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Katsuhiko Shimizu,1 Masao Nakata,1 Shinsuke Saisho,1 Masayuki Inubushi,2 Norihito Okumura,3 Tomohiro Murakawa,4 Motohiro Yamashita,5 Hiroshige Nakamura,6 Yoshifumi Sano,7 Kazuhiko Kataoka,8 Shinichi Toyooka9 1Department of General Thoracic Surgery, Kawasaki Medical School, Kurashiki, Japan; 2Division of Nuclear Medicine, Department of Radiology, Kawasaki Medical School, Kurashiki, Japan; 3Department of Thoracic Surgery, Kurashiki Central Hospital, Kurashiki, Japan; 4Department of Thoracic Surgery, Kansai Medical University, Osaka, Japan; 5Department of Thoracic Surgery, Shikoku Cancer Center, Matsuyama, Japan; 6Division of General Thoracic Surgery, Tottori University Hospital, Yonago, Japan; 7Department of Cardiovascular and Thoracic Surgery, Ehime University Graduate School of Medicine, Toon, Japan; 8Department of Thoracic Surgery, National Hospital Organization Iwakuni Clinical Center, Iwakuni, Japan; 9Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, JapanCorrespondence: Katsuhiko Shimizu, Department of General Thoracic Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan, Tel +81-86-462-1124, Fax +81-86-464-1124, Email kshimizu@med.kawasaki-m.ac.jpBackground: Induction therapy followed by surgery is recommended as an alternative treatment strategy for locally advanced non-small cell lung cancer (NSCLC). Patients who achieve pathologic response after induction therapy have better outcomes than non-responders; therefore, therapeutic response must be evaluated. Recently, new approaches for monitoring therapeutic responses, which are based on 18F‐Fluorodeoxyglucose positron emission tomography (FDG‐PET), have been developed. In this study, we evaluated the predictive value of Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST), which uses standardized uptake values corrected for lean body mass (SUL) and total lesion glycolysis (TLG).Methods: A total of 130 patients in the Setouchi Lung Cancer Group who underwent FDG-PET imaging before and after induction therapy prior to a planned surgical resection for NSCLC between 2007 and 2016 were studied retrospectively. The pathologic responses of the primary lung tumors and metastatic lymph nodes were compared with their responses based on evaluation using PERCIST.Results: Postoperative pathologic studies revealed pathologic complete response (pCR) in 42 (32.3%) patients. PERCIST was significantly correlated with pathologic response (p < 0.001). The sensitivity, specificity, and accuracy of PERCIST for predicting pCR were 16.7% (7/42), 88.6% (78/88), and 65.4% (85/130), respectively. Patients with pCR had significantly higher reduction rates in SULpeak for both primary lung tumors and metastatic lymph nodes and TLG for primary tumors than non-responders. In a multivariate Cox regression analysis, tumor site in upper lobes, reduction rate of TLG in primary tumor, and pathologic N0 were independent predictors of favorable recurrence-free survival (RFS).Conclusion: Our study suggested that PERCIST, especially the rate of TLG reduction rate, are useful to predict the pathological response and prognosis after induction therapy. Although improvement is necessary, PERCIST can be a promising method of the post-induction status in lung cancer. Further research is needed to confirm our findings.Keywords: non-small cell lung cancer, FDG PET, PERCIST, SUL, TLG

Yuki Ikeda,1 Masahiro Iwakawa,1 Hajime Kiyokawa,1 Takahiro Nakagami,1 Shinya Kanzaki,2 Akihiro Ogawa,2 Tsuyoshi Tabata,3 Mao Takahashi,1 Toshio Kinoshita,1,3 Kazuhiro Shimizu1 1Department of Internal Medicine, Toho University Sakura Medical Center, Chiba, Japan; 2Department of Rehabilitation, Toho University Sakura Medical Center, Chiba, Japan; 3Department of Clinical Functional Physiology, Toho University Sakura Medical Center, Chiba, JapanCorrespondence: Kazuhiro Shimizu, Department of Internal Medicine, Toho University Sakura Medical Center, Chiba, Japan, Tel +81-43-462-8811, Fax +81-43-462-8820, Email k432@sakura.medtoho-u.ac.jpAbstract: Obesity-induced heart failure (HF) in young people is a serious problem. The treatments for HF have developed in recent years. The following four basic HF drugs have been widely recognized as the “Fantastic Four”: beta-adrenergic blocking agents, mineralocorticoid receptor antagonists (MRA), sodium glucose transporter 2 inhibitors (SGLT2 inhibitors), and angiotensin receptor neprilysin inhibitors (ARNI). However, the interaction between the heart and blood vessels has not received much attention. The cardio-ankle vascular index (CAVI) is an arterial stiffness index that is unaffected by blood pressure at the time of measurement. A 34-year-old obese man was admitted with dyspnea and edema. His cardiac function was severely impaired, and CAVI was increased. After administration of multidisciplinary HF treatment centered on the “Fantastic Four”, his cardiac function and CAVI improved dramatically in a short time period. This case suggests the importance of improvement both cardiac and vascular function for the treatment of HF.Keywords: obesity, hypertension, obstructive sleep apnea, arterial stiffness, cardio ankle vascular index

Kazuhiro Shimizu,1 Tsuyoshi Tabata,2 Masahiro Iwakawa,1 Shuji Sato,1 Toshio Kinoshita1,2 1Division of Cardiovascular Medicine, Department of Internal Medicine, Toho University Sakura Medical Center, Chiba, Japan; 2Department of Clinical Functional Physiology (Sakura), Toho University Sakura Medical Center, Chiba, JapanCorrespondence: Kazuhiro Shimizu, Department of Internal Medicine, Toho University Sakura Medical Center, 564-1 Shimoshizu, Sakura-shi, Chiba, 285-8741, Japan, Tel +81-43-462-8811, Fax +81-43-462-8820, Email k432@sakura.med.toho-u.ac.jpAbstract: A 72-year-old man presented to our clinic with hypertension. Arterial stiffness evaluated by cardio ankle vascular index (CAVI) was markedly increased at 13.5. We treated him using 80 mg/day of valsartan for three months. CAVI was decreased from 13.5 to 13.0. However, his BP fluctuations were still high. We changed the treatment to angiotensin receptor-neprilysin inhibitor (ARNI) with increasing doses up to 400 mg. Independent of the change in blood pressure at the time of measurement, CAVI improved with ARNI dose. Hypertension treatment with an awareness of the cardio-vascular interaction might be a possibility prevents future heart failure development effectively.Keywords: hypertension, angiotensin receptor-neprilysin inhibitor, arterial stiffness, cardio ankle vascular index

Kazuhiro Shimizu,1 Mao Takahashi,1 Shuji Sato,1 Atsuhito Saiki,1 Daiji Nagayama,1,2 Takashi Hitsumoto,3 Akira Takahara,4 Kohji Shirai1,5 1Department of Internal Medicine, Toho University Sakura Medical Center, Sakura, Chiba, Japan; 2Department of Internal Medicine, Nagayama Clinic, Oyama, Tochigi, Japan; 3Hitsumoto Medical Clinic, Shimonoseki, Yamaguchi, Japan; 4Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Chiba, Japan; 5Department of Internal Medicine, Seijinkai Mihama Hospital, Chiba, Chiba, JapanCorrespondence: Kazuhiro Shimizu, Department of Internal Medicine, Toho University Sakura Medical Center, 561-4 Shimoshizu, Sakura, Chiba, 285-8741, Japan, Tel +81-43-462-8811, Fax +81-43-462-8820, Email k432@sakura.med.toho-u.ac.jpAbstract: Predictive factors for vascular events have not been established. The vasculature of the atheroma is supplied by penetration of the vasa vasorum through the smooth muscle cell layer from the adventitia. Smooth muscle cell contraction induces compression of the vasa vasorum, resulting in ischemia in intimal atheromatous lesions. Cardio-ankle vascular index (CAVI) has become known as an index of arterial stiffness of the arterial tree from the origin of the aorta to the ankle. CAVI reflects the progress of arteriosclerosis, and a rapid rise in CAVI indicates arterial smooth muscle cell contraction. We hypothesized that rapidly increased arterial stiffness evaluated by CAVI may be a predictor of impending cardiovascular events.Keywords: arterial stiffness, stress, plaque rupture, CAVI

