Julio César Figal, Jun Fujita, Jun Jiang, Junhua Li, Junqing Yang, Juntima Euathrongchit, Jyotsna Garg, K Manjula Rani, K Preethi, Kaatje Goetschalckx, Kai Eggers, Kamalakar Surineni, Kanae Hirase, T R Kapilamoorthy, Karen Calfas, Karen Gratrix, Karen Hallett, Karen Hultberg, Karen Nugent, Karen Petrosyan, Karen Swan, Karolina Kryczka, Karolina Wojtczak-Soska, Karolina Wojtera, Karsten Lenk, Karthik Ramasamy, Katarzyna Łuczak, Katarzyna Malinowska, Kate Pointon, Kate Robb, Katherine Martin, Kathleen Claes, Kathryn Carruthers, Kathy E Siegel, Katia Drouin, Katie Fowler-Lehman, Kavita Rawat, Kay Rowe, Keiichi Fukuda, Keith A A Fox, Ken Mahaffey, Kendra Unterbrink, Kenneth Giedd, Kerrie Van Loo, Kerry Lee, Kerstin Bonin, Kevin R Bainey, Kevin T Harley, Kevin Anstrom, Kevin Chan, Kevin Croce, Kevin Landolfo, Kevin Marzo, Keyur Patel, Khaled Abdul-Nour, Khaled Alfakih, Khaled Dajani, Khaled Ziada, Khaula Baloch, Khrystyna Kushniriuk, Kian-Keong Poh, Kim F Ireland, Kim Holland, Kimberly Ann Byrne, Kimberly E Halverson, Kimberly Elmore, Kimberly Miller-Cox, Kiran Reddy, Kirsten J Quiles, Kirsty Abercrombie, Klaus Matschke, Konrad Szymczyk, Koo Hui Chan, Kotiboinna Preethi, Kozhaya Sokhon, Krissada Meemuk, Kristian Thygesen, Kristin M Salmi, Kristin Newby, Kristina Wippler, Kristine Arges, Kristine Teoh, Krystal Etherington, Krystyna Łoboz-Grudzień, Krzysztof W Reczuch, Krzysztof Bury, Krzysztof Drzymalski, Krzysztof Kukuła, Kuo-Tzu Sung, Kurt Huber, Ladda Douangvila, Lance Sullenberger, Larissa Miranda Trama, Laszlone Matics, Laura Drew, Laura Flint, Laura Keinaite, Laura Sarti, Laurel Kolakaluri, Lawrence M Phillips, Lawrence Friedman, Lawrence Phillips, Lazar Velicki, Leah Howell, Leandro C Maranan, Leanne Cox, Ledjalem Daba, Lei Zhang, Lekshmi Dharmarajan, Leo Bockeria, Leonardo Pizzol Caetano, Leonardo Bridi, Leonid L Bershtein, Leszek Sokalski, Li Hai Yan, Li Li, Lia Nijmeijer, Lidia Sousa, Lihong Xu, Lihua Zhang, Lili Zhang, Lilia Schiavi, Lilian Mazza Barbosa, Lillian L Khor, Lina Felix-Stern, Linda L Hall, Linda M Hollenweger, Linda Arcand, Linda Davidson-Ray, Linda Schwarz, Lindsey N Sikora, Lingping Chi, Lino Patricio, Liping Zhang, Lisa Chaytor, Lisa Hatch, Lisa McCloy, Lisa Wong, Liselotte Persson, Lixin Jiang, Liz Low, Ljiljana Pupic, Loïc Bière, Lorenzo Monti, Lori Christensen, Lori Pritchard, Loriane Black, Lori-Ann Desimone, Lori-Ann Larmand, Lorraine McGregor, Louise Morby, Louise Thomson, Luc Harvey, Luciana de Pádua Baptista, Lucilla Garcia, Ludivine Eliahou, Ludmila Helmer, Luis F Smidt, Luis Bernanrdes, Luis Guzman, Luiz A Carvalho, Luyang Xiong, Lynette L Teo, Lynn M Neeson, Lynne Winstanley, M Barbara Srichai-Parsia, M Quintana Giner, M Sowjanya Reddy, M Valdés Chávarri, M Grazia Rossi, Maarten Simoons, Maayan Konigstein, Maciej Lesiak, Maciej Olsowka, Mafalda Selas, Magalie Corfias, Magdalena Madero Rovalo, Magdalena Łanocha, Magdalena Miller, Magdalena Misztal-Teodorczyk, Magdalena Rantinella, Magdy Abdelhamid, Magnolia Jimenez, Mahboob Alam, Mahevamma Mylarappa, Mahfouz El Shahawy, Mahmoud Mohamed, Mahmud Al-Bustami, Majo X Joseph, Malgorzata Frach, Małgorzta Celińska-Spodar, Malte Helm, Manas Chacko, Mandy Murphy, Manitha Vinod, Manjula Rani, Manu Dhawan, Manuela Mombelli, Marcel Weber, Marcello Galvani, Marcelo Jamus Rodrigues, Marcia F Dubin, Marcia F Werner Bayer, Marcin Szkopiak, Marco Antonio Monsalve, Marco Bizzaro Santos, Marco Magnoni, Marco Marini, Marco Sicuro, Marco Zenati, Marcos Valério Coimbra Resende, Marek Roik, Margalit Bentzvi, Margaret Gilsenan, Margaret Iraola, Margot C Quinn, Maria A Alfonso, Maria Antonieta Pereira Moraes, María Dolores Martínez-Ruíz, María Fernanda Canales, Maria Inês Caetano, Maria P Corral, Maria Pérez García, Maria Victoria Actis, Maria Aguirre, Maria Andreasson, Maria Aprile, Maria Colton, Maria Eugenia Martin, Maria Lasala, Maria Lorenzo, Maria Posada, Maria Shier, Maria Thottam, Mariana V Furtado, Mariana Yumi Okada, Marianna D A Dracoulakis, Marianne De Andrade, Mariano Rubio, Marie Essermark, Marielle Scherrer-Crosbie, Marija T Petrovic, Marija Zdravkovic, Marilyn Black, Marina Garcia, Mario J Garcia, Mariola