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Manabu Akazawa,1 Takahiro Sato,2 Nozomi Ebata,2 Michael LoPresti,3 Ryosuke Nishi3 1Department of Public Health and Epidemiology, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan; 2Medical Affairs, Rare Disease, Pfizer Japan Inc, Shibuya-ku, Tokyo, Japan; 3Value & Access, INTAGE Healthcare Inc., Chiyoda-ku, Tokyo, JapanCorrespondence: Takahiro Sato, Pfizer Japan Inc, 3-22-7 Yoyogi, Shibuya-ku, Tokyo, 151-8589, Japan, Tel +81 90-2935-0848, Email takahiro.sato@pfizer.comBackground: About one-third of caregivers of pediatric or adolescent growth hormone deficiency (pGHD) patients in Japan have reported poor treatment adherence. However, few studies have examined factors related to adherence for that group.Objective: The aim of this study is to consider factors related to poor adherence to daily treatment among caregivers of pGHD patients in Japan.Methods: A cross-sectional survey was conducted among caregivers of pGHD patients in Japan. Caregivers were asked about demographic and treatment characteristics, health literacy, treatment satisfaction, opinions about treatment, and treatment adherence. Health literacy was assessed using the 14-item health literacy scale (HLS-14). Adherence was assessed using the 8-item Morisky Medication Adherence Scale (MMAS-8). Statistical association with adherence was considered using Chi-square and Student’s t–testing. An exploratory factor analysis (EFA) and K-means cluster analysis was conducted to consider the influence of treatment satisfaction and opinions concerning treatment on adherence.Results: Responses were collected from 112 caregivers. The caregiver’s age being 30– 39 years old, the primary caregiver being male, the primary caregiver being employed, and low functional health literacy for the caregiver were associated with poor adherence. Patients being pre-elementary school age was also associated with poor adherence. Low satisfaction with drug treatment and/or their device and communication with healthcare professionals (HCPs), and lack of agreement with the importance of treatment management (eg, keeping injection records, getting informed about the disease/therapy, reporting non-adherence, and sticking to an administration schedule), were also associated with poor adherence.Conclusion: Strategies to improve treatment adherence among caregivers of pGHD patients in Japan should consider the age, gender, and employment status of the caregiver – as well as their functional literacy. Improvement in satisfaction with the drug or device used, better communication with HCPs, and greater awareness of the importance of treatment management, may also lead to better adherence.Keywords: growth hormone, adherence, determinants, satisfaction, communication, health literacy

Takahiro Suzuki,1 Takehito Sato,2 Kaori Masuhara,2 Mizuki Tokusanai,2 Hisako Akatsuka,2 Tomohiro Kashikawa,2 Yasuyuki Suzuki1 1Department of Ophthalmology, Tokai University School of Medicine, Kanagawa, Japan; 2Department of Immunology, Tokai University School of Medicine, Kanagawa, JapanCorrespondence: Takahiro Suzuki, Department of Ophthalmology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1143, Japan, Tel +81-463-93-1121, Fax +81-463-91-9328, Email youta@is.icc.u-tokai.ac.jpPurpose: To elucidate the antiglycation activity of Trapa bispinosa Roxb. extract (TBE) and the related mechanism using a mouse model with type 2 diabetes.Materials and Methods: We prepared control mice by giving them a normal diet, leptin-deficient ob/ob mouse (ob/ob mice) with a normal diet (normal ob/ob mice), and ob/ob mice with a diet containing TBE (TBE ob/ob mice). The effect of TBE on diabetic retina was evaluated by immunohistochemical staining and quantitative real-time polymerase chain reaction (qPCR) analysis.Results: In both groups with ob/ob mice, body weight and hyperglycemia levels increased over time. Immunohistochemical staining analysis revealed that glial fibrillary acidic protein (GFAP) and advanced glycation end products (AGEs) expression levels were higher in normal ob/ob mice than in control mice, and lower in the TBE ob/ob mice than in normal ob/ob mice. Light chain-3 (LC-3) expression levels reduced in normal ob/ob mice compared to the control mice, but increased in TBE ob/ob mice compared to normal ob/ob mice. In the qPCR analysis, LC-3 expression levels were significantly lower in normal ob/ob mice compared to control mice, and significantly higher in TBE ob/ob mice compared to normal ob/ob mice. Conversely, AKT1 and with-no-lysine kinases 1 (WNK1) expression levels were significantly higher in normal ob/ob mice compared to control mice, and significantly lower in TBE ob/ob mice than in normal ob/ob mice.Conclusion: In type 2 diabetes, it was suggested that TBE inhibits the insulin-dependent AKT/WNK1 pathway to induce autophagy, and thereby might promote anti-glycation and reduce retinal damage.Keywords: Trapa bispinosa Roxb. extract, type 2 diabetes, autophagy, insulin-dependent AKT/WNK1 pathway, advanced glycation end products, diabetic retinopathy

Takumi Sato,1 Ryota Ito,1,2 Masato Kawamura,1 Shigeru Fujimura1 1Division of Clinical Infectious Diseases & Chemotherapy, Tohoku Medical and Pharmaceutical University, Sendai, Japan; 2Department of Pharmacy, Japan Labor Health and Welfare Organization Tohoku Rosai Hospital, Sendai, JapanCorrespondence: Takumi Sato, Division of Clinical Infectious Diseases & Chemotherapy, Tohoku Medical and Pharmaceutical University, 4-4-1, Komatsushima, Aoba-ku, Sendai, 981-8558, Japan, Tel +81227270176, Fax +81227270177, Email tsato@tohoku-mpu.ac.jpObjective: Many fluoroquinolones, such as ciprofloxacin, are used clinically. We investigated the relationship between resistance acquisition and exposure duration in each drug through the exposure of fluoroquinolone to Escherichia coli clinical isolates in vitro.Methods: Eleven E. coli clinical isolates were exposed to each fluoroquinolone, ie, ciprofloxacin, levofloxacin, sitafloxacin, garenoxacin, and lascufloxacin, with the concentration of the mutant selection window for 5 days; these procedures were repeated 5-times. In addition, the DNA sequence in the quinolone-resistance determining region (QRDR) and the expression level in the drug efflux pump acrA were analyzed to determine the resistance mechanism.Results: Although resistant strains were not detected after 5 to 10 days of exposure to fluoroquinolone, after 25 days of exposure to ciprofloxacin and levofloxacin, 100% and 45% of isolates acquired resistance, respectively. Due to 25 days of exposure to sitafloxacin, garenoxacin, and lascufloxacin, MIC measurement was elevated 2- to 4096-fold for those of the parental strain, and the cross-resistance rate to levofloxacin was 72%, 54%, and 27%, respectively. In strains with high fluoroquinolone resistance, acrA overexpression was observed in addition to QRDR mutation.Conclusion: In our findings, fluoroquinolone resistance was not observed in the E. coli strain after 5- to 10-days of exposure. However, resistance acquisition was detected frequently after 15- to 25-days of exposure. Among fluoroquinolones, lascufloxacn had the least impact on the resistance acquisition in E. coli.Plain Language Summary: The need to combat quinolone-resistant E. coli is urgent. The resistance acquisition tendency of E. coli varies according to the drug used. After 25 days of exposure, 45% of E. coli showed levofloxacin resistance. Lascufloxacin may have the lowest influence on resistance acquisition to regular E. coli.Keywords: Escherichia coli, respiratory quinolone, mutant selection window, quinolone-resistance determining region, efflux pump