Daiji Nagayama,1,2 Kentaro Fujishiro,3 Keijiro Nakamura,4 Yasuhiro Watanabe,2 Takashi Yamaguchi,2 Kenji Suzuki,3 Kazuhiro Shimizu,5 Atsuhito Saiki,2 Kohji Shirai6 1Department of Internal Medicine, Nagayama Clinic, Tochigi, Japan; 2Center of Diabetes, Endocrinology and Metabolism, Toho University, Sakura Medical Center, Chiba, Japan; 3Japan Health Promotion Foundation, Tokyo, Japan; 4Division of Cardiovascular Medicine, Toho University, Ohashi Medical Center, Tokyo, Japan; 5Division of Cardiovascular Medicine, Toho University, Sakura Medical Center, Chiba, Japan; 6Department of Internal Medicine, Mihama Hospital, Chiba, JapanCorrespondence: Daiji NagayamaNagayama Clinic, 2-12-22, Tenjin-Cho, Oyama-City, Tochigi, 323-0032, Japan, Tel/Fax +81-285-22-0219, Email deverlast96071@gmail.comAim: Physiological tests to assess systemic vascular function are not included in the risk score for atrial fibrillation (AF). We aimed to examine whether cardio-ankle vascular index (CAVI), a systemic arterial stiffness parameter, is associated with the presence of AF in Japanese general population.Methods: A cross-sectional study (N = 47,687) and a cohort study (N = 5418, four consecutive years) in Japanese urban residents who participated in annual health screening were conducted.Results: A total of 164 subjects (0.34%) had AF in the cross-sectional data. After propensity score matching for age and gender, logistic regression analysis revealed that CAVI is independently associated with AF, as are body mass index and estimated glomerular filtration rate. In a 4-year cohort study, 22 subjects (0.41%) with new-appearance of AF showed higher CAVI at baseline than those without. In the receiver-operating-characteristic curve analysis, the area under the curve, which is a measure of predictability, of CAVI for the new-appearance of AF was 0.747, and the cut-off value of CAVI was 8.0. Kaplan–Meier analysis revealed that the cumulative incidence of new-appearance of AF was higher in subjects with CAVI ≥ 8.0 compared to those with CAVI < 8.0. In Cox-proportional hazards analysis, CAVI ≥ 8.0 as well as gender were identified as independent predictors for the new-appearance of AF, whereas age ≥ 65 years was not.Conclusion: Increased CAVI may represent a major modifiable risk factor for the development of AF. Studies are needed to confirm that CAVI is a predictor of AF independent of various AF risk factors and that CAVI-lowering interventions can prevent new-appearance or recurrence of AF.Keywords: atrial fibrillation, cardio-ankle vascular index, CAVI, arterial stiffness, health screening

Yuki Abe,1 Masaru Suzuki,1 Hiroshi Shima,2 Yusuke Shiraishi,2 Naoya Tanabe,2 Susumu Sato,2 Kaoruko Shimizu,1 Hirokazu Kimura,1 Hironi Makita,1,3 Toyohiro Hirai,2 Satoshi Konno,1 Masaharu Nishimura1,3 1Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-ku, Sapporo, 060-8638, Japan; 2Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan; 3Hokkaido Medical Research Institute for Respiratory Diseases, Chuo-ku, Sapporo, 060-0063, JapanCorrespondence: Masaru SuzukiDepartment of Respiratory Medicine, Faculty of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, 060-8638, JapanTel +81-11-706-5911Fax +81-11-706-7899Email suzumasa@med.hokudai.ac.jpPurpose: Low body mass index (BMI) has been reported to be associated with poor prognosis in patients with chronic obstructive pulmonary disease (COPD). In contrast, a detailed analysis of the association between body weight change over time and prognosis is not sufficient, particularly in Japanese patients with COPD who have been reported to be much thinner compared to Westerners. This study aimed to investigate the relationship between annual body weight change and long-term prognosis in Japanese patients with COPD in two independent cohorts.Patients and Methods: We analyzed 279 patients with COPD who participated in the Hokkaido COPD cohort study as a discovery cohort. We divided participants into three groups according to quartiles of annual body weight change calculated by the data from the first 5 years: weight loss group ( 0.20 kg/year). The association between annual body weight change and prognosis was replicated in the Kyoto University cohort (n = 247).Results: In the Hokkaido COPD cohort study, the weight loss group had significantly worse mortality than the other groups, whereas there was no difference in BMI at baseline. In the multivariate analysis, annual body weight change was an independent risk factor for all-cause mortality, which was confirmed in the Kyoto University cohort.Conclusion: Annual body weight loss is associated with poor prognosis in Japanese patients with COPD, independent of baseline BMI. Longitudinal assessment of body weight is important for the management of COPD.Keywords: annual body weight change, body mass index, chronic obstructive pulmonary disease, mortality, prognosis, weight loss

Yusuke Hanioka,1 Ryo Morita,2 Keiko Yamagami,1 Shuhei Yao,1 Ryota Nakamura,1 Tomoyuki Nakamura,1 Katsushu Shimizu,3 Toshimasa Yamaguchi,3 Hitoshi Goto1 1Department of Internal Medicine, Osaka City General Hospital, Osaka, Japan; 2Department of Infectious Diseases, Osaka City General Hospital, Osaka, Japan; 3Department of Primary Care and Advanced Triage Section, Osaka City General Hospital, Osaka, JapanCorrespondence: Yusuke HaniokaDepartment of Internal Medicine, Osaka City General Hospital, 2-13-22 Miyakojima-Hondori, Miyakojima-ku, Osaka, 534-0021, JapanTel +81-6-6929-1221Fax +81-6-6929-2041Email y-hanioka@med.osakacity-hp.or.jpPurpose: It is important to understand how COVID-19 is affecting general outpatient services, since hospitals see a wide variety of patients. This study aimed to evaluate the incidence and clinical picture of COVID-19 in general outpatient services. Currently, the diagnosis of COVID-19 depends strongly on the results of polymerase chain reaction (PCR) assays. However, since the sensitivity of PCR tests for SARS-CoV-2 is not high enough to assure confidence. On the other hand, the SARS-CoV-2 antibody (Ab) test is highly sensitive after 2 weeks of symptom onset, and might complement the PCR test. Therefore, we measured Ab in addition to PCR to obtain a more accurate clinical profile of COVID-19, which might be helpful in building future practice strategies.Patients: The study patients were those who visited our department for the first time between November 2020 and March 2021 and fulfilled the enrolment criteria.Methods: All patients underwent total SARS-CoV-2 Ab testing, and PCR tests were performed in only some of them; patients were classified according to the performance of PCR tests for comparisons.Results: Ninety-four patients who underwent Ab testing during the study period were eligible for study enrolment, and the PCR test was performed in 40 of them. Only one patient was diagnosed with acute stage COVID-19 based on a positive PCR test. Antibodies were positive in six (6.4%) of the 94 patients. Five of the six Ab-positive patients were negative for PCR, and the test was not performed in the sixth patient. All the six patients had prior symptoms suggestive of infection, and respiratory symptoms were more noticeable than fever. The Ab positivity rate was significantly higher than published data.Conclusion: COVID-19 is not rare in general outpatient services and can be missed based on PCR tests alone. The diagnosis should be made from a comprehensive perspective.Keywords: COVID-19, SARS-CoV-2 antibody, outpatient service, fever

Koji Shimizu, Masahiro Wakasugi, Toshiomi Kawagishi, Tomoya Hatano, Takamasa Fuchigami, Hiroshi Okudera Emergency and Disaster Medicine, University of Toyama, Toyama, JapanCorrespondence: Masahiro WakasugiEmergency and Disaster Medicine, University of Toyama, 930-0194 Sugitani, Toyama, JapanTel +81 76-434-7786Fax +81 76-434-5110Email mwaka@med.u-toyama.ac.jpPurpose: To obtain effective systemic blood flow and coronary perfusion by chest compressions during cardiopulmonary resuscitation, it is recommended that the interruption time of chest compressions be kept to a minimum, and that the chest compression fraction (CCF) should be kept high. In this study, we examined the effects of advanced airway management by paramedics in out-of-hospital cardiac arrest (OHCA) cases on CCF and on return of spontaneous circulation (ROSC) before arrival at the hospital.Participants and Methods: A total of 283 adult, non-traumatic OHCA cases who were in cardiopulmonary arrest at the time of EMS contact between April 2015 and March 2017 were registered for this study. We retrospectively investigated the presence or absence of advanced airway clearance, CCF and ROSC during CPR. CCF was calculated by measuring the chest compression interruption time from the ECG waveform recorded on a semiautomatic defibrillator (Philips HeartStart MRX). The data obtained were recorded on a computer, and comparisons between groups were examined using an untested t-test and χ2- test.Results: Of the 283 patients with OHCA, 159 were included in the analysis. The CCF of the AAM group was 89.4%, which was significantly higher than that in the BMV group (84.3%) (P< 0.01). Forty-one patients had ROSC at the time of arrival at the hospital, and the CCF of ROSC patients was 89.7%, which was significantly higher than that of non-ROSC patients (87.2%) (P< 0.01). ROSC was also obtained in 31.8% of the patients in the AAM group, which was significantly higher than that in the BMV group (12.2%).Conclusion: In this study, we found that advanced airway management during prehospital emergency transport by paramedics showed high CCF and ROSC rates and contributed to improving the prognosis of OHCA patients through high-quality resuscitation.Keywords: cardio pulmonary resuscitation, endotracheal intubation, supraglottic airways devices, outcome