Szulik, Marisa Orgera, Mark A de Belder, Mark Harbinson, Mark Hyun, Mark Peterson, Mark Xavier, Marlowe Mosley, Marta Capinha, Marta Marcinkiewicz-Siemion, Marta Swiderek, Martha Meyer, Martina Ceseri, Martina Tricoli, Marvin Kronenberg, Mary Williams, Mary Ann Champagne, Mary Colleen Rogge, Mary R Soltau, Mary Streif, Massimo Villella, Massoud Leesar, Matei Claudia, Mateusz Solecki, Matías Nicolás Mungo, Matthew Wall Jr, Matthew Budoff, Matthew Jezior, Matthew Luckie, Matthias Friedrich, Mauren P Haeffner, Maximilian Tscharre, Max-Paul Winter, Mayana Almeida, Mayil S Krishnam, Mayuri Patel, Meenakshi Mishra, Megan Manocchia, Meghana Kakade, Melanie J Munro, Melissa D Chaplin, Melissa LeFevre, Mervyn Andiapen, Michael A Gibson, Michael B Rubens, Michael C Turner, Michael D Shapiro, Michael W Lee, Michael Berlowitz, Michael Davidson, Michael Mack, Michael McDaniel, Michael Mumma, Michal Wlodarczyk, Michel G Khouri, Michel S Slama, Michele Rawlins, Michelle M Bonner, Michelle M Seib, Michelle Chang, Michelle Crowder, Michelle Dixon, Michelle Mayon, Michelle McEvoy, Michelle Yee, Miguel M Fernandes, Miguel Nobre Menezes, Miguel Souto Bayarri, Miguel Barrero, Mikhail T Torosoff, Milan R Dobric, Milan Dobric, Milica Nikola Dekleva, Milind Avdhoot Gadkari, Millie Gomez, Min Tun Kyaw, Miriam Brooks, Miroslav Stevo Martinovic, Mitchel B Lustre, Mohammad Tariq Vakani, Mohammad El-Hajjar, Mohammed Al-Amoodi, Mohammed Hussain, Mohammed Saleem, Moisés Blanco-Calvo, Moisés Jiménez-Santos, Mona Bhatia, Monica Rosca, Monika Laukyte, Montserrat Gracida Blanca, Montserrat Vila Perales, Mouaz H Al-Mallah, Moysés de Oliveira Filho, Mpiko Ntsekhe, Muhamed Saric, Mulei Chen, Myriam Brousseau, Myrthes Emy Takiuti, Nada Cemerlic-Adjic, Nadia Asif, Nadia Gakou, Nafisa Hussain, Nana O Katamadze, Nancy L Clapp, Nancy Aedy, Nandita Nataraj, Nanette K Wenger, Naomi Uchida, Nasrul Ismail, Natalia S Oliveira, Natalia de Carvalho Maffei, Natalie Spitzer, Natasha C Putnam, Naved Aslam, Neamat Mowafy, Neeraj Pandit, Neeraj Parakh, Nevena Garcevic, Ngaire Meadows, Nhi N Tran, Nicholas Danchin, Nicki Lakeman, Nicola Johnston, Nicolas W Shammas, Nicole Saint Vrestil, Nicole Deming, Nier Zhong, Niket Patel, Nikola N Boskovic, Nikolaos Karogiannis, Nikos Werner, Nina Johnston, Ning Zhang, Ning Zhou, Niree Hindoyan, Nirmal Kumar, Nitika Chadha, Nitish Naik, Nodira Aripova, Noloyiso Mtana, Nona A Eskelson, Noor Syamira Mokhtar, Noppon Taksaudom, Nor Asiah Basri, Nora Marchelletta, Norma Hogg, Nungshi Jungla, Nuno Ferreira, Oksana A Lubyanaya, Olga B Nikolaeva, Olga Cañavate, Olga Sobrino, Olga Walesiak, Olga Walter, Olga Zdończyk, Olivia J Lim, Olivia Anaya, Olivia Mancilla, Olivier Dubourg, Olugbenga Bello, Omar Almousalli, Omar Thompson, Oni Olurinde, Or Harel, Osama Raheem, Oscar Méndiz, Óscar Prada-Delgado, Oz Shapira, P Christian Schulze, Pachara Panpunuan, Pal Maurovich-Horvat, Pallav Garg, Paloma Moraga, Pam Singh, Pamela Julian, Pamela Ouyang, Pamela Sigel, Pamela Woodard, Panpan Zhou, Paola Emanuela Poggio, Paola Smanio, Paolo Calabro, Paramjit Jeetley, Pascal Goube, Patricia K Nguyen, Patricia Alarie, Patricia Arakelian, Patricia Arsenault, Patricia Blaise, Patricia Brito, Patricia Cowper, Patricia Endsley, Patricia Mieses, Patrick B Alexander, Patrick Donnelly, Patrick Wilmot, Patrycja Lebioda, Paul C Gordon, Paul Der Mesropian, Paul Galiwango, Paul Hauptman, Paul Kennedy, Paula Beardsley, Paula García-González, Paulo Cury Rezende, Paulo Ricardo Caramori, Pavel S Kozlov, Pedro Canas Silva, Pedro Gabriel Melo Barros E Silva, Pedro Píccaro de Oliveira, Pedro Carvalho, Pedro Modas, Pedro Rio, Peeyush Jain, Peiyu He, Peter A McCullough, Peter H Stone, Peter M Pollak, Peter Douglass, Peter Henriksen, Peter OKane, Peter Ong, Philip Jones, Philip Rogal, Philippe Généreux, Philippe Menasche, Philippe Rheault, Phoebe Goold, Pierre Gervais, Pierre Michaud, Pilar Calvillo, Ping Chai, Piotr Jakubowski, Piotr Pruszczyk, Piotr Slomka, Piyamitr Sritara, Poay-Huan Loh, Poonam Sonawane, Pouneh Samadi, Pragnesh P Parikh, Prakash Deedwania, Pranav M Patel, Praneeth Polamuri, Pratiksha Sharma, Precilia Vasquez, Preeti