Masahiro Shinoda,1 Shinichiro Ota,1 Yuto Yoshida,1,2 Takatomo Hirouchi,1,2 Kanako Shinada,1 Takashi Sato,1 Miwa Morikawa,1 Naoki Ishii,3 Masaharu Shinkai1 1Department of Respiratory Medicine, Tokyo Shinagawa Hospital, Tokyo, Japan; 2Department of Respiratory Medicine, Toho University Ohashi Medical Center, Tokyo, Japan; 3Department of Gastroenterology, Tokyo Shinagawa Hospital, Tokyo, JapanCorrespondence: Masahiro Shinoda, Department of Respiratory Medicine, Tokyo Shinagawa Hospital, 6-3-22 Higashi-Oi, Shinagawa, Tokyo, 140-8522, Japan, Tel +81-3-3764-0511, Fax +81-3-3764-3415, Email mshinopy@gmail.comIntroduction: Currently, infection control measures for SARS-COV2 are being relaxed, and it is important in daily clinical practice to decide which findings to focus on when managing patients with similar background factors.Methods: We retrospectively evaluated 66 patients who underwent blood tests (complete blood count, blood chemistry tests, and coagulation tests) and thin slice CT between January 1 and May 31, 2020, and performed a propensity score-matched case–control study. Cases and controls were a severe respiratory failure group (non-rebreather mask, nasal high-flow, and positive-pressure ventilation) and a non-severe respiratory failure group, matched at a ratio of 1:3 by propensity scores constructed by age, sex, and medical history. We compared groups for maximum body temperature up to diagnosis, blood test findings, and CT findings in the matched cohort. Two-tailed P-values < 0.05 were considered statistically significant.Results: Nine cases and 27 controls were included in the matched cohort. Significant differences were seen in maximum body temperature up to diagnosis (p=0.0043), the number of shaded lobes (p=0.0434), amount of ground-glass opacity (GGO) in the total lung field (p=0.0071), amounts of GGO (p=0.0001), and consolidation (p=0.0036) in the upper lung field, and pleural effusion (p=0.0117).Conclusion: High fever, the wide distribution of viral pneumonia, and pleural effusion may be prognostic indicators that can be easily measured at diagnosis in COVID-19 patients with similar backgrounds.Keywords: COVID-19, prognosis, fever, ground-glass opacity, consolidation, pleural effusion

Toru Ishikawa,1 Iori Hasegawa,2 Hiroshi Hirosawa,2 Tsubasa Honmou,2 Nobuyuki Sakai,2 Takanori Igarashi,1 Shun Yamazaki,1 Takamasa Kobayashi,1 Toshifumi Sato,1 Akito Iwanaga,1 Tomoe Sano,1 Junji Yokoyama,1 Terasu Honma1 1Department of Gastroenterology, Saiseikai Niigata Hospital, Niigata, Japan; 2Department of Clinical Engineering, Saiseikai Niigata Hospital, Niigata, JapanCorrespondence: Toru Ishikawa, Department of Gastroenterology, Saiseikai Niigata Hospital, Teraji 280-7, Niigata, Japan, Tel +81-25-233-6161, Fax +81-25-233-8880, Email toruishi@ngt.saiseikai.or.jpBackground: Microwave ablation (MWA) is a standard percutaneous local therapy for hepatocellular carcinoma (HCC). Next-generation MWA is reported to create a more spherical ablation zone than radiofrequency ablation (RFA). We compared the ablation zone and aspect ratio of two 2.45 GHz MWA ablation probes; Emprint® (13G) and Mimapro® (17G). We compared the ablation zone to the applied energy after MWA in patients with hepatocellular carcinoma (HCC). Furthermore, we investigated local recurrence.Materials and Methods: We included 20 patients with HCC, with an average tumour diameter of 33.2 ± 12.2 mm, who underwent MWA using Emprint®, and 9 patients who underwent MWA using Mimapro® with an average tumour diameter of 31.1 ± 10.5 mm. Both groups underwent the same ablation protocol using the same power settings. The images obtained after MWA showed the treatment ablation zone and aspect ratio, which were measured and compared using three-dimensional image analysis software.Results: The aspect ratios in the Emprint® and Mimapro® groups were 0.786 ± 0.105 and 0.808 ± 0.122, respectively, with no significant difference (p = 0.604). The ablation time was significantly shorter in the Mimapro® group than in the Emprint® group, and there was no significant difference in the frequency of popping or the ablation volume. There were no significant differences in local recurrence between the two groups.Conclusion: There was no significant difference in the aspect ratios of the ablation diameter, and the ablation zone was almost spherical in both cases. Mimapro® at 17G was less invasive than Emprint® at 13G.Keywords: hepatocellular carcinoma, microwave ablation, ablation zone

Takahiko Tanimoto,1,2 Yoshihiro Eriguchi,1 Tomonori Sato,1 Akiko Yonekawa,1 Noriko Miyake,1 Koichi Akashi,1 Nobuyuki Shimono3 1Department of Clinical Immunology and Rheumatology / Infectious Disease, Kyushu University Hospital, Fukuoka, Japan; 2Department of Infectious Diseases, Kagoshima Seikyo Hospital, Kagoshima, Japan; 3Center for the Study of Global Infection, Kyushu University Hospital, Fukuoka, JapanCorrespondence: Yoshihiro Eriguchi, Department of Clinical Immunology and Rheumatology / Infectious Disease, Kyushu University Hospital, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan, Tel +81 92-801-1011, Fax +81 92-862-8200, Email eriguchi.yoshihiro.145@m.kyushu-u.ac.jpAbstract: Platypnea-orthodeoxia syndrome (POS) is a rare disorder associated with coronavirus disease 2019 (COVID-19) pneumonia. However, POS may be underdiagnosed. We report the case of a 59-year-old female patient with POS complicated by pulmonary embolism in COVID-19. Imaging revealed ground-glass opacities predominantly in the lower lobes and a pulmonary embolus in the right upper lobe. She was diagnosed with POS due to marked postural discrepancies between supine and upright oxygen saturations and blood oxygenation. Intracardiac shunt, one of the etiologies of POS, was not detected by bubble contrast echocardiography, and postural de-saturation gradually improved with methylprednisolone and edoxaban administration. In our literature review, only 3 of the 16 patients with POS associated with COVID-19 had cardiac shunting, suggesting that moderate to severe COVID-19 causes POS without cardiac shunts. COVID-19-associated vasculopathy and lower lung lesion predominance in COVID-19 pneumonia may cause ventilation-perfusion mismatch due to gravitational shunting of blood into the poorly ventilated lower lungs in the upright position, which may ultimately cause POS. Hypoxemia impedes rehabilitation, whereas early initiation of supine positioning in bed, with knowledge of the pathophysiology of POS, may have a positive effect.Keywords: platypnea, orthodeoxia, COVID-19, ventilation-perfusion mismatch