Akihiro Uchida,1,&ast; Taro Yasuma,1,2,&ast; Atsuro Takeshita,1,2,&ast; Masaaki Toda,2 Yuko Okano,1,2 Kota Nishihama,1 Corina N D’Alessandro-Gabazza,2 Valeria Fridman D’Alessandro,2 Chisa Inoue,1 Takehiro Takagi,3 Hiroyuki Mukaiyama,4 Norio Takagi,4 Katsumi Shimizu,4 Yutaka Yano,1 Esteban C Gabazza2 1Department of Diabetes and Endocrinology, Mie University Faculty and Graduate School of Medicine, Tsu, Mie, Japan; 2Department of Immunology, Mie University Faculty and Graduate School of Medicine, Tsu, Mie, Japan; 3Iwasaki Hospital, Tsu, Mie, Japan; 4Tanisake Corporation, Gifu, Japan&ast;These authors contributed equally to this workCorrespondence: Esteban C GabazzaDepartment of Immunology, Mie University School of Medicine, Edobashi 2-174, Tsu-City, Mie, 514-8507, JapanTel +81 59 231 5037Fax +81 59 231 5225Email gabazza@doc.medic.mie-u.ac.jpIntroduction: Diabetes mellitus is a serious threat to public health worldwide. It causes a substantial economic burden, mental and physical disabilities, poor quality of life, and high mortality. Limonite is formed when iron-rich materials from the underground emerge and oxidized on the ground surface. It is currently used to purify contaminated water, absorption of irritant gases, and improve livestock breeding. Limonite can change the composition of environmental microbial communities. In the present study, we evaluated whether limonite can ameliorate glucose metabolism abnormalities by remodeling the gut microbiome.Methods: The investigation was performed using mouse models of streptozotocin-induced diabetes mellitus and high-calorie diet-induced metabolic syndrome.Results: Oral limonite supplement was associated with significant body weight recovery, reduced glycemia with improved insulin secretion, increased number of regulatory T cells, and abundant beneficial gut microbial populations in mice with diabetes mellitus compared to control. Similarly, mice with obesity fed with limonite supplements had significantly reduced body weight, insulin resistance, steatohepatitis, and systemic inflammatory response with significant gut microbiome remodeling.Conclusion: This study demonstrates that limonite supplement ameliorates abnormal glucose metabolism in diabetes mellitus and obesity. Gut microbiome remodeling, inhibition of inflammatory cytokines, and the host immune response regulation may explain the limonite’s beneficial activity under pathological conditions in vivo.Keywords: insulin resistance, limonite, diabetes, streptozotocin, metabolic syndrome, gut microbiome

Shuji Sato,1 Kazuhiro Shimizu,1 Takuro Ito,1 Masakazu Tsubono,1 Akihiro Ogawa,2 Takeshi Sasaki,3 Mao Takahashi,1 Mahito Noro,1 Kohji Shirai4 1Department of Cardiology, Toho University Sakura Medical Center, Chiba, Japan; 2Department of Rehabilitation, Toho University Sakura Medical Center, Chiba, Japan; 3Department of Clinical Functional Physiology, Toho University Sakura Medical Center, Chiba, Japan; 4Department of Internal Medicine, Mihama Hospital, Chiba, JapanCorrespondence: Kazuhiro ShimizuDepartment of Cardiology, Toho University Sakura Medical Center, 564-1 Shimoshizu, Sakura City, Chiba, 285-8741, JapanTel +81-43-462-8811Fax +81-43-462-8820Email k432@sakura.med.toho-u.ac.jpBackground: The role of arterial stiffness in the pathophysiology of chronic thromboembolic pulmonary hypertension (CTEPH) is unclear. The cardio-ankle vascular index (CAVI) is a novel arterial stiffness index reflecting stiffness of the arterial tree from the origin of the aorta to the ankle, independent from blood pressure at the time of measurement. CAVI reflects functional stiffness, due to smooth muscle cell contraction or relaxation, and organic stiffness, due to atherosclerosis. Here, we report the case of a patient with an increased CAVI due to CTEPH and the improvement after riociguat administration and balloon pulmonary angioplasty (BPA).Case Presentation: A 65-year-old man suffered from dyspnea on exertion, and he was diagnosed with distal CTEPH. The mean pulmonary artery pressure (mPAP) was 51 mmHg, and the initial CAVI was 10.0, which is high for patient’s age. In addition to right ventricular dysfunction, left ventricular dysfunction was observed as reduced global longitudinal strain (GLS-LV). After riociguat administration, CAVI decreased to 9.1 and GLS-LV improved from − 10.3% to − 17.3%, although pulmonary hypertension remained (mPAP 41 mmHg). Subsequently, a total of five BPA sessions were performed. Six months after the final BPA, mPAP decreased to 19 mmHg and GLS-LV improved to 19.3%. The patient was symptom free and his 6-minute walk distance improved from 322 m to 510 m. CAVI markedly decreased to 5.8, which is extremely low for his age.Conclusion: These observations suggested that arterial stiffness as measured by CAVI was increased in CTEPH, potentially deteriorating cardiac function because of enhanced afterload. The mechanism of the increase of CAVI in this case of CTEPH was obscure; however, riociguat administration and BPA might improve the pathophysiology of CTEPH partly by decreasing CAVI.Keywords: cardio-ankle vascular index, chronic thromboembolic pulmonary hypertension, arterial stiffness, ventricular afterload

Kazuhiro Shimizu,1 Mao Takahashi,1 Shuji Sato,1 Atsuhito Saiki,1 Daiji Nagayama,1 Masashi Harada,2 Chikao Miyazaki,2 Akira Takahara,3 Kohji Shirai1 1Department of Internal Medicine, Toho University Sakura Medical Center, Sakura, Chiba, Japan; 2Department of Neurosurgery, Toho University Omori Medical Center, Omori, Tokyo, Japan; 3Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Chiba, JapanCorrespondence: Kohji ShiraiDepartment of Internal Medicine, Toho University Sakura Medical Center, 561-4 Shimoshizu, Sakura City, Chiba, 285-8741, JapanTel +81-43-462-8811Fax +81-43-462-8820Email kshirai@kb3.so-net.ne.jpAbstract: Cardiovascular diseases have been recognized as the main cause of death all over the world. Recently, the established cardio-ankle vascular index (CAVI) has become known as an index of arterial stiffness of the arterial tree from the origin of the aorta to the ankle. CAVI reflects the progress of arteriosclerosis, and a rapid rise in CAVI indicates arterial smooth muscle cell contraction. Considering the vasculature of the atheroma where vasa vasorum penetrates the smooth muscle cell layer and supplies blood to the intimal atheromatous lesion, a rapid rise of CAVI means “choked” atheroma. Thus, we proposed a “smooth muscle cell contraction” hypothesis of plaque rupture.Keywords: arterial stiffness, atherosclerosis, smooth muscle cell contraction, CAVI