Kamath, Prince Thomas, Priyadarshani Arambam, Puja K Mehta, Purvez Grant, Pushpa Naik, Qi Zhong, Qian Zhao, Qiang Zhou, Qianqian Yuan, Qin Yu, Qingxian Li, Qiulan Xie, Qiutang Zeng, R J Vindhya, R James Gerlach, Rachel King, Rada Vučić, Radmila Lyubarova, Radoslaw Pracon, 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Jeffrey Kanters, Jeffrey Lorin, Jeffrey Moses, Jelena J Stepanovic, Jelena Celutkiene, Jelena Djokic, Jelena Stojkovic, Jenne M Jose, Jenne Manchery, Jennifer A Mull, Jennifer H Czerniak, Jennifer L Stanford, Jennifer Gillis, Jennifer Horst, Jennifer Isaacs, Jennifer Langdon, Jennifer Thomson, Jennifer Tomfohr, Jennifer White, Jen-Yuan Kuo, Jeremy Rautureau, Jerome Fleg, Jessica Berg, Jessica Rodriguez, Jessica Waldron, Jhina Patro, Jia Li, Jiajia Mao, Jiamin Liu, Jian'an Wang, Jianhua Li, Jianxin Zhang, Jie Qi, Jihyun Lyo, Jill Marcus, Jim Blankenship, Jing Zhang, Jingjing Liu, Jing-Yao Fan, Jiun-Yi Li, Jiwan Pradhan, Jiyan Chen, J M Rivera Caravaca, Jo Evans, Joan Garcia Picart, Joan Hecht, Joanna Jaroch, Joanna Zalewska, Joanne Kelly, Joanne Taaffe, João Reynaldo Abbud, João V Vitola, Joaquín V Peñafiel, Jocelyne Benatar, Jody Bindeman, Joe Sabik, Joel Klitch, Johann Christopher, Johannes Aspberg, John D Friedman, John F Beltrame, John F Heitner, John Joseph Graham, John R Davies, John Doan, John Kotter, John Kurian, John Mukai, John Pownall, Jolanta Sobolewska, Jon Kobashigawa, Jonathan L Goldberg, Jonathan W Bazeley, Jonathan Byrne, Jonathan Himmelfarb, Jonathan Leipsic, Jonean Thorsen, Jorge F Trejo Gutierrez, Jorge Escobedo, Jorik Timmer, José A Ortega-Ramírez, José Antonio Marin-Neto, Jose D Salas, Jose Enrique Castillo, Jose Francisco Saraiva, José J Cuenca-Castillo, Jose L Diez, José Luis Narro Villanueva, José Luiz da Vieira, José M Flores-Palacios, Jose Ramon Gonzalez, Jose Seijas Amigo, Jose Fragata, Josep Maria Padró, Josheph F X McGarvey Jr, Joseph Hannan, Joseph Sacco, Joseph Sweeny, Joseph Wiesel, Josephine D Abraham, Joshua P Loh, Joy Burkhardt, Joyce R White, Joyce Riestenberg-Smith, Judit Sebo, Judith L Meadows, Judith Wright, Judy Mae Foltz, Judy Hung, Judy Otis, Juergen Stumpf, Jui-Peng Tsai, Julia S Dionne, Julia de Aveiro Morata, Julie Bunke, Julie Morrow, Julio César Figal, Jun Fujita, Jun Jiang, Junhua Li, Junqing Yang, Juntima Euathrongchit, Jyotsna Garg, K Manjula Rani, K Preethi, Kaatje Goetschalckx, Kai Eggers, Kamalakar Surineni, Kanae Hirase, T R Kapilamoorthy, Karen Calfas, Karen Gratrix, Karen Hallett, Karen Hultberg, Karen Nugent, Karen Petrosyan, Karen Swan, Karolina Kryczka, Karolina Wojtczak-Soska, Karolina Wojtera, Karsten Lenk, Karthik Ramasamy, Katarzyna Łuczak, Katarzyna Malinowska, Kate Pointon, Kate Robb, Katherine Martin, Kathleen Claes, Kathryn Carruthers, Kathy E Siegel, Katia Drouin, Katie Fowler-Lehman, Kavita Rawat, Kay Rowe, Keiichi Fukuda, Keith A A Fox, Ken Mahaffey, Kendra Unterbrink, Kenneth Giedd, Kerrie Van Loo, Kerry Lee, Kerstin Bonin, Kevin R Bainey, Kevin T Harley, Kevin Anstrom, Kevin Chan, Kevin Croce, Kevin Landolfo, Kevin Marzo, Keyur Patel, Khaled Abdul-Nour, Khaled Alfakih, Khaled Dajani, Khaled Ziada, Khaula Baloch, Khrystyna Kushniriuk, Kian-Keong Poh, Kim F Ireland, Kim Holland, Kimberly Ann Byrne, Kimberly E Halverson, Kimberly Elmore, Kimberly Miller-Cox, Kiran Reddy, Kirsten J Quiles, Kirsty Abercrombie, Klaus Matschke, Konrad Szymczyk, Koo Hui Chan, Kotiboinna Preethi, Kozhaya Sokhon, Krissada Meemuk, Kristian Thygesen, Kristin M Salmi, Kristin Newby, Kristina Wippler, Kristine Arges, Kristine Teoh, Krystal Etherington, Krystyna Łoboz-Grudzień, Krzysztof W Reczuch, Krzysztof Bury, Krzysztof Drzymalski, Krzysztof Kukuła, Kuo-Tzu Sung, Kurt Huber, Ladda Douangvila, Lance Sullenberger, Larissa Miranda Trama, Laszlone Matics, Laura Drew, Laura Flint, Laura Keinaite, Laura Sarti, Laurel Kolakaluri, Lawrence M Phillips, Lawrence Friedman, Lawrence Phillips, Lazar Velicki, Leah Howell, Leandro C Maranan, Leanne Cox, Ledjalem Daba, Lei Zhang, Lekshmi Dharmarajan, Leo Bockeria, Leonardo Pizzol Caetano, Leonardo Bridi, Leonid L Bershtein, Leszek Sokalski, Li Hai Yan, Li Li, Lia