Manabu Akazawa,1 Daisuke Shima,2 Takahiro Sato,2 Emi Shoji,2 Michael LoPresti,3 Ryosuke Nishi3 1Department of Public Health and Epidemiology, Meiji Pharmaceutical University, Tokyo, Japan; 2Medical Affairs, Rare Disease, Pfizer Japan Inc, Tokyo, Japan; 3Market Access, INTAGE Healthcare Inc, Tokyo, JapanCorrespondence: Takahiro Sato, Medical Affairs, Rare Disease, Pfizer Japan Inc, 3-22-7 Yoyogi, Shibuya-ku, Tokyo, 151-8589, Japan, Tel +81 90-2935-0848, Email takahiro.sato@pfizer.comBackground: Poor adherence to daily human growth hormone (hGH) treatment has been shown to be associated with poor clinical outcomes for growth hormone deficiency (GHD) patients. However, few studies have examined the perception of adherence to hGH treatment among both physicians and caregivers in Japan.Objective: The aim of this study is to examine the perception of adherence for daily hGH treatment among physicians and caregivers of pediatric and adolescent patients treated with GH in Japan. Moreover, we explore reasons for skipping treatment and the potential impact of a once-weekly treatment on adherence.Methods: A cross-sectional survey was conducted in Japan among physicians that prescribe daily hGH treatment and caregivers that have administered daily hGH treatment to children/adolescents for 3 months or longer. The Morisky Medication Adherence Scale (MMAS-8) was used to gauge perceived adherence for both physician and caregiver groups. Caregivers were also questioned regarding reasons for missing injections. Moreover, both groups were asked about the impact of a once-weekly treatment on adherence.Results: Responses were collected from 123 physicians and 112 caregivers. Physicians reported that 18.1% of patients have poor adherence based on the MMAS-8 instrument. In contrast, 32.1% of the caregivers reported poor adherence. “Simply forgetting”, “Patient refused/resisted”, and being “Busy with school activities, etc” were the most commonly selected reasons by caregivers for missing an injection. Physicians felt that a once-weekly injection could improve adherence for 64.5% of patients with poor adherence. Moreover, 56.9% of the caregivers that reported an experience of missed injections felt that a once-weekly injection would improve their adherence.Conclusion: Approaches to improve adherence to hGH treatment in Japan are continuously needed. While further research is needed to understand factors most likely to improve adherence, availability of a once-weekly treatment is expected to help improve adherence.Keywords: adherence, growth hormone, Japanese, recombinant, injections, MMAS

Ryota Ito, Masato Kawamura, Takumi Sato, Shigeru Fujimura Tohoku Medical and Pharmaceutical University, Division of Clinical Infectious Diseases & Chemotherapy, Sendai, Miyagi, JapanCorrespondence: Ryota Ito, Tohoku Medical and Pharmaceutical University, Division of Clinical Infectious Diseases & Chemotherapy, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi, 981-8558, Japan, Tel +81-22-727-0169, Fax +81-22-727-0176, Email 21951503@is.tohoku-mpu.ac.jpPurpose: Cefmetazole (CMZ), a cephamycin antibiotic, is primarily used as a definitive therapy for Extended Spectrum β-Lactamase (ESBL)-producing Escherichia coli infections. However, the mechanism of CMZ resistance in E. coli is still unknown. To elucidate the resistance mechanism and to determine combined drugs for prevention of resistance acquisition.Methods: Clinical isolates of 14 ESBL-producing E. coli and non-producing 12 isolates were used in in vitro testing of CMZ resistance acquisition. After 10-day of CMZ exposure (1st subculture), these strains were incubated in an antibacterial-free medium for 14-day. These strains were again exposed to CMZ for 10-day (2nd subculture) and confirmed for changes in MIC. For each strain detected after 1st subculture, each mRNA expression level of porin, chromosomal ampC, and drug-efflux pump was measured using real-time RT-PCR. Relebactam (REL) has the potency to recover antimicrobial activity against carbapenem-resistant Enterobacterales that has porin deficiency. REL was added to the CMZ dilution series, and MIC changes and those of porin were confirmed.Results: Of these 26 strains, 15 strains (57.7%) acquired resistance after 1st subculture, but after passage culture on the antibacterial-free medium, 11 strains recovered susceptibility. These 11 strains showed resistance after 2nd subculture. The expression levels of ompF and ompC were significantly decreased in these strains (P< 0.05). When REL was added, all strains suppressed resistance acquisition after 1st subculture. The mechanism was the activation of ompF.Conclusion: Our results showed that the mRNA expression levels of genes encoding porin were decreased in the strains that acquired resistance due to CMZ exposure, and that ompF and ompC in particular were thought to be involved in the acquisition of resistance. The CMZ acquisition of resistance was also suppressed by the concomitant use of REL and actually suppressed the decrease in mRNA expression in ompF. It was confirmed that porin reactivated by REL.Keywords: cefmetazole, porin, relebactam, extended spectrum β-lactamase, ESBL, Escherichia coli

Takumi Sato, Ryota Ito, Masato Kawamura, Shigeru Fujimura Division of Clinical Infectious Diseases & Chemotherapy, Tohoku Medical and Pharmaceutical University, Sendai, JapanCorrespondence: Takumi Sato, Division of Clinical Infectious Diseases & Chemotherapy, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, 981-8558, Japan, Tel/Fax +81227270176, Email tsato@tohoku-mpu.ac.jpObjective: Due to the spread of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA), the demand for trimethoprim/sulfamethoxazole (SXT) is increasing in the world. It is not clear whether the resistant strain emerges by overuse of SXT. We investigated here the emergent risk of the SXT-resistant mutant in S. aureus by an in vitro SXT exposure experiment.Methods: A total of 40 S. aureus clinical isolates (20 MSSA and 20 MRSA isolates) were exposed to sub-MIC of SXT for consecutive days, and MIC of SXT was determined every day. In addition, the dfrB DNA sequencing was performed to detect the mutation in the SXT-resistant strain.Results: The SXT-resistant strain began to emerge on the eighth day and accounted for 45% (18/40 clinical isolates) after 14 days. Moreover, one half of these resistant strains showed F98Y mutation in DfrB to retain SXT-resistance without selective pressure.Conclusion: The emergent risk was SXT exposure of 14 days or more.Keywords: Staphylococcus aureus, antimicrobial resistance, trimethoprim/sulfamethoxazole, dfrB

Keita Suzuki,1 Hiromasa Tsujiguchi,1– 3 Akinori Hara,1– 3 Oanh Kim Pham,1 Sakae Miyagi,3,4 Thao Thi Thu Nguyen,5 Haruki Nakamura,1 Fumihiko Suzuki,2,6 Tomoko Kasahara,2 Yukari Shimizu,7 Yohei Yamada,2 Yasuhiro Kambayashi,8 Hirohito Tsuboi,9 Takehiro Sato,3,10 Takayuki Kannon,3,10 Kazuyoshi Hosomichi,3,10 Atsushi Tajima,3,10 Toshinari Takamura,11 Hiroyuki Nakamura1– 3 1Department of Hygiene and Public Health, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan; 2Department of Public Health, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan; 3Kanazawa University Advanced Preventive Medical Sciences Research Center, Kanazawa, Ishikawa, Japan; 4Innovative Clinical Research Center, Kanazawa University, Kanazawa, Ishikawa, Japan; 5Department of Epidemiology, Faculty of Public Health, Haiphong University of Medicine and Pharmacy, Hai Phong, Vietnam; 6Community Medicine Support Dentistry, Ohu University Hospital, Koriyama, Fukushima, Japan; 7Department of Nursing, Faculty of Health Sciences, Komatsu University, Komatsu, Ishikawa, Japan; 8Department of Public Health, Faculty of Veterinary Medicine, Okayama University of Science, Imabari, Ehime, Japan; 9Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan; 10Department of Bioinformatics and Genomics, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan; 11Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, JapanCorrespondence: Keita Suzuki, Department of Hygiene and Public Health, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 13-1, Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan, Tel +81 76 265 2218, Fax +81 76 234 4233, Email ksuzuk@staff.kanazawa-u.ac.jpBackground: Previous studies examined the association between chronic pain (CP) and serum 25-hydroxyvitamin D (25(OH)D) concentrations; however, the findings obtained were inconsistent. Single nucleotide polymorphisms (SNP) associated with the transcriptional activity of the vitamin D receptor (VDR) gene may influence the association of 25(OH)D levels with CP. We aimed to clarify the association between CP, serum 25(OH)D concentration, and SNPs.Methods: In the Shika study, we performed a cross-sectional analysis of 551 participants older than 40 years who were asked whether they had been having persistent pain lasting for at least 3 months in any part of the body on a self-administered questionnaire. Serum 25(OH)D concentrations were assessed as a biomarker of the vitamin D status using a radioimmunoassay. rs731236, rs7975232, rs1544410, rs2228570, and rs11568820 were identified using peripheral blood samples, and participants were assigned to those with or without the minor allele for each SNP.Results: The prevalence of CP was 37.2%. We observed a tendency for lower 25(OH)D levels in participants with CP than in those without CP in the hetero/minor group of rs11568820, which is a polymorphism within the CDX2-binding site in the 1e promoter region of the VDR gene. Furthermore, a logistic regression analysis revealed that lower serum 25(OH)D concentrations were significantly associated with CP in the hetero/minor group, but not in the major group.Conclusion: These results suggest that sufficient serum 25(OH)D concentration reduces the risk of CP in individuals with the minor allele of the CDX2 polymorphism.Keywords: chronic pain, 25-hydroxyvitamin D, vitamin D receptor gene, promoter, polymorphism, epidemiology