Masakazu Tsubono,1,2 Kazuhiro Shimizu,2 Shuji Sato,2 Takuro Ito,2 Takanori Ikeda1 1Department of Internal Medicine, Toho University Omori Medical Center, Tokyo, Japan; 2Department of Internal Medicine, Toho University Sakura Medical Center, Chiba, JapanCorrespondence: Kazuhiro ShimizuDepartment of Internal Medicine, Sakura Medical Center, School of Medicine, Toho University, 561-4 Shimoshizu, Sakura City, Chiba, 285-8741, JapanTel +81-43-462-8811Fax +81-43-462-8820Email k432@sakura.med.toho-u.ac.jpBackground: Venous thromboembolism (VTE) may present acutely as pulmonary embolism (PE), and its late complications include chronic thromboembolic pulmonary hypertension (CTEPH). PEs may arise from thrombi originating in a venous aneurysm, in rare cases of the popliteal vein.Case Presentation: A 77-year-old woman was referred to our hospital due to respiratory distress. Computed tomography revealed pulmonary thrombi and a thrombus in a popliteal vein aneurysm (PVA); PE was diagnosed. After 3 months of anticoagulant therapy (rivaroxaban), her pulmonary hypertension showed little improvement. She underwent perfusion scintigraphy, which showed multiple perfusion defects, and Swan–Ganz catheterization. Mean pulmonary artery pressure was 26 mmHg. Pulmonary angiography revealed organized distal thrombi. Based on these findings, we diagnosed CTEPH due to recurrent formation of thrombi in the PVA.Conclusion: Asymptomatic PVA can lead silently to PE and CTEPH. The possibility of asymptomatic recurrent VTE should be considered in patients with pulmonary hypertension and PVA.Keywords: chronic thromboembolic pulmonary hypertension, popliteal vein aneurysm, pulmonary embolism, pulmonary hypertension, venous thromboembolism

Masafumi Yamamoto,1 Satoshi Konno,2 Hironi Makita,2,3 Katsuaki Nitta,4 Kaoruko Shimizu,2 Masaru Suzuki,2 Mutsumi Nishida,1 Junichi Sugita,1 Takanori Teshima,1 Masaharu Nishimura2,3 1Division of Laboratory and Transfusion Medicine, Hokkaido University Hospital, Sapporo, Hokkaido, Japan; 2Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan; 3Hokkaido Institute of Respiratory Diseases, Sapporo, Hokkaido, Japan; 4Makita Hospital, Sapporo, Hokkaido, JapanCorrespondence: Masaharu NishimuraDepartment of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, N-15 W-7, Kita-Ku, Sapporo, 060-8638, JapanTel +81-11-706-5911Fax +81-11-706-7899Email ma-nishi@med.hokudai.ac.jpBackground: Generally, the maximal expiratory flow–volume (MEFV) curve must be measured for the diagnosis and staging of chronic obstructive pulmonary disease (COPD). As this test is effort dependent, international guidelines recommend that three acceptable trials are required for each test. However, no study has examined the magnitude and factors for the variability in parameters among three acceptable trials.Methods: We evaluated the intra-individual variations in several parameters among three acceptable MEFV curves obtained at one-time point in patients with COPD (n = 28, stage 1; n = 36, stage 2; n = 21, stages 3– 4). Next, the factors for such variations were examined using forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC).Results: The averages of coefficient of variation (CV) for FEV1 and FVC were 2.0% (range: 1.0– 3.0%) and 1.6% (0.9– 2.2%), respectively. Both parameters were significantly better than peak expiratory flow rate, forced expiratory flow at 50% of expired FVC, and forced expiratory flow at 75% of expired FVC (CVs: 5.0– 6.9%). A higher spirometric stage was significantly associated with higher CVs for FVC and FEV1, and older age was significantly correlated with a higher variation in FEV1 alone. Furthermore, a significantly inverse association was observed between emphysema severity, and the CVs for FEV1, but not that for FVC, regardless of spirometric stage.Conclusion: Both FVC and FEV1 are highly reproducible; nevertheless, older age, lower FEV1 at baseline, and non-emphysema phenotype are factors for a higher variability in FEV1 in patients with COPD.Keywords: chronic obstructive pulmonary disease, coefficient of variation, flow–volume curve, forced expiratory volume in 1 second, variability

Yuki Abe, Masaru Suzuki, Hirokazu Kimura, Kaoruko Shimizu, Hironi Makita, Masaharu Nishimura, Satoshi Konno Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-ku, Sapporo 060-8638, JapanCorrespondence: Masaru SuzukiDepartment of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, JapanTel +81-11-706-5911Fax +81-11-706-7899Email suzumasa@med.hokudai.ac.jpPurpose: Fractional exhaled nitric oxide (FENO) reflects eosinophilic inflammation of the airways. However, the significance of longitudinal assessment of FENO, including its variability, in the clinical course of severe asthma remains unclear. The aim of this study is to examine the association between long-term changes in FENO and the development of exacerbations in severe asthma.Patients and Methods: Among the severe asthma patients enrolled in the Hokkaido Severe Asthma Cohort Study, 100 patients with severe asthma who completed a 3-year follow-up in which FENO was measured annually were included. According to the FENO level at baseline, 1 year, and 2 years, the patients were classified into three groups: the sustained high group (≥ 50 ppb at all three visits), the sustained low group (< 25 ppb at all three visits), and the intermediate group (other). Subjects in the intermediate group were further classified into two groups based on the median value of the coefficient of variation (CV) of FENO during the 3 years (high CV and low CV intermediate groups).Results: The sustained high group experienced shorter exacerbation-free survival and more frequent exacerbations than the sustained low group (median number of exacerbation events, 3 vs 0, p = 0.01). In the intermediate group, the high CV group experienced shorter exacerbation-free survival than the low CV group, and the CV of FENO was an independent contributing factor to the development of exacerbations.Conclusion: Persistence of FENO above 50 ppb over the years as well as the presence of large variations in FENO levels was associated with the development of exacerbations in patients with severe asthma.Keywords: asthma, coefficient of variation, exacerbation, fractional exhaled nitric oxide, longitudinal assessment, variability

Preceding a core-collapse supernova (CCSN), various processes produce an increasing amount of neutrinos of all flavors characterized by mounting energies from the interior of massive stars. Among them, the electron antineutrinos are potentially detectable by terrestrial neutrino experiments such as KamLAND and Super-Kamiokande (SK) via inverse beta decay interactions. Once these pre-supernova (pre-SN) neutrinos are observed, an early warning of the upcoming CCSN can be provided. In light of this, KamLAND and SK, both located in the Kamioka mine in Japan, have been monitoring pre-SN neutrinos since 2015 and 2021, respectively. Recently, we performed a joint study between KamLAND and SK on pre-SN neutrino detection. A pre-SN alert system combining the KamLAND detector and the SK detector was developed and put into operation, which can provide a supernova alert to the astrophysics community. Fully leveraging the complementary properties of these two detectors, the combined alert is expected to resolve a pre-SN neutrino signal from a 15 M ⊙ star within 510 pc of the Earth at a significance level corresponding to a false alarm rate of no more than 1 per century. For a Betelgeuse-like model with optimistic parameters, it can provide early warnings up to 12 hr in advance.

Kenji Inoue,1 Junji Inoue,2 Shiho Kunimatsu-Sanuki,2 Norie Nozaki,3 Kosuke Shimizu,4 Kyoko Ishida,5 Goji Tomita1,5 1Inouye Eye Hospital, Chiyoda-Ku, Tokyo, Japan; 2Nishikasai Inouye Eye Hospital, Edogawa-Ku, Tokyo, Japan; 3Omiya Inouye Eye Clinic, Saitama-Shi, Saitama, Japan; 4Sapporo Inouye Eye Clinic, Sapporo-Shi, Sapporo, Japan; 5Department of Ophthalmology, Toho University Ohashi Medical Center, Meguro-ku, Tokyo, JapanCorrespondence: Kenji InoueInouye Eye Hospital, Chiyoda-Ku, Tokyo, JapanTel +81 03 3295 0911Fax +81 03 3295 0917Email 2inoue-k@inouye-eye.or.jpPurpose: To retrospectively evaluate the short-term efficacy of omidenepag isopropyl (EYBELIS 0.002%) by assessing its intraocular pressure (IOP)-lowering capability and safety in patients with normal-tension glaucoma (NTG).Patients and Methods: Fifty-four NTG patients (54 eyes) who were newly administrated with omidenepag isopropyl were enrolled in the study. The subjects comprised 22 men and 32 women, and the mean age of the subjects was 55.0 ±  14.1 years. The mean deviation value using the Humphrey visual field test program (30– 2 SITA Standard) was − 5.03 ±  3.38 dB. The following data were retrieved from the medical records and used for retrospective analyses: IOP at baseline 1– 2 months and 3– 4 months after administration. The frequency of non-responder patients who had less than 10% IOP reduction was evaluated. Patients were observed for adverse reactions and dropouts at each time point.Results: IOP at baseline, after 1– 2 months and after 3– 4 months was 15.7 ±  2.6 mmHg, 13.5 ±  2.3 mmHg, and 13.6 ±  2.4 mmHg, respectively. There was a significant decrease in IOP after administration (p< 0.0001). Eleven patients (22.4%) were non-responders. Adverse reactions occurred in 4 patients (7.4%), including conjunctival hyperemia in 3 patients (after 1 week, 2 weeks, and 1 month, respectively) and eye pain in 1 patient (after 1 month). Five patients (9.3%) dropped out of the study because of an adverse reaction in 3 patients, insufficient IOP reduction in 1 patient, and discontinuation of follow-up of 1 patient at our institution.Conclusion: After administration of omidenepag isopropyl, IOP in patients with NTG was significantly decreased. However, adverse reactions occurred in 7.4% of patients.Keywords: intraocular pressure, adverse reactions, EP2 receptor agonist, conjunctival hyperemia