Nijmeijer, Lidia Sousa, Lihong Xu, Lihua Zhang, Lili Zhang, Lilia Schiavi, Lilian Mazza Barbosa, Lillian L Khor, Lina Felix-Stern, Linda L Hall, Linda M Hollenweger, Linda Arcand, Linda Davidson-Ray, Linda Schwarz, Lindsey N Sikora, Lingping Chi, Lino Patricio, Liping Zhang, Lisa Chaytor, Lisa Hatch, Lisa McCloy, Lisa Wong, Liselotte Persson, Lixin Jiang, Liz Low, Ljiljana Pupic, Loïc Bière, Lorenzo Monti, Lori Christensen, Lori Pritchard, Loriane Black, Lori-Ann Desimone, Lori-Ann Larmand, Lorraine McGregor, Louise Morby, Louise Thomson, Luc Harvey, Luciana de Pádua Baptista, Lucilla Garcia, Ludivine Eliahou, Ludmila Helmer, Luis F Smidt, Luis Bernanrdes, Luis Guzman, Luiz A Carvalho, Luyang Xiong, Lynette L Teo, Lynn M Neeson, Lynne Winstanley, M Barbara Srichai-Parsia, M Quintana Giner, M Sowjanya Reddy, M Valdés Chávarri, M Grazia Rossi, Maarten Simoons, Maayan Konigstein, Maciej Lesiak, Maciej Olsowka, Mafalda Selas, Magalie Corfias, Magdalena Madero Rovalo, Magdalena Łanocha, Magdalena Miller, Magdalena Misztal-Teodorczyk, Magdalena Rantinella, Magdy Abdelhamid, Magnolia Jimenez, Mahboob Alam, Mahevamma Mylarappa, Mahfouz El Shahawy, Mahmoud Mohamed, Mahmud Al-Bustami, Majo X Joseph, Malgorzata Frach, Małgorzta Celińska-Spodar, Malte Helm, Manas Chacko, Mandy Murphy, Manitha Vinod, Manjula Rani, Manu Dhawan, Manuela Mombelli, Marcel Weber, Marcello Galvani, Marcelo Jamus Rodrigues, Marcia F Dubin, Marcia F Werner Bayer, Marcin Szkopiak, Marco Antonio Monsalve, Marco Bizzaro Santos, Marco Magnoni, Marco Marini, Marco Sicuro, Marco Zenati, Marcos Valério Coimbra Resende, Marek Roik, Margalit Bentzvi, Margaret Gilsenan, Margaret Iraola, Margot C Quinn, Maria A Alfonso, Maria Antonieta Pereira Moraes, María Dolores Martínez-Ruíz, María Fernanda Canales, Maria Inês Caetano, Maria P Corral, Maria Pérez García, Maria Victoria Actis, Maria Aguirre, Maria Andreasson, Maria Aprile, Maria Colton, Maria Eugenia Martin, Maria Lasala, Maria Lorenzo, Maria Posada, Maria Shier, Maria Thottam, Mariana V Furtado, Mariana Yumi Okada, Marianna D A Dracoulakis, Marianne De Andrade, Mariano Rubio, Marie Essermark, Marielle Scherrer-Crosbie, Marija T Petrovic, Marija Zdravkovic, Marilyn Black, Marina Garcia, Mario J Garcia, Mariola Szulik, Marisa Orgera, Mark A de Belder, Mark Harbinson, Mark Hyun, Mark Peterson, Mark Xavier, Marlowe Mosley, Marta Capinha, Marta Marcinkiewicz-Siemion, Marta Swiderek, Martha Meyer, Martina Ceseri, Martina Tricoli, Marvin Kronenberg, Mary Williams, Mary Ann Champagne, Mary Colleen Rogge, Mary R Soltau, Mary Streif, Massimo Villella, Massoud Leesar, Matei Claudia, Mateusz Solecki, Matías Nicolás Mungo, Matthew Wall Jr, Matthew Budoff, Matthew Jezior, Matthew Luckie, Matthias Friedrich, Mauren P Haeffner, Maximilian Tscharre, Max-Paul Winter, Mayana Almeida, Mayil S Krishnam, Mayuri Patel, Meenakshi Mishra, Megan Manocchia, Meghana Kakade, Melanie J Munro, Melissa D Chaplin, Melissa LeFevre, Mervyn Andiapen, Michael A Gibson, Michael B Rubens, Michael C Turner, Michael D Shapiro, Michael W Lee, Michael Berlowitz, Michael Davidson, Michael Mack, Michael McDaniel, Michael Mumma, Michal Wlodarczyk, Michel G Khouri, Michel S Slama, Michele Rawlins, Michelle M Bonner, Michelle M Seib, Michelle Chang, Michelle Crowder, Michelle Dixon, Michelle Mayon, Michelle McEvoy, Michelle Yee, Miguel M Fernandes, Miguel Nobre Menezes, Miguel Souto Bayarri, Miguel Barrero, Mikhail T Torosoff, Milan R Dobric, Milan Dobric, Milica Nikola Dekleva, Milind Avdhoot Gadkari, Millie Gomez, Min Tun Kyaw, Miriam Brooks, Miroslav Stevo Martinovic, Mitchel B Lustre, Mohammad Tariq Vakani, Mohammad El-Hajjar, Mohammed Al-Amoodi, Mohammed Hussain, Mohammed Saleem, Moisés Blanco-Calvo, Moisés Jiménez-Santos, Mona Bhatia, Monica Rosca, Monika Laukyte, Montserrat Gracida Blanca, Montserrat Vila Perales, Mouaz H Al-Mallah, Moysés de Oliveira Filho, Mpiko Ntsekhe, Muhamed Saric, Mulei Chen, Myriam Brousseau, Myrthes Emy Takiuti, Nada Cemerlic-Adjic, Nadia Asif, Nadia Gakou, Nafisa Hussain, Nana O Katamadze, Nancy L Clapp, Nancy Aedy, Nandita Nataraj, Nanette K Wenger, Naomi Uchida, Nasrul Ismail, Natalia