Satoshi Igawa,1 Masashi Kasajima,1 Taihei Ono,1 Takahiro Ozawa,1 Mikiko Kakegawa,1 Seiichiro Kusuhara,1 Takashi Sato,1 Yoshiro Nakahara,1 Tomoya Fukui,1 Masanori Yokoba,2 Masaru Kubota,2 Hisashi Mitsufuji,3 Jiichiro Sasaki,4 Katsuhiko Naoki1 1Department of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara-city, Kanagawa, Japan; 2School of Allied Health Sciences, Kitasato University, Sagamihara-city, Kanagawa, Japan; 3Kitasato University School of Nursing, Sagamihara-city, Kanagawa, Japan; 4Kitasato University School of Medicine, Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Sagamihara-city, Kanagawa, JapanCorrespondence: Satoshi IgawaDepartment of Respiratory Medicine, Kitasato University School of Medicine, 1-15-1, Kitasato, Minami-ku, Sagamihara-city, Kanagawa, 252-0374, JapanTel +81-42-778-8506Fax +81-42-778-6412Email igawa@kitasato-u.ac.jpBackground: The clinical outcomes of elderly patients with EGFR-mutated non-small cell lung cancer (NSCLC) who are treated with osimertinib have not been sufficiently evaluated. This study aimed to assess the efficacy and safety of osimertinib in elderly chemotherapy-naive patients with NSCLC harboring sensitive EGFR mutations.Patients and Methods: We assessed the clinical effects of osimertinib as a first-line treatment for elderly NSCLC patients (≥ 75 years of age) with an exon 19 deletion or exon 21 L858R mutation in EGFR. All patients were administered 80 mg/day osimertinib as initial treatment.Results: Forty-three patients (24 women and 19 men) with adenocarcinoma who were treated between August 2018 and July 2021 were included in this study; their median age was 79 years (range, 75– 90 years). The overall objective response rate was 60.5%. The median progression-free survival (PFS) and time to treatment failure (TTF) of the entire patient population were 22.1 months and 14.6 months, respectively. The most common adverse event was rash acneiform (42%), followed by diarrhea (33%) and paronychia (28%); none of these were grades ≥ 3. Interstitial lung disease developed in 8 patients (18.6%); however, no treatment-related deaths occurred. Multivariate analysis identified performance status and disease stage as predictors of PFS and TTF.Conclusion: Considering the findings of this study and despite an observed discordance between PFS and TTF, osimertinib appears to be an effective and safe treatment option in elderly patients with advanced NSCLC harboring sensitive EGFR mutations. To obtain conclusive results, further studies in a larger elderly population are warranted.Keywords: non-small cell lung carcinoma, chemotherapy-naïve patients, efficacy

Motoyasu Kato,1,2 Fumiyuki Takahashi,1,2 Tadashi Sato,1,2 Yoichiro Mitsuishi,1,2 Ken Tajima,1,2 Hiroaki Ihara,1,2 Fariz Nurwidya,1,2 Hario Baskoro,1,2 Akiko Murakami,1,2 Isao Kobayashi,1,2 Moulid Hidayat,1,2 Naoko Shimada,1– 3 Shinichi Sasaki,1,2 Reiko Mineki,4 Tsutomu Fujimura,5 Toshio Kumasaka,6 Shin-ichiro Niwa,7 Kazuhisa Takahashi1– 3 1Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan; 2Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, Tokyo, Japan; 3Leading Center for the Development and Research of Cancer Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan; 4Laboratory of Proteomics and Biomolecular Science, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo, Japan; 5Laboratory of Bioanalytical Chemistry, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan; 6Department of Pathology, Japanese Red Cross Medical Center, Tokyo, Japan; 7Link Genomics, Incorporated, Tokyo, JapanCorrespondence: Motoyasu KatoDepartment of Respiratory Medicine, Juntendo University, Graduate School of Medicine, Bunkyo-Ku, Tokyo 113-8431, JapanTel +81-3-5802-1063Fax +81-3-5802-1617Email mtkatou@juntendo.ac.jpPurpose: Idiopathic pulmonary fibrosis (IPF) is characterized by the accumulation of extracellular matrix (ECM) protein in the lungs. Transforming growth factor (TGF) β-induced ECM protein synthesis contributes to the development of IPF. Tranilast, an anti-allergy drug, suppresses TGFβ expression and inhibits interstitial renal fibrosis in animal models. However, the beneficial effects of tranilast or its mechanism as a therapy for pulmonary fibrosis have not been clarified.Methods: We investigated the in vitro effect of tranilast on ECM production and TGFβ/SMAD2 pathway in TGFβ 2-stimulated A549 human alveolar epithelial cells, using quantitative polymerase chain reaction, Western blotting, and immunofluorescence. In vitro observations were validated in the lungs of a murine pulmonary fibrosis model, which we developed by intravenous injection of bleomycin.Results: Treatment with tranilast suppressed the expression of ECM proteins, such as fibronectin and type IV collagen, and attenuated SMAD2 phosphorylation in TGFβ 2-stimulated A549 cells. In addition, based on a wound healing assay in these cells, tranilast significantly inhibited cell motility, with foci formation that comprised of ECM proteins. Histological analyses revealed that the administration of tranilast significantly attenuated lung fibrosis in mice. Furthermore, tranilast treatment significantly reduced levels of TGFβ, collagen, fibronectin, and phosphorylated SMAD2 in pulmonary fibrotic tissues in mice.Conclusion: These findings suggest that tranilast inhibits pulmonary fibrosis by suppressing TGFβ/SMAD2-mediated ECM protein production, presenting tranilast as a promising and novel anti-fibrotic agent for the treatment of IPF.Keywords: tranilast, idiopathic pulmonary fibrosis, TGFβ, SMAD2

Masanori Fukumoto, Takaki Sato, Shou Oosuka, Teruyo Kida, Hidehiro Oku, Tsunehiko Ikeda Department of Ophthalmology, Osaka Medical College, Takatsuki-City, Osaka, JapanCorrespondence: Tsunehiko IkedaDepartment of Ophthalmology, Osaka Medical College, 2-7 Daigaku-Machi, Takatsuki-City, Osaka 569-8686, JapanTel +81-72-684-6434Fax +81-72-682-0995Email tikeda@osaka-med.ac.jpPurpose: To retrospectively review and analyze the clinical and imaging data of patients with vitreomacular traction syndrome (VMTS) with strong peripheral vitreoretinal adhesion.Subjects and Methods: This retrospective case-series study involved 4 eyes of 4 VMTS patients with vitreoretinal adhesion in both the macular region and the periphery who underwent vitreous surgery. In all 4 cases, preoperative refraction, fundoscopic findings, optical coherence tomography (OCT) findings, and intraoperative findings were evaluated.Results: The preoperative fundoscopy and OCT findings revealed fibrous membranes around the optic nerve head in 3 eyes. Thickened posterior vitreous membranes extending from the posterior pole to the periphery were observed in all eyes. Apparent VMTS or epimacular membrane was also found in the fellow eyes of 2 patients. The preoperative refractive errors ranged from +0.5 diopters (D) to +2.75 D (mean, +1.13 D). Intraoperatively, a thickened posterior vitreous membrane was found strongly adhered to the retina in the macula regions, optic nerve head, and periphery. In 2 eyes, when artificial posterior vitreous detachment (PVD) was created, an iatrogenic tear developed in the periphery.Conclusion: The features of VMTS that cause strong peripheral vitreoretinal adhesion include the preoperative presence of a thickened posterior vitreous membrane over a wide area, hypermetropia, and a short axial length.Keywords: hypermetropic, iatrogenic tear, peripheral vitreoretinal adhesion, posterior vitreous detachment, vitreomacular traction syndrome, vitreous surgery