Hironi Makita,1,2,* Masaru Suzuki,1,* Satoshi Konno,1 Kaoruko Shimizu,1 Yasuyuki Nasuhara,1 Katsura Nagai,1,3 Yasushi Akiyama,3 Satoshi Fuke,4 Hiroshi Saito,5 Takeshi Igarashi,5 Kimihiro Takeyabu,6 Masaharu Nishimura1,2 1Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan; 2Hokkaido Medical Research Institute for Respiratory Diseases, Sapporo, Japan; 3Center for Respiratory Diseases, JCHO Hokkaido Hospital, Sapporo, Japan; 4Department of Internal Medicine, KKR Sapporo Medical Center, Sapporo, Japan; 5Department of Internal Medicine, Hokkaido Chuo Rosai Hospital, Iwamizawa, Japan; 6Department of Respiratory Medicine, Otaru Kyokai Hospital, Otaru, Japan*These authors contributed equally to this workCorrespondence: Masaharu NishimuraDepartment of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, JapanTel +81 11 706 5911Fax +81 11 706 7899Email ma-nishi@med.hokudai.ac.jpPurpose: Causes of death may be unique and different in Japanese patients with COPD because they are generally older, thinner, experience fewer exacerbations, and live longer than those in other countries. We investigated the detailed mortality profile in the Hokkaido COPD cohort study, which completed a 10-year follow-up with a very low dropout rate.Patients and Methods: We prospectively examined the 10-year natural history in 279 Japanese patients with COPD (GOLD 1, 26%; GOLD 2, 45%; GOLD 3, 24%; and GOLD 4, 5%). The majority of patients were male, and the average age at baseline was 69 years old. About 95% of all patients had accurate mortality data. The risk factors for mortality were also analyzed.Results: During the 10 years, 112 patients (40%) died. Their median survival time was 6.1 years (interquartile range: 4.7– 7.9 years), and age at death was 79 ± 6 years old (mean ± SD). Respiratory diseases, including pneumonia, were the leading causes of death in 45 (40%), followed by lung cancer in 24 (21%), other cancers in 18 (16%), and cardiovascular diseases in 12 (11%). In particular, lung cancer-related death was equally distributed across all COPD stages, with a higher proportion of lung cancer in the relatively younger generation (< 64 years old). Older age at baseline, lower BMI, and severer emphysema were significant risk factors for all-cause mortality.Conclusion: The unique mortality profile observed in this study should be considered when designing strategies for the management of patients with COPD in any geographic region.Keywords: chronic obstructive pulmonary disease, mortality, cause of death, cohort study

Nozomu Takei,1,* Masaru Suzuki,1,* Hironi Makita,2 Satoshi Konno,1 Kaoruko Shimizu,1 Hiroki Kimura,1 Hirokazu Kimura,1 Masaharu Nishimura1,2 1Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan; 2Hokkaido Medical Research Institute for Respiratory Diseases, Sapporo, Japan*These authors contributed equally to this workCorrespondence: Masaharu NishimuraDepartment of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, North 15 West 7, Kita-ku, Sapporo 060-8638, JapanTel +81 11 706 5911Fax +81 11 706 7899Email ma-nishi@med.hokudai.ac.jpPurpose: Alpha-1 antitrypsin deficiency is associated with the development of chronic obstructive pulmonary disease (COPD), whereas increased levels of serum alpha-1antitrypsin occur in response to inflammation. The effects of alpha-1 antitrypsin levels on the clinical course of COPD had been unclear. We investigated the association of serum alpha-1 antitrypsin levels with the clinical course of COPD patients based on data from a 10-year prospective cohort study.Patients and methods: We analyzed 278 COPD patients who participated in the Hokkaido COPD cohort study and who did not meet the criteria for alpha-1 antitrypsin deficiency. We divided the subjects into 3 groups according to quartiles of serum alpha-1 antitrypsin levels at baseline: lower group (141 mg/dL, n = 67). The annual change in forced expiratory volume in 1 s (FEV1) and events of COPD exacerbation were monitored during the first 5 years, and mortality was followed-up during the entire 10 years.Results: At baseline, the higher group showed lower body mass index; higher computed tomography emphysema score; lower diffusing capacity; higher levels of acute-phase proteins; and higher blood neutrophil counts. Longitudinal analyses revealed that in the higher group, the annual decline in FEV1 was rapid and the 10-year mortality was higher, but there was no association between serum alpha-1 antitrypsin levels and time to first exacerbation.Conclusion: COPD subjects with higher serum alpha-1 antitrypsin levels were associated with a worse systemic inflammation status and higher 10-year mortality.Keywords: chronic obstructive pulmonary disease, alpha-1 antitrypsin, inflammation, lung function decline, mortality

Abe Y, Suzuki M, Shima H, et al. Int J Chron Obstruct Pulmon Dis. 2021;16:3243–3253. The authors have advised there is an error with the ethics approval number of Kyoto University on pages 3245 and 3252. On page 3245, Kyoto University Cohort section, last sentence, the text “(E182 and R03112)” should read “(E182, R0311-2, and R1660-1)”. On page 3252, Ethics Approval and Informed Consent section, the text “(E182 and R0311-2)” should read “(E182, R0311-2, and R1660-1)”. The authors apologize for these errors. Read the original article

Katsuhiko Shimizu, Riki Okita, Shinsuke Saisho, Ai Maeda, Yuji Nojima, Masao NakataDepartment of General Thoracic Surgery, Kawasaki Medical School, Kurashiki, Okayama, JapanIntroduction: Numerous studies conducted until date have reported that the chemotherapy regimen could affect the programmed cell death ligand 1 (PD-L1) expression status in patients with non-small cell lung cancer (NSCLC).Materials and methods: A total of 36 NSCLC patients for whom both the surgically resected specimens of the primary tumors and re-biopsy specimens of the recurrent tumors were available were enrolled in this study. The PD-L1 expression status and tumor-infiltrating CD8-positive T lymphocytes (CD8+TILs) count were measured in paired samples by immunohistochemistry. The concordance rate in the tumor immune microenvironment (TIME) classification based on the PD-L1 expression status and CD8+TILs count was analyzed.Results: While the PD-L1 expression levels were similar between the surgical and re-biopsy specimens in 77.8% of cases, in 16.7% of cases, the expression levels were higher in the re-biopsy specimens. When the analysis was confined to patients who had received platinum-based chemotherapy, the percentage increased to 42.9%. The TIME classification changed in the re-biopsy specimens as compared to the surgical specimens in one-third of the patients, especially in those who had received chemotherapy previously. The TIME classification in the re-biopsy specimens more closely resembled that in the metastatic lymph nodes as compared to that in the primary tumor.Conclusion: In patients with recurrent NSCLC, especially those who have received chemotherapy previously, a recent re-biopsy sample is required to determine whether PD-1/PD-L1 inhibitors should be used for treatment or not.Keywords: non-small cell lung cancer, NSCLC, programmed cell death ligand 1 (PD-L1), tumor-infiltrating T lymphocytes, tumor immunemicroenvironment (TIME), re-biopsy