S Oliveira, Natalia de Carvalho Maffei, Natalie Spitzer, Natasha C Putnam, Naved Aslam, Neamat Mowafy, Neeraj Pandit, Neeraj Parakh, Nevena Garcevic, Ngaire Meadows, Nhi N Tran, Nicholas Danchin, Nicki Lakeman, Nicola Johnston, Nicolas W Shammas, Nicole Saint Vrestil, Nicole Deming, Nier Zhong, Niket Patel, Nikola N Boskovic, Nikolaos Karogiannis, Nikos Werner, Nina Johnston, Ning Zhang, Ning Zhou, Niree Hindoyan, Nirmal Kumar, Nitika Chadha, Nitish Naik, Nodira Aripova, Noloyiso Mtana, Nona A Eskelson, Noor Syamira Mokhtar, Noppon Taksaudom, Nor Asiah Basri, Nora Marchelletta, Norma Hogg, Nungshi Jungla, Nuno Ferreira, Oksana A Lubyanaya, Olga B Nikolaeva, Olga Cañavate, Olga Sobrino, Olga Walesiak, Olga Walter, Olga Zdończyk, Olivia J Lim, Olivia Anaya, Olivia Mancilla, Olivier Dubourg, Olugbenga Bello, Omar Almousalli, Omar Thompson, Oni Olurinde, Or Harel, Osama Raheem, Oscar Méndiz, Óscar Prada-Delgado, Oz Shapira, P Christian Schulze, Pachara Panpunuan, Pal Maurovich-Horvat, Pallav Garg, Paloma Moraga, Pam Singh, Pamela Julian, Pamela Ouyang, Pamela Sigel, Pamela Woodard, Panpan Zhou, Paola Emanuela Poggio, Paola Smanio, Paolo Calabro, Paramjit Jeetley, Pascal Goube, Patricia K Nguyen, Patricia Alarie, Patricia Arakelian, Patricia Arsenault, Patricia Blaise, Patricia Brito, Patricia Cowper, Patricia Endsley, Patricia Mieses, Patrick B Alexander, Patrick Donnelly, Patrick Wilmot, Patrycja Lebioda, Paul C Gordon, Paul Der Mesropian, Paul Galiwango, Paul Hauptman, Paul Kennedy, Paula Beardsley, Paula García-González, Paulo Cury Rezende, Paulo Ricardo Caramori, Pavel S Kozlov, Pedro Canas Silva, Pedro Gabriel Melo Barros E Silva, Pedro Píccaro de Oliveira, Pedro Carvalho, Pedro Modas, Pedro Rio, Peeyush Jain, Peiyu He, Peter A McCullough, Peter H Stone, Peter M Pollak, Peter Douglass, Peter Henriksen, Peter OKane, Peter Ong, Philip Jones, Philip Rogal, Philippe Généreux, Philippe Menasche, Philippe Rheault, Phoebe Goold, Pierre Gervais, Pierre Michaud, Pilar Calvillo, Ping Chai, Piotr Jakubowski, Piotr Pruszczyk, Piotr Slomka, Piyamitr Sritara, Poay-Huan Loh, Poonam Sonawane, Pouneh Samadi, Pragnesh P Parikh, Prakash Deedwania, Pranav M Patel, Praneeth Polamuri, Pratiksha Sharma, Precilia Vasquez, Preeti Kamath, Prince Thomas, Priyadarshani Arambam, Puja K Mehta, Purvez Grant, Pushpa Naik, Qi Zhong, Qian Zhao, Qiang Zhou, Qianqian Yuan, Qin Yu, Qingxian Li, Qiulan Xie, Qiutang Zeng, R J Vindhya, R James Gerlach, Rachel King, Rada Vučić, Radmila Lyubarova, Radoslaw Pracon, Raewyn Fisher, Rafael Beyar, Rafael Diaz, Rafael Selgas, Raffaele Bugiardini, Raffaele Fanelli, Raisa Kavalakkat, V S Rajalekshmi, Rajat S Barua, Rajeev Menon, Rajesh Gopalan Nair, Rajesh Francis, Rajiv Narang, Rakesh Yadav, Ralph Alan Huston, T Ramakrishnan, Ramesh de Silva, Rami El Mahmoud, Ramiro Carvalho, Ramon de Jesús-Pérez, Ramona Stevens, Ran Leng, Ranjan Kachru, Ranjit Kumar Nath, Raquel Sanchez, Raven R Dwyer, Raven Lee, Ray Wyman, Raymond C Wong, Raymond W Little, Raymundo Ocaranza Sanchez, Rebecca J Wimmer, Rebecca Bariciano, Rebecca Otis, Rebekah R Herrmann, Reem Yunis, Reinette Hampson, Renato Abdala Karam, Renee C Hessian, Renee Kaneshiro, Reshma Ravindran, Reto Andreas Gamma, Reyna Bhandari, Reza Arsanjani, Ricardo L Lopes, Ricardo Mendes Oliveira, Ricardo Costa, Richa Bhatt, Richard F Davies, Richard H J Trimlett, Richard Goldweit, Rik Hermanides, Rine Nakanishi, Rinu R Sidh, Risha Patel, Rita Coram, Rizwan A Siddiqui, Rob S Beanlands, Robert J Hamburger, Robert K Riezebos, Robert M Donnino, Robert Bojar, Robert Chilton, Robert Guyton, Robert Henderson, Robert Kornberg, Robert Leber, Robert Mao, Robert Stenberg, Roberta P Santos, Roberto René Favaloro, Roberto Amati, Rodolfo G S D Lima, Rodrigo J Cerci, Rogerio Tumelero, Rohit Tandon, Roma Tewari, Romalisa Miranda-Peats, Ron Wald, Ronald A Mastouri, Ronald G Morford, Ronald G Schwartz, Ronald P Pedalino, Rongrong Hu, Ronnell A Hansen, Ronny A Cohen, Rory Hachamovitch, Rosa Homem, Rosa Sandonato, Rosane Laimer, Rosann Gans, Roxanne Yost, Roy Mathew, Rubén Baleón-Espinosa, Ruben Ramos, Rubine Gevorgyan, Rui Ferreira, Rui Jing, Ruth