Shigeto Nishikawa,1 Toshi Menju,1 Koji Takahashi,1 Ryo Miyata,1 Toyofumi Fengshi Chen-Yoshikawa,1 Makoto Sonobe,1 Akihiko Yoshizawa,2 Hisataka Sabe,3 Tosiya Sato,4 Hiroshi Date11Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; 2Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan; 3Department of Molecular Biology, Faculty of Medicine, Hokkaido University, Sapporo, Japan; 4Department of Biostatistics, Kyoto University School of Public Health, Kyoto, JapanPurpose: The epithelial to mesenchymal transition (EMT) is pivotal for driving metastasis and recurrence in lung cancer. Some in vitro reports have shown that statins suppress EMT by inactivating mutant p53 functions. Several clinical trials of conventional treatments with statins have been performed, but the effect of these drugs on prognosis is still uncertain. The purpose of this study is to examine the impact of statins on EMT and the prognosis of patients with lung adenocarcinoma.Materials and methods: Morphological changes were evaluated and EMT markers (E-cadherin, vimentin) were analyzed by Western blotting in p53-overexpressing H1650 and mutant p53-harboring H1975 lung adenocarcinoma cells, with and without simvastatin administration. The invasive ability of these cells was analyzed in a Matrigel chemoinvasion assay. A total of 250 lung adenocarcinoma specimens were also collected from patients who underwent surgery in our institute. EMT markers in these tumor specimens were evaluated by immunostaining and p53 mutation status was determined by direct sequencing. Associations among EMT status, p53 mutation status, and statin use were evaluated, and prognosis was analyzed using a marginal structural model.Results: Mutant p53 induced EMT and increased the invasive ability of H1650 cells. Simvastatin restored the epithelial phenotype and decreased the invasive ability of both H1650 and H1975 cells. Statin administration was associated with inactivation of EMT only in patients with mutant p53, which was consistent with the in vitro results. Moreover, in patients with mutant p53, statin users had significantly better survival than non-statin users. In contrast, statins significantly worsened the prognosis of patients with wild type p53 (HR 2.10, 95% CI 1.14–3.85).Conclusion: Statins suppress EMT and change the prognosis of patients with lung adenocarcinoma in a p53 mutation-dependent manner.Keywords: p53, epithelial to mesenchymal transition, statin, survival analysis, non-small cell lung cancer

Yoshinori Terashima,1,2 Tsuneo Takebayashi,3 Shunsuke Jimbo,1 Izaya Ogon,1 Tatsuya Sato,2 Nobutoshi Ichise,2 Noritsugu Tohse,2 Toshihiko Yamashita1 1Department of Orthopaedic Surgery, School of Medicine, Sapporo Medical University, Sapporo 060-0061, Japan; 2Department of Cellular Physiology and Signal Transduction, School of Medicine, Sapporo Medical University, Sapporo 060-0061, Japan; 3Sapporo Maruyama Orthopaedic Hospital, Sapporo 060-0007, Japan Purpose: Radicular pain is a frequently observed symptom of lumbar disk herniation or lumbar spinal canal stenosis. Achieving radicular pain relief is difficult. This type of pain may progress to chronic neuropathic pain. Calcitonin (elcatonin [eCT]) has been used mainly for hypercalcemia and pain associated with osteoporosis. The purpose of this study was to investigate analgesic effects of repeated eCT administration on radicular pain in male rats and changes in mRNA-expression levels of voltage-dependent sodium channels in the dorsal root ganglion (DRG). Methods: Seventy male Sprague-Dawley rats were used. A right L5 hemilaminectomy and an L5–L6 partial facetectomy were performed to expose the right L5 nerve root. Under a microscope, the right L5 spinal nerve root was tightly ligated extradurally with 8-0 nylon suture proximally to the DRG to cause radicular pain in rats. Mechanical hyperalgesia, thermal hyperalgesia, and analgesic effects of eCT were compared among rats with radicular pain that received eCT, those that received the vehicle, and sham rats that received the vehicle. Real-time reverse-transcription PCR was performed to measure mRNA-expression levels of tetrodotoxin-sensitive (NaV1.3 and NaV1.6) and tetrodotoxin-resistant (NaV1.8 and NaV1.9) sodium channels in the DRG. Results: Mechanical and thermal hyperalgesic reactions occurring in rats with radicular pain significantly improved on days 5 and 9 of eCT administration, respectively. In rats with radicular pain, mRNA-expression levels of NaV1.3, NaV1.8, and NaV1.9 increased. After repeated eCT administration, mRNA-expression levels of these sodium channels in rats with radicular pain improved to the same levels as in sham rats. Conclusion: The present study demonstrated that repeated systemic eCT administration was effective for radicular pain. No serious side effects of eCT have been reported thus far. Therefore, calcitonin may be a preferred therapeutic option for patients with radicular pain or for those requiring long-term treatment. Keywords: radiculopathy, hyperalgesia, lumbar disk herniation, lumbar spinal canal stenosis, sodium channel, elcatonin

Shunsuke Jimbo,1 Yoshinori Terashima,1,2 Atsushi Teramoto,1 Tsuneo Takebayashi,3 Izaya Ogon,1 Kota Watanabe,4 Tatsuya Sato,2,5 Nobutoshi Ichise,2 Noritsugu Tohse,2 Toshihiko Yamashita1 1Department of Orthopaedic surgery, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan; 2Department of Cellular Physiology and Signal Transduction, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan; 3Sapporo Maruyama Orthopaedic Hospital, Sapporo 060-0007, Japan; 4Department of Second Division of Physical Therapy, Sapporo Medical University School of Health Sciences, Sapporo 060-8556, Japan; 5Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan Purpose: Ankle osteoarthritis (OA) causes significant pain and debilitation; yet, its underlying mechanisms remain unclear. Clinically, hyaluronic acid (HA) is widely used to treat OA. The present study aimed to investigate the roles of HA in pain-related behavior, joint function, swelling, and pathological changes in cartilage in a rat model of monoiodoacetate (MIA)-induced ankle OA. Materials and methods: Male Sprague Dawley rats were assigned to three experimental groups as follows: 1) MIA rats injected with 1 mg MIA in the right tibiotarsal joint for two consecutive days; 2) sham rats injected with saline instead of MIA; and 3) MIA-HA rats injected with HA in the tibiotarsal joint at 7, 14, and 21 days after MIA injection. Joint swelling, range of motion (ROM), and pain-related behavior were evaluated 1 day before and on the 7th, 14th, 21st, and 28th day after MIA or saline injection. Pathological changes in the ankle joint were assessed 28 days after MIA or saline injection. Results: No significant difference in the degree of ankle swelling or ROM reduction was observed between MIA rats and MIA-HA rats. However, compared with those in MIA rats, mechanical and thermal hypersensitivity was significantly reduced and stride length significantly improved in MIA-HA rats. Histologic analysis revealed that cartilage degeneration was significantly suppressed in MIA-HA rats compared with that in MIA rats, reflecting the chondroprotective effects of HA. Conclusion: HA improved pain-related behavior and stride length and suppressed MIA-induced cartilage degeneration. HA may thus inhibit OA progression and suppress peripheral and/or central sensitization. Keywords: ankle osteoarthritis, monoiodoacetate, osteoarthritis pain, hyaluronic acid