Taku Saito,1 Masanori Nagamine,2 Jun Shigemura,1 Masaaki Tanichi,1 Hiroyuki Toda,1 Kunio Shimizu,2 Aihide Yoshino1 1Department of Psychiatry, National Defense Medical College, Tokorozawa, Saitama, Japan; 2Division of Behavioral Science, National Defense Medical College Research Institute, Tokorozawa, Saitama, Japan Purpose: The importance of resilience as a mental health outcome has been reported in recent occupational health studies, although resilience is yet to be assessed in the Japan Ground Self-Defense Force (JGSDF) population. Our objective was to test whether the Tachikawa Resilience Scale (TRS), developed to measure the resilience of Japanese individuals, is useful for evaluating the resilience of the JGSDF. Patients and methods: We performed a cross-sectional study of 353 JGSDF peacekeeping personnel engaged in the United Nations Mission in the Republic of South Sudan from November 2015 to May 2016. We evaluated resilience using two psychological measures: the TRS and the Resilience Competence Scale – Japanese Short Version (RCS-JS). To verify the construct validity of the TRS, we performed exploratory factor analysis and confirmatory factor analysis. We subsequently conducted hierarchical multivariate regression analysis to evaluate the relationship of the TRS and the RCS-JS with psychological distress measured by the Japanese version of the Kessler Psychological Distress Scale. Results: Of those recruited, 281 (79.6%) agreed to participate. The exploratory factor analysis revealed a one-factor model of the TRS. The confirmatory factor analysis model showed good fit (ratio of χ2 to the degrees of freedom =1.409, P=0.105, comparative fit index =0.994, root mean square error of approximation =0.038). Both the TRS and the RCS-JS showed a significant inverse correlation with the Kessler Psychological Distress Scale, and the regression coefficient of the TRS was equivalent to that of the RCS-JS. Conclusion: We confirmed the construct validity and reliability of the TRS when applied to the JGSDF, and demonstrated the usefulness of the TRS in this population. Keywords: psychological resilience, psychological measure, United Nations peacekeeping operations, mental health, occupational health

Keiko Azuma,1 Ryo Asaoka,1 Aya Matsuda,2 Jihee Lee,3 Kimiko Shimizu,1 Hiroko Inui,1 Hiroshi Murata,1 Asako Ogawa,1 Motoshi Yamamoto,1 Tatsuya Inoue,1 Ryo Obata1 1Department of Ophthalmology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan; 2Department of Ophthalmology, Toranomon Byoin, Tokyo, Japan; 3Department of Ophthalmology, Miyata Eye Hospital, Miyakonojo, Japan Background: The purpose of the study was to evaluate the 2-year outcome and predictive factors of treat-and-extend aflibercept in patients with eyes affected by typical neovascular age-related macula degenelation (t-AMD) or polypoidal choroidal vasculopathy (PCV), who were switched from ranibizumab. Patients and methods: The patients underwent three monthly aflibercept injections and subsequent administration following the treat-and-extend protocol. Sixty-two eyes of 62 patients were reviewed retrospectively. R statistical software was used for statistical analysis. Results: Twenty-two eyes were t-AMD and the remaining 40 eyes were PCV. There was no significant difference in the logarithm of the minimal angle of resolution visual acuity (VA) between baseline and 2 years after switching to aflibercept (0.40 vs 0.40; P=0.99). Multivariate analyses suggested that the following factors were significantly correlated with better VA at 2 years after switching to aflibercept: patients with PCV, the absence of intraretinal fluid at baseline, and better VA at baseline. Conclusion: In conclusion, VA was maintained and there was an anatomical improvement at 2 years in patients with t-AMD and PCV who were switched from ranibizumab to treat-and-extend aflibercept. PCV patients showed more favorable visual outcomes and less injections at 2 years compared to t-AMD patients. Intraretinal fluid and VA at baseline were predictors of VA at 2 years. Keywords: typical neovascular age-related macular degeneration, polypoidal choroidal vasculopathy, persistent exudative changes with ranibizumab, aflibercept, 2-year outcome

Masahiro Takeshima,1,* Hiroyasu Ishikawa,1,2,* Kazumi Shimizu,3 Takashi Kanbayashi,1 Tetsuo Shimizu1 1Department of Neuropsychiatry, Akita University Graduate School of Medicine, Akita, Japan; 2Department of Neuropsychiatry, Nakadori Rehabilitation Hospital, Akita, Japan; 3Palliative Care Center, Akita University Hospital, Akita, Japan *These authors contributed equally to this work Purpose: Venous thromboembolism (VTE) is the combination of pulmonary embolism (PE) and deep vein thrombosis. In recent years, VTE has been gaining attention in the field of psychiatry as it can cause sudden deaths in patients hospitalized in psychiatric departments. The purpose of this study was to investigate the incidence of VTE in psychiatric inpatients using contrast-enhanced computed tomography (CT). Patients and methods: At the psychiatric department of the Akita University Hospital, NANOPIA® D-dimer was measured in patients with suspected symptomatic VTE or believed to be at risk for asymptomatic VTE. A follow-up contrast-enhanced CT was also performed in cases of D-dimer values over 1 µg/mL. Patients diagnosed with VTE based on contrast-enhanced CT during hospitalizations between May 1, 2009 and April 30, 2017 were analyzed. VTE incidence was compared in restrained and unrestrained catatonic and noncatatonic patients. We also investigated whether VTE was symptomatic or asymptomatic as well as its outcomes. Results: The overall incidence of VTE was 2.3% (39/1,681) in the 8-year period. VTE was observed in 61.1% (11/18) of catatonic patients, 4.1% (11/270) of noncatatonic restrained patients, and 1.2% (17/1,393) of noncatatonic unrestrained patients. PE was observed in 76.9% (30/39) of VTE patients and 97.4% (38/39) of VTE patients were asymptomatic. Recovery was achieved in all cases of VTE treated with anticoagulation therapy. Conclusion: These results indicate that the risk of VTE is high in psychiatric inpatients and that PE is common in these population. The data may also suggest that contrast-enhanced CT is important in surveying thrombus in suspected cases of VTE. In the psychiatric field, proper attention must be given to VTE, regardless of the presence or absence of catatonia or restraint, particularly given that PE was observed in more than 75% of cases of VTE. Keywords: computed tomography, deep vein thrombosis, D-dimer, psychiatric patients, catatonia, pulmonary embolism

Kazuhiro Shimizu, Takuo Iiduka, Shuji Sato, Hajime Kiyokawa, Takahiro Nakagami, Hiroshi Mikamo, Masayo Kawazoe, Mao Takahashi, Mahito Noro Department of Internal Medicine, Toho University Sakura Medical Center, Sakura City, Chiba, Japan Background: For the management of venous thromboembolism (VTE), providing anticoagulant therapy within the therapeutic range has been a major challenge, as conventional therapy with unfractionated heparin (UFH) and vitamin K antagonist (VKA) requires frequent laboratory monitoring and dose adjustment. Recently, fondaparinux and edoxaban are being used as beneficial alternatives to UFH and VKA.Methods: We evaluated the clinical course of symptomatic deep vein thrombosis (DVT) in patients who received the 3-month anticoagulation therapy with fondaparinux/edoxaban (Group A; n=40) in comparison with the findings from our previous experience of patients who received the fondaparinux/VKA combination (Group B; n=33).Results: In both Groups A and B, serum D-dimer was significantly improved after treatment (p

Kenichi Goto,1,2 Emiko Ogawa,1,3 Kaoruko Shimizu,4 Hironi Makita,4 Hidenobu Suzuki,5 Yoshiki Kawata,5 Noboru Niki,5 Masaharu Nishimura,4 Yasutaka Nakano1 1Division of Respiratory Medicine, Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, 2Department of Pulmonary Medicine, Takatsuki Red Cross Hospital, Takatsuki, Osaka, 3Health Administration Center, Shiga University of Medical Science, Otsu, Shiga, 4First Department of Medicine, Hokkaido University Hospital, Sapporo, Hokkaido, 5Institute of Technology and Science, Tokushima University, Tokushima, Tokushima, Japan Background: Osteoporosis is a well-known comorbidity in COPD. It is associated with poor health status and prognosis. Although the exact pathomechanisms are unclear, osteoporosis is suggested to be either a comorbidity due to shared risk factors with COPD or a systematic effect of COPD with a cause–effect relationship. This study aimed to evaluate whether progression of osteoporosis is synchronized with that of COPD. Materials and methods: Data from 103 patients with COPD included in the Hokkaido COPD cohort study were analyzed. Computed tomography (CT) attenuation values of thoracic vertebrae 4, 7, and 10 were measured using custom software, and the average value (average bone density; ABD4,7,10) was calculated. The percentage of low attenuation volume (LAV%) for each patient was also calculated for evaluation of emphysematous lesions. Annual change in thoracic vertebral CT attenuation, which is strongly correlated with dual-energy X-ray absorptiometry-measured bone mineral density, was compared with that in FEV1.0 or emphysematous lesions. Results: In the first CT data set, ABD4,7,10 was significantly correlated with age (ρ=–0.331; p=0.0006), body mass index (BMI; ρ=0.246; p=0.0136), St George’s Respiratory Questionnaire (SGRQ) activity score (ρ=–0.248; p=0.0115), eosinophil count (ρ=0.229; p=0.0198), and LAV% (ρ=–0.372; p=0.0001). However, ABD4,7,10 was not associated with FEV1.0. After adjustment for age, BMI, SGRQ activity score, and eosinophil count, no significant relationship was found between ABD4,7,10 and LAV%. Annual change in ABD4,7,10 was not associated with annual change in LAV% or FEV1.0. Conclusion: Progression of osteoporosis and that of COPD are not directly related or synchronized with each other. Keywords: osteoporosis, quantitative CT analysis, FEV1.0, low attenuation volume, automatic analysis, systemic effect