Pérez-Fernández, S K Dwivedi, S Ramakrishnan, Saadat Khan, Sabahat Bokhari, Sabu Thomas, Sadath Lubna, Sajeeda Parveen Khan, Sajeev Chakanalil Govindan, Saket Girotra, Saleem Kassam, Sallie Canada, Salvador Cruz-Flores, Samaa Mohamed, Samantha Ly, Sameh El Kaffas, Samia Massalha, Sampoornima Setty, Samuel Nwosu, Sandeep Seth, Sandeep Singh, Sander R Niehe, Sandra M Rivest, Sandra S Zier, Sandra Ahoud, Sandy Carr, Sanjay Ganapathi, Sanjay Shetty, Sanjeev Sharma, Santa Jimenez, Santhosh Satheesh, Santiago A Garcia, Sara Fernandez, Sara Karlsson, Sara Salkind, Sara Temiyasathit, Sarah Medina Rodriguez, Sarah Beaudry, Sarah Hadjih, Sarah Williams, Sarah Zahrani, Sarju Ralhan, Sasa Hinic, Sasko Kedev, Satinder Singh, Satoshi Yasuda, Satvic Cholenahally Manjunath, Sau Lee, Scott M Kaczkowski, Scott Kinlay, Sean W Hayes, Sebastian Sobczak, Senait Asier, Sergey A Sayganov, Seth I Sokol, Shaheen Pandie, Shaiful Azmi Yahaya, Shamir Mehta, Shao-Ping Nie, Sharad Chandra, Sharder Islam, Sharon Tai, Sheetal Rupesh Karwa, Sheri Ussery, Sheromani Bajaj, Sherron C Crook, Shigeyuki Nishimura, Shintaro Nakano, Shirin Heydari, Shiv Kumar Choudhary, Shivali Patel, Shobana Ganesan, Shruti Pandey, Shuyang Zhang, Shweta Hande, Siddharth Gadage, Sik-Yin V Tan, Silvia Zottis Poletti, Silvia Riera, Silvia Valbuena, Simon Walsh, Simona Maspoli, Simone Savaris, Si-Ting Feng, So Yang Cho, Solomon Yakubov, Songlin Zhu, Songtao Wang, Sonia Guerrero, Sonika Gupta, Sonja Salinger Martinovic, Sonya Brons, Sorin Brener, Sothinathan Gurunathan, Souheil Saba, Soundarya Nayak, Sowjanya Reddy, Srinivasa Potluri, Sriram Sudarshan, Srun Kuanprasert, Stacie Van Oosterhout, Stamatios Lerakis, Stanley E Cobos, Stefan C Bertog, Stefan M Simović, Stefan Weikl, Stefano Di Marco, Stefano Provasoli, Stephanie A Tirado, Stephanie C Boer, Stephanie M Lane, Stephanie Ferket, Stephanie Kelly, Stephanie Wasmiller, Stephen H McKellar, Stephen P Hoole, Stephen Fremes, Stephen Preston, Steve Leung, Steven A Fein, Steven J Lindsay, Steven P Sedlis, Steven Giovannone, Steven Michael, Steven Weitz, Stijn van Vugt, Subhash Banerjee, Sudhir Naik, Suellen Hosino, Sukie Desire, Sukit Yamwong, Suku T Thambar, Sulagna Mookherjee, Suman Singh, Sundeep Mishra, Sunil Kumar Verma, Supap Kulthawong, Supatchara Khwakhong, Surendra Naik, Suresh Babu, Surin Woragidpoonpol, Suryaprakash Narayanappa, Susan Derbyshire, Susan Gent, Susan Mathus, Susan Milbrandt, Susan Moore, Susan Regan, Susan Stinson, Susan Webber, Susana Silva, Susanna Stevens, Susanne Gruensfelder, Suthara Aramcharoen, Suvarna Kolhe, Suzana Tavares, Suzanne Arnold, Suzanne Welsh, Svetlana Apostolovic, Swapna Kunhunny, Ta-Chuan Hung, Taissa Zappernick, Tali Sharir, Talita Silva, Tamara Colaiácovo Soares, Tapan Umesh Pillay, Tarun K Mittal, Tatiana Trifonova, Tauane Bello Duarte, Tauqir Huk, Téodora Dutoiu, Terrance Chua, Terry Weyand, Thabitha Charles, Theodoros Kofidis, Theresa McCreary, Thierry Lefevre, Thippeekaa Arumairajah, Thitipong Tepsuwan, Thomas J Mulhearn, Thomas M Meyer, Thomas P Rocco, Thomas R Downes, Thomas Crain, Thomas Haldis, Thomas Mathew, Thomas Redick, Thounaojam Indira Devi, Thuraia Nageh, Tia Cauthren, Tiago Silva, Tiffany Little, Tijana Andric, Tina Harding, Titus Lau, Tiziana Formisano, Tiziano Moccetti, Tomasz Ciurus, Tomasz Mazurek, Tomasz Tarchalski, Toshiyuki Nagai, Tri Tran, Tricia Youn, Trish Tucker, Trudie Milner, Tuhina Bose, Tushar Kotecha, Udo Sechtem, Uma S Valeti, Umberto Cucchini, Umesh Badami, Upendra Kaul, V K Bahl, V S Narain, Valentina Casali, Valeria Godoy, Valerie Robesyn, Vamshi P Priya, Vandana Yadav, Vera McKinney, Veronica De Lenges, Veronica Tinnirello, Vicente Miro, Victor Navarro, Victoria Gumerova, Victoria Hernandez, Vidya Seeratan, Vijay Kumar, Vikentiy Y Kozulin, Viktoria Bulkley, Vilmar Veiga Jr, Vincent Setang, C P Vineeth, Virginai Pubull Nuñez, Virginia Fernández-Figares, Vitor Gomes, Viviana Gabriel, Viviane Dos Santos, Viviane Almeida, Vlad A Iliescu, Vladan Mudrenovic, Vladimir Dzavik, Vojislav L Giga, Walter Enrique Mogrovejo, Wan Xian Chan, Wanda C Marfori, Wanda Parker, Warangkana Mekara, Wassim Nona, Wayne Old, Wayne