The incorporation of boron into a diamond lattice holds the potential to advance X-ray optics, offering the capability to manipulate various parameters of the lattice. This includes enhancing near-infrared absorption relative to pure diamond, thereby enabling Q-switchable optics. The use of MeV boron implantation emerges as a promising method for precisely doping the diamond lattice. However, for these optics to function effectively as Bragg-reflecting mirrors, ion implantation must be executed with meticulous attention to maintaining a strain-free, perfect diamond lattice. This study aimed to investigate the feasibility of utilizing a 9 MeV ion beam for high energy boron implantation. Different areas of a high-pressure, high-temperature (HPHT) diamond sample were subjected to irradiation with 9 MeV Boron ions, ranging in fluences from 5×1015 to 2.5×1016ions/cm2. Following boron implantation, high-temperature vacuum annealing was performed to restore the diamond lattice. Our assessment utilized X-ray rocking curve imaging, surface profilometry, and micro-Raman spectroscopy, with additional observations on near-infrared transmission properties. Our measurement of high-quality Bragg reflection through X-ray rocking curve imaging, sensitive to implantation-induced strain and defects, served as an key diagnostic for the effectiveness of this ion-implanted sample as a Bragg-reflecting optic.

Takashi Sato,1 Takeshi Shimosato,2 Dennis M Klinman3 1Department of Pulmonology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; 2Department of Interdisciplinary Genome Sciences and Cell Metabolism, Institute for Biomedical Sciences, Shinshu University, Nagano 399-4598, Japan; 3Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702, USA Abstract: “Silica” refers to crystalline particles formed by the combination of silicon with oxygen. Inhalation of silica particles promotes the development of pulmonary fibrosis that over prolonged periods increases the risk of lung cancer. The International Agency for Research on Cancer (IARC) classified crystalline silica as a human carcinogen in 1997. This categorization was questioned due to 1) the absence of dose–response findings, 2) the presence of confounding variables that complicated interpretation of the data and 3) potential selection bias for compensated silicosis. Yet, recent epidemiologic studies strongly support the conclusion that silica exposure increases the risk of lung cancer in humans independent of confounding factors including cigarette smoke. Based on this evidence, the US Occupational Safety and Health Administration (OSHA) lowered the occupational exposure limit for crystalline silica from 0.1 to 0.05 mg/m3 in 2013. Further supporting the human epidemiologic data, murine models show that chronic silicosis is associated with an increased risk of lung cancer. In animals, the initial inflammation induced by silica exposure is followed by the development of an immunosuppressive microenvironment that supports the growth of lung tumors. This work will review our current knowledge of silica-associated lung cancers, highlighting how recent mechanistic insights support the use of cutting-edge approaches to diagnose and treat silica-related lung cancer. Keywords: silicosis, lung cancer, inflammation, fibrosis, occupational lung disease

Tomoki Sato,1 Takahiro Kawaji,1 Akira Hirata,2 Takanori Mizoguchi3 1Sato Eye and Internal Medicine Clinic, Arao City, Kumamoto, Japan; 2Hayashi Eye Hospital, Hakata-ku, Fukuoka, Japan; 3Mizoguchi Eye Clinic, Sasebo, Nagasaki, Japan Purpose: The purpose of this study was to evaluate the efficacy of 360-degree suture trabeculotomy (360S-LOT) ab interno for treating open-angle glaucoma (OAG). Risk factors of surgical failure were examined. Patients and methods: 360S-LOT ab interno alone was performed for patients with uncontrolled OAG, and combined 360S-LOT ab interno/phacoemulsification was performed for patients with controlled OAG with a visually significant cataract between March 2014 and September 2015 at a single center. The patients were prospectively followed for 2 years. The main outcome measures included 2-year intraocular pressure (IOP), number of anti-glaucoma medications used, postoperative complications, and predictive factors of surgical failure. Kaplan–Meier analysis was performed, with surgical success (with or without medication use) defined as postoperative IOP ≤15 mmHg and IOP reduction ≥20% (criterion A) or IOP ≤12 mmHg and IOP reduction ≥30% (criterion B). Predictive factors were evaluated using Cox proportional hazard ratios. Results: A total of 64 eyes of 64 patients were included, and 50 (78%) eyes of 64 eyes underwent a phacoemulsification combination procedure. Surgery significantly reduced IOP from 18.4 ± 2.9 mmHg before surgery to 13.4 ± 3.0 mmHg after surgery (P < 0.001). Patients used an average of 1.8 ± 1.5 medications before surgery and 1.3 ± 1.5 medications after surgery (P = 0.101). No serious postoperative complications were observed. The probability of surgical success was 49.2% and 16.0% using criteria A and B, respectively. No risk factors of surgical failure were identified. Conclusion: The 360S-LOT ab interno procedure is a favorable option for treating eyes with mild or moderate OAG. Keywords: 360-degree suture trabeculotomy ab interno, open-angle glaucoma, minimally invasive glaucoma surgery, phacoemulsification

Atsuko Kawai,1,2 Masatake Kurita,1,3,4 Satoshi Nishino,3,4 Eishin Hirata,5 Tadahiro Sato,5 Yoshiro Okubo1 1Department of Psychiatry and Behavioral Science, Nippon Medical School, Bunkyo-ku, 2Total Health Clinic, Nanyo, 3Natori Station Front Clinic, Natori, 4Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, 5Sato Hospital, Nanyo, Japan Abstract: Many smokers find it difficult to stop smoking without assistance. The antidepressants bupropion and nortriptyline can aid smoking cessation. The main aim of this study was to understand the pathophysiology of smoking cessation better based on biological backgrounds. We investigated the following biological markers for any alterations during smoking cessation in the absence of pharmacotherapy: the dopamine metabolite homovanillic acid (HVA), the noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) and brain-derived neurotrophic factor (BDNF). Assessment and blood sampling were performed at a baseline (the start) time point and at a critical time point during smoking cessation. Seven of 30 smokers quit during a 16-week follow-up period; these smokers were defined as remission group from tobacco dependence. The remaining 23 smokers were categorized as hardcore smokers. The smoking group was compared with 23 non-smokers matched for age and gender. We compared blood levels of biological markers in each of the three groups. The hardcore smoker group showed significant decreases in HVA and MHPG levels between baseline and the critical time point (p=0.018 and p=0.033, respectively). However, the remission from tobacco dependence group exhibited no significant changes in any of the biomarkers examined. They had lower scores on the Minnesota nicotine withdrawal scale than the hardcore smoker group (p=0.002). The hardcore smoker group had higher MHPG and BDNF levels than the non-smoker group (p=0.002 and p