Katsuhiko Shimizu, Riki Okita, Shinsuke Saisho, Ai Maeda, Yuji Nojima, Masao Nakata Department of General Thoracic Surgery, Kawasaki Medical School, Kurashiki, Okayama, Japan Abstract: Programmed cell death-1 ligand 1 (PD-L1), tumor-infiltrating CD8-positive T lymphocytes (CD8-positive TILs), and cyclooxygenase-2 (Cox-2) have been used as prognostic tools in patients with lung adenocarcinoma. We conducted a retrospective review of data from 170 patients who had undergone pulmonary resection as an initial treatment for clinical T1-2 N0 lung adenocarcinoma. We then investigated the expressions of three biomarkers using immunohistochemical analyses and compared the expression levels with the clinicopathological characteristics and outcomes of the patients. Next, we classified the tumors into four groups based on the PD-L1 and CD8-positive TILs statuses and evaluated the prognostic significance of Cox-2 expression according to the tumor immune microenvironment classification. Tumors with positive PD-L1 expression levels had a significantly larger number of CD8-positive TILs than tumors with negative PD-L1 expression levels, whereas tumors with high Cox-2 expressions had significantly fewer CD8-positive TILs than tumors with low Cox-2 expressions. A multivariate analysis showed that histological subtype, nodal metastasis, CD8-positive TILs count, and PD-L1 expression were independent predictors of patient outcome. Using a classification based on the PD-L1 and CD8-positive TILs statuses, the outcomes of patients with a negative PD-L1 expression and a high CD8-positive TIL count were significantly better than those with other classifications. In patients with negative PD-L1 and low CD8-positive TILs, the rate of EGFR mutation was significantly higher than that in other classifications, and Cox-2 expression was a powerful predictor of outcome. Clinical and pathological features in conjunction with the tumor immune microenvironment classification indicate that lung adenocarcinoma should be divided into different subgroups for prognosis and treatment. Classification according to the PD-L1 and CD8-positive TILs statuses might enable the effects of Cox-2 inhibitor to be predicted. Keywords: non-small-cell lung cancer, tumor microenvironment, programmed cell death-1 ligand 1 (PD-L1), tumor-infiltrating CD8-positive T lymphocytes, cyclooxygenase-2 (Cox-2)

Kimiko Shimizu,1 Yohei Hashimoto,1 Keiko Azuma,1 Yoko Nomura,1 Ryo Obata,1 Hidenori Takahashi,1,2 Yasuo Yanagi3,4 1Department of Ophthalmology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Tokyo, 2Department of Ophthalmology, Jichi Medical University, Tochigi, Japan; 3Singapore Eye Research Institute, Singapore National Eye Center, 4Ophthalmology and Visual Sciences Program, Duke-NUS Medical School, National University of Singapore, Singapore Purpose: To evaluate the morphological changes in retinal microstructures following modified photodynamic therapy (PDT) for chronic central serous chorioretinopathy. Subjects and methods: Retrospective study of 21 consecutive eyes (age, 59±8.0 years [mean ± SD]) of 21 patients with chronic central serous chorioretinopathy. Inner foveal thickness (the distance between the internal limiting membrane and external limiting membrane), photoreceptor outer segment (PROS) length at the point without serous retinal detachment and choroidal thickness were assessed with enhanced depth imaging optical coherence tomography before treatment and at 1, 3 and 6 months after modified PDT. Results: Six eyes had half-dose and 15 eyes had half-fluence PDT. PROS length within the irradiated area was significantly decreased by 3.9% at 1 month compared with that before modified PDT (43.5±5.72 and 40.5±7.53, P=0.020 [paired t-test]) and returned to baseline length at 3 and 6 months (43.0±5.42 and 43.5±4.33 µm [mean ± SD]; P=0.53 and 1.00 [paired t-test]). PROS length of the nonirradiated area at 1, 3 and 6 months after modified PDT did not significantly differ from that before PDT (41.8±6.35, 41.4±5.33, 41.9±4.67 and 42.3±4.26 µm [mean ± SD]; P=0.66, 0.90 and 0.60, respectively [paired t-test]). There was no significant change in inner foveal thickness during the observation period. At all time points, choroidal thickness was significantly thinner than it was before PDT (P

Kazuhiro Shimizu,1 Tomoyuki Yamamoto,2,3 Kohji Shirai2,4 1Department of Internal Medicine, Toho University Sakura Medical Center, Chiba, Japan; 2Department of Vascular Function, Toho University Sakura Medical Center, Chiba, Japan; 3Biological Information Analysis Section, Fukuda Denshi Co., Ltd., Tokyo, Japan; 4Department of Internal Medicine, Mihama Hospital, Chiba, Japan Abstract: The cardio–ankle vascular index (CAVI) is an indicator of arterial stiffness from the heart to the ankles. The CAVI increases as arteriosclerosis progresses, but it can be decreased by appropriate treatment. There are several risk factors for coronary artery disease, however, the degree of stress caused by each separate risk factor to arteries cannot be assessed. CAVI increases with age and according to the severity of atherosclerosis. We found that CAVI also changes in response to the control of risk factors, which may be associated with the functional stiffness of arteries. CAVI can be a useful indicator of risk control for coronary artery disease. We followed a patient aged 71 years who had diabetes mellitus and obstructive sleep apnea (OSA) by measuring CAVI for 8 years from age 63. He underwent coronary artery bypass grafting due to angina pectoris when he was 63 years old. Before coronary artery bypass grafting, CAVI was 11.8 on the right and 11.5 on the left. Three years later he was found to have OSA and received treatment with continuous positive airway pressure. There was a marked improvement in CAVI after continuous positive airway pressure (age 68; right 10.4, left 10.2). However, following a gradual increase in body weight and worsening of diabetes mellitus, CAVI showed an increasing trend. CAVI decreased with biguanides treatment, but increased again with an increase in body weight. In conclusion, CAVI responded to the patient’s conditions including obesity, diabetes mellitus, and OSA. CAVI is not only a marker of arterial stiffness, but can also be a useful indicator of physiological status; it may be effective in total risk control for coronary artery disease. Keywords: obstructive sleep apnea, continuous positive airway pressure, cardio-ankle vascular index, biguanides, obesity

Kazuhiro Shimizu,1 Tomoyuki Yamamoto,2,3 Mao Takahashi,1 Shuji Sato,1 Hirofumi Noike,1 Kohji Shirai2 1Department of Internal Medicine, 2Department of Vascular Function, Toho University Sakura Medical Center, Chiba, 3Biological Information Analysis Section, Fukuda Denshi Co., Ltd, Tokyo, Japan Purpose: The purpose of this study was to clarify the difference between effects of nitroglycerin (NTG) on the functional stiffness in patients with and without coronary artery disease (CAD) using a newly developed stiffness index, cardio-ankle vascular index (CAVI).Subjects and methods: The two subject groups in this study were normal controls (n=31) and CAD patients (n=25). The normal controls had no medical history and were not on regular medications. On the other hand, the CAD patients had received various treatments like antihypertensive drugs, hypoglycemic agents, and statins. This study was conducted in CAD patients under medications. After a single sublingual administration of NTG 0.3 mg, CAVI, blood pressure (BP), and heart rate (HR) were measured every 5 minutes for 20 minutes. Comparisons of each parameter before and after taking NTG were evaluated for statistical significance using analysis of variance and post hoc tests. Tukey–Kramer test was used for post hoc comparisons.Results: In the normal controls, CAVI significantly decreased from baseline after 5, 10, and 15 minutes (from 6.5±0.9 to 5.2±0.9, 5.5±0.9, and 5.7±0.9, respectively). Systolic BP and HR were not significantly changed. Diastolic BP significantly decreased from baseline after 5 and 10 minutes (from 72±8 to 64±9 and 63±9 mmHg, respectively). On the other hand, CAVI, HR, and diastolic BP were not changed significantly in CAD patients. Systolic BP was significantly decreased from baseline after 5, 10, and 15 minutes (from 147±16 to 131±14, 129±12, and 129±13 mmHg, respectively). In the comparison of the two groups, ΔCAVI was not significantly different between the normal controls and CAD patients (–1.4±0.7 vs –1.4±0.9, –1.1±0.7 vs –1.4±1.0, –0.8±0.7 vs –1.2±1.0, and –0.5±0.7 vs –1.1±1.0 at 5, 10, 15, and 20 minutes, respectively). ΔHR was not significantly different between the two groups. ΔSystolic BP in the CAD patients was significantly higher than in the normal controls at 5, 10, 15, and 20 minutes (normal controls vs CAD; –3±7 vs –10±11, –3±5 vs –10±11, –3±6 vs –13±10, and –1±6 vs –11±10 mmHg, respectively). ΔDiastolic BP in the normal controls was significantly higher than in the CAD patients at 5 and 10 minutes (normal controls vs CAD; –8±6 vs –4±4 and –9±4 vs –6±5 mmHg, respectively). Conclusion: After NTG administration, the stiffness of the arteries from the origin of the aorta to the ankle as measured by CAVI decreased in both the normal controls and CAD patients, indicating that the response of arterial smooth muscle cells to nitric oxide is preserved even in CAD patients under medication. Keywords: arterial stiffness, cardio-ankle vascular index, nitroglycerin, nitric oxide, stiffness parameter