Pennachi, Weerachai Nawarawong, Wei Chen, Wei Su, Weibing Xing, Wei-Ren Lan, Wenda Crawford, Wendy L Stewart, Wendy Drewes, Wenhua Lin, William B Abernethy, William D Salerno, William F Fearon, William Vergoni, William Weintraub, Winnie C Sia, Wlodzimierz J Musial, Xacobe Flores-Ríos, Xavier Garcia-Moll Marimon, Xi Su, Xiang Ma, Xiangqiong Gu, Xiao Wang, Xiaomei Li, Xiaowei Yao, Xin Fu, Xin Su, Xin Zeng, Xinchun Yang, Xiuhong Li, Xuehua Fang, Xutong Wang, Yaming Geng, Yan Yan, Yanek Pépin-Dubois, Yanfu Wang, Yang Wang, Yanmeng Tian, Yaping Huang, Yechen Han, Yesenia Zambrano, Yi-Hsuan Yang, Ying Tung Sia, Yining Yang, Yitong Ma, Yolayfi Peralta, Yongjian Wu, Yu Kunwu, Yu Zhao, Yudong Peng, Yueh-Hung Lin, Yulan Zhao, Yumei Dong, Yunhai Zhao, Yutthaphan Wannasopha, Yvonne Taul, Zakir Sahul, Zalina Kudzoeva, Zbigniew Kalarus, Zeljko Z Markovic, Zhen Huang, Zheng Ji, Zhenyu Liu, Zhou Yue, Zhulin Zhang, Zhuxi Li, Zile Singh Meharwal, Ziliang Bai, Zixiang Yu, Zohra Huda, Zoltan Davidovits
Subjects: Male, Cardiac Catheterization, Computed Tomography Angiography, medicine.medical_treatment, Myocardial Ischemia, Coronary Disease, Coronary Artery Disease, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, Coronary Angiography, ISCHEMIA Research Group, law.invention, Angina, Coronary artery disease, 0302 clinical medicine, Randomized controlled trial, law, Cardiovascular Disease, Myocardial Revascularization, 030212 general & internal medicine, Coronary Artery Bypass, 11 Medical and Health Sciences, Cardiac catheterization, General Medicine, Middle Aged, humanities, Cardiovascular Diseases, Cardiology, Female, Human, medicine.medical_specialty, Ischemia, Article, 03 medical and health sciences, Geriatric cardiology, Percutaneous Coronary Intervention, General & Internal Medicine, Internal medicine, medicine, Humans, Angina, Unstable, Aged, business.industry, Coronary Artery Bypa, Percutaneous coronary intervention, Bayes Theorem, medicine.disease, Heart failure, Quality of Life, business
Abstract: BACKGROUND: Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS: We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS: Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, -1.8 percentage points; 95% CI, -4.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS: Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).
Published: 2020

47. Laparoscopic intraperitoneal mesh repair of a large incisional hernia in a kidney transplantation patient: A case report

Author: Tomoharu Miyashita, Ryosuke Kin, Yoritaka Fujii, Hiroyuki Takamura, Akifumi Hashimoto, Takashi Miyata, Daisuke Kaida, Seiko Miura, Hisashi Nishiki, Yasuto Tomita, Naohiko Nakamura, Nobuhiko Ueda, Jun Fujita, and Hideto Fujita
Subjects: medicine.medical_specialty, Mesh repair, Incisional hernia, business.industry, Abdominal wall defect, Transplanted kidney, General Medicine, 030230 surgery, medicine.disease, Surgery, Abdominal wall, 03 medical and health sciences, surgical procedures, operative, 0302 clinical medicine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, medicine, Abdomen, Hernia, business, Kidney transplantation
Abstract: A 73-year-old woman presented to our hospital because of painful bulging in the right lower abdomen, and developed a 17 × 12 cm incisional hernia after kidney transplantation using right oblique incision. Laparoscopic intraperitoneal onlay mesh (IPOM) repair was performed. Since a transplanted kidney is close to the abdominal wall defect, the space between the transplanted kidney and the abdominal wall was peeled off to secure enough space for the mesh to be place. After that the fascial defect was detected precisely, and the polypropylene-polyglycolic acid composite mesh was fixed with 3 cm overlapping of the hernia ring by non-absorbable tacks. The patient was discharged 9 days after surgery. In general, abdominal incisional hernias after kidney transplantation are relatively large with boundary defect of abdominal wall ensuing between the abdominal and allograft. However, laparoscopic IPOM repair of incisional hernia after kidney transplantation can be performed safely and effectively.