Teruyo Kida,1 Seita Morishita,2 Masanori Fukumoto,1 Takaki Sato,1 Hidehiro Oku,1 Tsunehiko Ikeda1 1Department of Ophthalmology, Osaka Medical College, Takatsuki, 2Department of Ophthalmology, Osaka Kaisei Hospital, Osaka, Japan Purpose: To investigate the characteristics in spontaneous release of epiretinal membrane (ERM) during watchful waiting and to introduce a possible mechanism of pathogenesis as a photo essay.Methods: Records from all patients with ERM were obtained from Osaka Medical College Hospital from January 2001 to October 2012. Visual acuity (VA), fundus photo, and optical coherence tomography (OCT) were reviewed using the medical records. For statistical analysis, VA measured with a Landolt chart was converted to the logarithm of the minimum angle of resolution (logMAR). To investigate the pathogenesis of ERM, tryptase activity in vitreous, which plays a role in tissue fibrosis and remodeling, was measured in patients that underwent a vitrectomy for ERM, macular hole, and proliferative diabetic retinopathy (PDR).Results: ERM was observed in 604 patients and spontaneous release of the ERM was observed in 13 patients with 14 eyes (four males and nine females, aged 33–78 years). Among the 14 eyes, mean VA did not change significantly through the release of the ERMs (0.17±0.18 before and 0.24±0.40 after release, P=0.544). Nine eyes showed posterior vitreous detachment or vitreomacular traction on OCT images and five eyes did not. ERM was released in five eyes with no accompanying vitreous traction by OCT during watchful waiting and seems to have peeled off by itself by contracting and rolling from the inferior side. Three eyes with deteriorated VA underwent vitrectomy due to macular hole or pseudomacular hole. Vitreal tryptase activity was significantly higher in patients with ERM compared to those with PDR (P

Hiroyuki Suzuki,1 Seita Morishita,1 Ryohsuke Kohmoto,1 Masanori Fukumoto,1 Takaki Sato,1 Teruyo Kida,1 Mari Ueki,1 Hidehiro Oku,1 Kimitoshi Nakamura,2 Tsunehiko Ikeda1 1Department of Ophthalmology, Osaka Medical College, Takatsuki-City, Osaka, Japan; 2Nakamura Eye Clinic, Matsumoto-City, Nagano, Japan Purpose: To investigate whether vitreomacular adhesion (VMA) affects the outcome of anti-vascular endothelial growth factor (VEGF) therapy for the treatment of exudative age-related macular degeneration (AMD) in Japanese patients. Subjects and methods: Of 88 Japanese AMD patients (28 men and 60 women, mean age: 72.7±7.5 years) who underwent intravitreal injection of ranibizumab for 3 years from 2010 to 2013, this study involved 12 eyes of 12 patients (10 men and two women) in whom VMA was observed based on optical coherence tomography (OCT) findings (VMA [+] group) and 17 eyes of 16 patients (seven men and nine women, control group) in whom no VMA was observed (VMA [-] group). In all enrolled patients, ranibizumab was administered monthly for 3 months, and then administered as needed (ie, pro re nata) when deterioration was observed. The two groups were then compared in regard to changes in visual acuity (VA) and the frequency of ranibizumab administration over a 1-year period. Results: No significant difference was found between the two groups in regard to the transformation of the mean logarithm of the minimum angle of resolution VA change after the first visit. Over the 1-year treatment, the mean frequency of ranibizumab administration for the VMA (+) group was 5.6±2.5 times and for the VMA (-) group was 3.8±1.1 times, thus illustrating a significant difference between the two groups (Mann–Whitney’s U-test: P

Kohei Kubota,1,2 Kohei Onishi,3 Kazuaki Sawaki,3 Tianshu Li,4 Kaoru Mitsuoka,5 Takaaki Sato,6 Shinji Takeoka1,3,4 1Cooperative Major in Advanced Biomedical Sciences, Graduate School of Advanced Sciences and Engineering, Waseda University (TWIns), Tokyo, Japan; 2Formulation Research and Phramaceutical Process Group, CMC R&D Center, Kyowa Hakko Kirin Co., Ltd, Shizuoka, Japan; 3Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering,Waseda University (TWIns), Tokyo, Japan; 4Research Organization for Nano and Life Innovation, Waseda University (TWIns), Tokyo, Japan; 5Research Center for Ultra-High Voltage Electron Microscopy, Osaka University, Osaka, Japan; 6Department of Chemistry and Materials, Faculty of Textile Science and Technology, Shinshu University, Nagano, Japan Abstract: Two lipid-based nanoformulations have been used to date in clinical studies: lipoplexes and lipid nanoparticles (LNPs). In this study, we prepared small interfering RNA (siRNA)-loaded carriers using lipid components of the same composition to form molecular assemblies of differing structures, and evaluated the impact of structure on cellular uptake and immune stimulation. Lipoplexes are electrostatic complexes formed by mixing preformed cationic lipid liposomes with anionic siRNA in an aqueous environment, whereas LNPs are nanoparticles embedding siRNA prepared by mixing an alcoholic lipid solution with an aqueous siRNA solution in one step. Although the physicochemical properties of lipoplexes and LNPs were similar except for small increases in apparent size of lipoplexes and zeta potential of LNPs, siRNA uptake efficiency of LNPs was significantly higher than that of lipoplexes. Furthermore, in the case of LNPs, both siRNA and lipid were effectively incorporated into cells in a co-assembled state; however, in the case of lipoplexes, the amount of siRNA internalized into cells was small in comparison with lipid. siRNAs in lipoplexes were thought to be more likely to localize on the particle surface and thereby undergo dissociation into the medium. Inflammatory cytokine responses also appeared to differ between lipoplexes and LNPs. For tumor necrosis factor-α, release was mainly caused by siRNA. On the other hand, the release of interleukin-1β was mainly due to the cationic nature of particles. LNPs released lower amounts of tumor necrosis factor-α and interleukin-1β than lipoplexes and were thus considered to be better tolerated with respect to cytokine release. In conclusion, siRNA-loaded nanoformulations effect their cellular uptake and immune stimulation in a manner that depends on the structure of the molecular assembly; therefore, nanoformulations should be optimized before extending studies into the in vivo environment. Keywords: nanoformulation, siRNA, cryo-TEM, confocal microscopy, endocytosis, immune stimulation

Michiko Yamamoto,1 Hirohisa Doi,1 Ken Yamamoto,2 Kazuhiro Watanabe,2 Tsugumichi Sato,3 Machi Suka,4 Takeo Nakayama,5 Hiroki Sugimori6 1Department of Drug Informatics, Center for Education & Research on Clinical Pharmacy, Showa Pharmaceutical University, Tokyo, Japan; 2Department of Pharmacy Practice, Center for Education & Research on Clinical Pharmacy, Showa Pharmaceutical University, Tokyo, Japan; 3Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan; 4Department of Public Health and Environmental Medicine, The Jikei University School of Medicine, Tokyo, Japan; 5Department of Health Informatics, Kyoto University School of Public, Kyoto, Japan; 6Department of Preventive Medicine, Graduate School of Sports and Health Sciences, Daito Bunka University, Saitama, Japan Background: The safe use of drugs relies on providing accurate drug information to patients. In Japan, patient leaflets called Drug Guide for Patients are officially available; however, their utility has never been verified. This is the first attempt to improve Drug Guide for Patients via user testing in Japan.Purpose: To test and improve communication of drug information to minimize risk for patients via user testing of the current and revised versions of Drug Guide for Patients, and to demonstrate that this method is effective for improving Drug Guide for Patients in Japan.Method: We prepared current and revised versions of the Drug Guide for Patients and performed user testing via semi-structured interviews with consumers to compare these versions for two guides for Mercazole and Strattera. We evenly divided 54 participants into two groups with similar distributions of sex, age, and literacy level to test the differing versions of the Mercazole guide. Another group of 30 participants were divided evenly to test the versions of the Strattera guide. After completing user testing, the participants evaluated both guides in terms of amount of information, readability, usefulness of information, and layout and appearance. Participants were also asked for their opinions on the leaflets.Results: Response rates were 100% for both Mercazole and Strattera. The revised versions of both Guides were superior or equal to the current versions in terms of accessibility and understandability. The revised version of the Mercazole guide showed better ratings for readability, usefulness of information, and layout (p

Net primary production (NPP) is a central and fundamental carbon-related term in global change studies. We proposed a top-down method to quantifying forest NPP which overcomes the deficits of the traditional bottom-up method. The new top-down method combines eddy flux data, climate variables, tree inventory and metabolic theory. Our method was tested in six forests and provides reliable annual NPP estimations which are consistent with bottom-up results. Carbon use efficiency also supports this new method. Taking advantage of fine temporal resolution of our top-down method, we examined whether and confirmed NPP was well correlated with leaf area index at a seasonal scale, as suggested by past studies. The potential value of our new method as a standard NPP method is high because of the world-wide network on eddy tower and inventory plot, however further data of performance of the new method is needed to fully evaluate its performance under different conditions.