Sonoko Tatsui,1 Hitoshi Ishikawa,2 Kimiya Shimizu,1 Kimiyo Mashimo1 1Department of Ophthalmology, School of Medicine, Kitasato University, 2Department of Orthoptics and Visual Sciences, School of Allied Health Sciences, Kitasato University, Sagamihara, Japan Purpose: Brimonidine is an imidazoline compound used for the treatment of glaucoma, but having very little effect on pupil diameter. Like para-aminoclonidine, most imidazoline compounds interact with postsynaptic α-adrenoceptors and cause pupil dilatation. Therefore, as part of an investigation of the mechanism of action of brimonidine on pupil diameter, the present study was initiated to measure, in vitro, the relative potency of brimonidine on the pre- and postsynaptic α-adrenoceptors of rabbit iris dilator muscle. Methods: The contractile activity of brimonidine and its effect on twitch contraction evoked by electrical field stimulation were studied in isolated rabbit iris dilator muscles by isometric tension recording. Results: Brimonidine significantly inhibited the twitch contraction of the dilator muscle caused by field stimulation, without affecting the response to exogenously applied phenylephrine. Compared to phenylephrine, brimonidine caused only a small contractile response with % maximum contraction values of

Katsuhiko Shimizu, Riki Okita, Shinsuke Saisho, Takuro Yukawa, Ai Maeda, Yuji Nojima, Masao Nakata Department of General Thoracic Surgery, Kawasaki Medical School, Kurashiki, Japan Background: Adjuvant chemotherapy after the complete resection of non-small-cell lung cancer (NSCLC) is now the standard of care. To improve survival, it is important to identify risk factors for the continuation of adjuvant chemotherapy. In this study, we analyzed chemotherapy compliance and magnitude of the prognostic impact of the prognostic nutritional index (PNI) before adjuvant chemotherapy. Methods: We conducted a retrospective review of data from 106 patients who had received adjuvant chemotherapy. The adjuvant chemotherapy consisted of an oral tegafur agent (OT) or platinum-based chemotherapy (PB). The correlations between the PNI values and recurrence-free survival (RFS) were then evaluated. Results: In the PB group, the percentage of patients who completed the four planned cycles of chemotherapy was not correlated with the PNI. In the OT group, however, a significant difference was observed in the percentage of patients who completed the planned chemotherapy according to the PNI before adjuvant chemotherapy. The RFS of patients with a PNI

Kenichiro Shimizu,1 Yutaka Yoshii,1 Miyuki Morozumi,2 Naoko Chiba,2 Kimiko Ubukata,2 Hironori Uruga,3 Shigeo Hanada,3 Nayuta Saito,1 Tsukasa Kadota,1 Saburo Ito,1 Hiroshi Wakui,1 Naoki Takasaka,1 Shunsuke Minagawa,1 Jun Kojima,1 Hiromichi Hara,1 Takanori Numata,1 Makoto Kawaishi,1 Keisuke Saito,4 Jun Araya,1 Yumi Kaneko,1 Katsutoshi Nakayama,1 Kazuma Kishi,3 Kazuyoshi Kuwano1 1Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University School of Medicine, 2Department of Infectious Diseases, Keio University School of Medicine, 3Department of Respiratory Medicine, Respiratory Center, Toranomon Hospital, 4Department of Respiratory Medicine, The Jikei University Daisan Hospital, Tokyo, Japan Abstract: Respiratory infection is a major cause of exacerbation in chronic obstructive pulmonary disease (COPD). Infectious contributions to exacerbations remain incompletely described. We therefore analyzed respiratory tract samples by comprehensive real-time polymerase chain reaction (PCR) in combination with conventional methods. We evaluated multiple risk factors for prolonged hospitalization to manage COPD exacerbations, including infectious agents. Over 19 months, we prospectively studied 46 patients with 50 COPD exacerbations, collecting nasopharyngeal swab and sputum samples from each. We carried out real-time PCR designed to detect six bacterial species and eleven viruses, together with conventional procedures, including sputum culture. Infectious etiologies of COPD exacerbations were identified in 44 of 50 exacerbations (88%). Infections were viral in 17 of 50 exacerbations (34%). COPD exacerbations caused by Gram-negative bacilli, including enteric and nonfermenting organisms, were significantly associated with prolonged hospitalization for COPD exacerbations. Our results support the use of a combination of real-time PCR and conventional methods for determining both infectious etiologies and risk of extended hospitalization. Keywords: COPD, exacerbation, etiology, real-time PCR, prolonged hospitalization, risk factor

Katsura Nagai,1 Hironi Makita,1 Masaru Suzuki,1 Kaoruko Shimizu,1 Satoshi Konno,1 Yoichi M Ito,2 Masaharu Nishimura1 On behalf of the Hokkaido COPD Cohort Study Investigators 1First Department of Medicine, Hokkaido University School of Medicine, 2Department of Biostatistics, Hokkaido University Graduate School of Medicine, Sapporo, Japan Background: The aim of the study was to examine the longitudinal change in quality of life components of patients with chronic obstructive pulmonary disease (COPD).Methods: In the Hokkaido COPD Cohort Study, 261 subjects were appropriately treated and followed over 5 years with a 74% follow-up rate at the end. The longitudinal changes in St George’s Respiratory Questionnaire (SGRQ) scores were annually evaluated with forced expiratory volume in 1 second (FEV1). The subjects were classified into the rapid decliners, slow decliners, and sustainers based on ∆FEV1/year.Results: The activity component of SGRQ generally deteriorated over time, and its annual decline was the greatest in the rapid decliners (75 percentile), and it did not deteriorate even in the rapid decliners. Of the baseline data, predictors for worsening of the activity component were older age and lower body mass index. Larger reversibility was related to symptom component improvement. Of the follow-up data, ∆FEV1/year was the best predictor for worsening of the components of SGRQ. Continuous smoking was another factor for worsening of the activity component. For the symptom component, a history of exacerbation by admission definition was the determinant of its deterioration, whereas use of beta agonists was related to improvement.Conclusion: The longitudinal changes of quality of life and their determinants are markedly different and independent between its components. The activity component of SGRQ generally deteriorated over years, while the symptom component rather improved in some patients with COPD under appropriate treatment. Keywords: annual change, forced expiratory volume in 1 second, SGRQ, smoking, exacerbation

Kei Iijima, Kimiya Shimizu, Yoshiaki Ichibe Department of Ophthalmology, Kitasato University, Kanagawa, Japan Purpose: To investigate the etiology of bilateral disc swelling in Japanese.Methods: Using Kitasato University’s Department of Neuro-Ophthalmology medical records and fundus photographs of the period December 1977 through November 2010, we retrospectively identified 121 outpatients who had been initially confirmed with bilateral disc swelling. Results: The most common cause of the bilateral disc swelling was increased intracranial pressure (ICP) (59%); followed by pseudopapillitis (16%); uveitis (8%); hypertensive retinopathy (5%); bilateral optic neuritis, acute disseminated encephalomyelitis (ADEM) and optic disc drusen (all at 2% each); and leukemia (1%). Unknown etiology accounted for 6% of the cases.Conclusion: Although increased ICP is the most common etiology for bilateral disc swelling, it can also be triggered by a variety of other causes. Pseudopapillitis is the most important progenitor of bilateral disc swelling in Japanese. Keywords: bilateral, disc swelling, papilledema, increased ICP, intracranial pressure