Published: 2021

48. Correlation between cerebral blood flow and olfactory function in mild cognitive impairment and Alzheimer's disease

Author: Naoto Kamimura, Tetsuo Kashibayashi, Ryuichi Takahashi, Hiroaki Kazui, Ryoko Fujito, Jun Fujita, and Fumino Okutani
Subjects: Olfactory system, medicine.medical_specialty, business.industry, Neuropsychology, Brain, Disease, Neuropsychological Tests, Correlation, Psychiatry and Mental health, Odor, Cerebral blood flow, Alzheimer Disease, Cerebrovascular Circulation, Internal medicine, Cardiology, medicine, Humans, Cognitive Dysfunction, Geriatrics and Gerontology, business, Cognitive impairment, Frontal Pole
Abstract: OBJECTIVE Olfactory dysfunction is common in patients with mild cognitive impairment (MCI) or Alzheimer's disease (AD). We sought to elucidate brain regions associated with olfactory dysfunction in patients with MCI and early AD by using 123I-IMP-SPECT to detect regional cerebral blood flow (CBF). METHODS We included 218 patients diagnosed with AD or MCI, who underwent a comprehensive battery of neuropsychiatric and neuropsychological tests, Alzheimer's Disease Assessment Scale-Cognitive Part (ADAS-Cog), and forward- and backward-digit span. Olfactory function was assessed using TT patients stated whether they experienced any smell (detection test) and identified the odor (identification test). The association between single-photon emission computerized tomography based regional CBF and olfactory function was examined by voxel-by-voxel multiple regression analysis, considering sex, age, and education as covariate parameters. RESULTS Of the 218 patients, 78 had mildly impaired olfactory detection and 15 had olfactory detection loss; additionally, 213 had mild olfactory identification impairment. The odor detection score correlated significantly with the ADAS-Cog word recall score (r = 0.193, p = 0.004). The odor identification score correlated significantly with the ADAS memory (r = 0.408, p
Published: 2021

49. Intramyocardial Transplantation of Human iPS Cell–Derived Cardiac Spheroids Improves Cardiac Function in Heart Failure Animals

Author: Ryota Tabei, Yujiro Kawai, Kazuaki Nakajima, Satoshi Kunita, Shota Someya, Jun Fujita, Hidenori Tani, Keiichi Fukuda, Yoshikazu Kishino, Hideaki Kanazawa, Shugo Tohyama, Takumi Teratani, Akira Ito, Noriko Handa, Akinori Hirano, Rei Shibata, Sho Tanosaki, Eiji Kobayashi, Shuji Hishikawa, Marina Okada, Hideyuki Shimizu, Masataka Yamazaki, Shigeo Okuda, Yoshitake Yamada, Yusuke Soma, Yasuhiko Tabata, Yuika Morita, Shinji Kawaguchi, and Toyoaki Murohara
Subjects: 0301 basic medicine, Cardiac function curve, medicine.medical_specialty, LVEDV, left ventricular end-diastolic volume, Cell, heart failure, cardiomyocyte, 030204 cardiovascular system & hematology, HF, heart failure, human iPS cells, 03 medical and health sciences, 0302 clinical medicine, sCM, single cardiomyocyte, CMR, cardiac magnetic resonance, Internal medicine, hiPSC, human induced pluripotent stem cell, medicine, dp/dtmax, maximum rate of left ventricular pressure rise, EF, ejection fraction, CM, cardiomyocyte, Induced pluripotent stem cell, cell transplantation, LV, left ventricular, Ejection fraction, business.industry, Spheroid, medicine.disease, FAC, fractional area change, VEGF, vascular endothelial growth factor, Transplantation, 030104 developmental biology, medicine.anatomical_structure, GH, gelatin hydrogel, hPSC, human pluripotent stem cell, cardiac spheroids, Heart failure, Cardiology, LVESV, left ventricular end-systolic volume, ECG, electrocardiogram, Teratoma, Preclinical Research, Cardiology and Cardiovascular Medicine, business, CS, cardiac spheroid
Abstract: Visual Abstract, Highlights • hiPSCs are differentiated into CMs with large-scale 2-dimensional culture system, and refined by metabolic purification. • hiPSC-derived CMs are developed into CSs in special microwell plates. • Intramyocardial transplantation of CSs and GH improves cardiac function in small and large animal models. • Engraftment of CMs and angiogenesis are mechanisms for improvement of cardiac function. • Intramyocardial transplantation of CSs with a transplant injection device is a safe, effective, and feasible strategy for the treatment of HF., Summary The severe shortage of donor hearts hampered the cardiac transplantation to patients with advanced heart failure. Therefore, cardiac regenerative therapies are eagerly awaited as a substitution. Human induced pluripotent stem cells (hiPSCs) are realistic cell source for regenerative cardiomyocytes. The hiPSC-derived cardiomyocytes are highly expected to help the recovery of heart. Avoidance of teratoma formation and large-scale culture of cardiomyocytes are definitely necessary for clinical setting. The combination of pure cardiac spheroids and gelatin hydrogel succeeded to recover reduced ejection fraction. The feasible transplantation strategy including transplantation device for regenerative cardiomyocytes are established in this study.
Published: 2021

50. Predictive factors for developing acute cholangitis and/or cholecystitis in patients undergoing delayed cholecystectomy: A retrospective study

Author: Hideto Fujita, Takashi Miyata, Daisuke Matsui, Nobuhiko Ueda, Fumio Futagami, Hiroyuki Takamura, Daisuke Kaida, Yasuto Tomita, Tomoharu Miyashita, Koji Nishijima, Naohiko Nakamura, Yuta Fujiwara, Takashi Nakamura, Yoshinao Ohbatake, Jun Fujita, and Hiroto Saito
Subjects: Adult, Male, Risk, medicine.medical_specialty, Cholangitis, medicine.medical_treatment, Cholecystitis, Acute, Operative Time, lcsh:Surgery, Gallstones, Severity of Illness Index, Group B, Time-to-Treatment, 03 medical and health sciences, 0302 clinical medicine, Postoperative Complications, Risk Factors, Elective surgical procedure, medicine, Humans, In patient, Cholecystectomy, Risk factor, Intraoperative Complications, Watchful Waiting, Aged, Aged, 80 and over, business.industry, Retrospective cohort study, lcsh:RD1-811, Middle Aged, medicine.disease, Surgery, Acute cholangitis, Acute cholecystitis, Treatment Outcome, Elective Surgical Procedures, 030220 oncology & carcinogenesis, Acute Disease, Cholecystitis, 030211 gastroenterology & hepatology, Female, Elective Surgical Procedure, business
Abstract: Background: /Objective: We evaluated the risk of acute cholangitis and/or cholecystitis while waiting for cholecystectomy for gallstones. Methods: We retrospectively enrolled 168 patients who underwent cholecystectomy for gallstones after conservative therapy. We compared clinical data of 20 patients who developed acute cholangitis and/or cholecystitis while waiting for cholecystectomy (group A) with 148 patients who did not develop (group B). We investigated surgical outcomes and risk factors for developing acute cholangitis and/or cholecystitis. Results: Preoperatively, significant numbers of patients with previous history of acute grade II or III cholecystitis (55.0% vs 10.8%; p
Published: 2021

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