Kazuhito Yuhashi,1 Yuka Yagihara,1 Yoshiki Misawa,1 Tomoaki Sato,1 Ryoichi Saito,2 Shu Okugawa,1 Kyoji Moriya1 1Department of Infection Control and Prevention, Faculty of Medicine, The University of Tokyo, 2Department of Microbiology and Immunity, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan Purpose: The enzyme immunoassay (EIA) has lower sensitivity for Clostridium difficile toxins A and B than the polymerase chain reaction in the diagnosis of C. difficile-associated diarrhea (CDAD). Furthermore, toxin positivity with EIA performed on C. difficile isolates from stool cultures may be observed even in patients with EIA glutamate dehydrogenase (GDH)-positive and toxin-negative stool specimens. It is unclear whether such patients should be treated as having CDAD.Methods: The present study retrospectively compared patient characteristics, treatment, and diarrhea duration among three groups of patients who underwent stool EIA testing for CDAD diagnosis: a toxin-positive stool group (positive stool group; n=39); a toxin-negative stool/toxin-positive isolate group (discrepant negative/positive group, n=14); and a dual toxin-negative stool and isolate group (dual negative group, n=15). All cases included were confirmed to be GDH positive on EIA test.Results: Patients’ backgrounds and comorbidities were not significantly different among three groups. No difference was observed among the three groups with regard to antimicrobial drug use before diarrhea onset. Treatment was received by 82.1% of the positive stool group compared to 7.1% of the discrepant positive/negative group and 0% of the dual negative group, while mean diarrhea duration was 10.6 days compared to 7.9 days (P=0.6006) and 3.4 days (P=0.0312), respectively.Conclusion: Even without treatment, patients with toxin-negative stool specimens had shorter diarrhea duration than those with toxin-positive stool specimens even with toxin-positive isolates. These findings may suggest a limited need for CDAD treatment for GDH-positive patients and toxin-negative stool specimens. Keywords: Clostridium difficile toxin, diarrhea duration, treatment

Takahiro Kawaji,1,2 Tomoki Sato,2 Hidenobu Tanihara11Department of Ophthalmology, Faculty of Life Sciences, Kumamoto University, Chuo-ku, 2Sato Eye & Internal Medicine Clinic, Kumamoto, JapanPurpose: To report the results of sutureless scleral fixation of a posterior chamber intraocular lens (IOL) by using our developed simple technique.Methods: We retrospectively reviewed the medical records of 48 eyes of 47 patients who underwent sutureless intrascleral IOL fixation by using our modified technique. A 25-gauge microvitreoretinal knife was used to perform sclerotomies and create limbus-parallel scleral tunnels with lamellar dissection in which the haptics were fixed.Results: The IOLs were fixed and centered well. The mean follow-up period was 26.7 months. Postoperative complications included smooth vitreous hemorrhage in four eyes (8.3%), cystoid macular edema in two eyes (4.2%), and iris capture of the IOL in two eyes (4.2%). No other complications, such as breakage of the IOL, spontaneous IOL dislocation, or retinal detachment, were detected during the follow-up period.Conclusion: The lamellar dissection of the limbus-parallel scleral tunnel can simplify the forceps-assisted introduction of the haptics into the scleral tunnel, and this technique seemed to be safe.Keywords: intraocular lenses, ophthalmologic surgical procedures, intrascleral fixation, sutureless fixation

Takanori Mizoguchi,1 Shiro Nishigaki,2 Tomoki Sato,3 Harumi Wakiyama,4 Nobuchika Ogino2 1Mizoguchi Eye Clinic, Ophthalmology, Sasebo, 2Nishigaki Eye Clinic, Ophthalmology, Nagoya, 3Sato Eye Clinic, Ophthalmology, Arao, 4Japanese Red Cross Nagasaki Genbaku Hospital, Nagasaki, Japan Background: The purpose of this study was to determine outcomes when using Trabectome surgery and to evaluate factors associated with its effects in primary open-angle glaucoma (POAG) and exfoliation glaucoma (EXG). Methods: This was a prospective, non-randomized, observational, comparative cohort study in which Trabectome surgery was used alone in patients with POAG or EXG. Trabectome surgery was considered to have failed when at least one of the following three criteria was fulfilled: intraocular pressure (IOP) ≥21 mmHg and a

Toshimi Sato,1 Neil Alles,1,2 Masud Khan,1,3 Kenichi Nagano,1,4 Mariko Takahashi,1 Yukihiko Tamura,1 Asako Shimoda,5,6 Keiichi Ohya,1 Kazunari Akiyoshi,5,6 Kazuhiro Aoki1 1Department of Bio-Matrix (Pharmacology), Graduate School, Tokyo Medical and Dental University, Tokyo, Japan; 2Department of Biochemistry, Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka; 3Department of Dental Pharmacology, City Dental College and Hospital, Dhaka, Bangladesh; 4Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA; 5Department of Polymer Chemistry, Graduate School of Engineering, Kyoto University, Katsura, 6ERATO Akiyoshi Bio-Nanotransporter Project, Japan Science and Technology Agency, Katsura Int’tech Center Kyotodaigaku-Katsura, Nishikyo-ku, Kyoto, Japan Abstract: We investigated the biological activity of W9, a bone resorption inhibitor peptide, using NanoClik nanoparticles as an injectable carrier, where acryloyl group-modified cholesterol-bearing pullulan (CHPOA) nanogels were crosslinked by pentaerythritol tetra (mercaptoethyl) polyoxyethylene. Thirty 5-week-old male C57BL/6J mice were fed a low calcium diet and received once-daily subcutaneous injections of the carrier alone, W9 24 mg/kg/day alone, W9 24 mg/kg/day incorporated in cholesterol bearing pullulan (CHP) nanogels, or W9 (8 and 24 mg/kg/day) incorporated in NanoClik nanoparticles for 4 days (n=5). Mice that received a normal calcium diet with NanoClik nanoparticle injections without W9 were used as a control group. Radiological analyses showed that administration of W9 24 mg/kg/day significantly prevented low calcium-induced reduction of bone mineral density in the long bones and lumbar vertebrae, but only when the NanoClik nanoparticles were used as a carrier. Histomorphometric analyses of the proximal tibiae revealed that W9 24 mg/kg/day incorporated in NanoClik nanoparticles prevented the increase in bone resorption indices induced by a low calcium diet, which was confirmed by measurement of serum bone resorption markers. These data suggest that NanoClik nanoparticles could be a useful carrier for peptide therapeutics, and also demonstrate that daily subcutaneous injections of the W9 peptide with the nanoparticles were able to inhibit bone loss in vivo. An osteoclastogenesis inhibition assay performed in vitro confirmed a slower release profile of W9 from NanoClik nanoparticles compared with conventional CHP nanogels. Keywords: nanocarrier, peptide drug, injectable drug carrier, polyethylene glycol crosslinking, cholesterol-bearing pullulan, controlled release

Masatake Kurita,1–3 Satoshi Nishino,1,2 Yukio Numata,1 Yoshiro Okubo,3 Tadahiro Sato11Sato Hospital, Koutokukai, Nanyo, Yamagata, Japan; 2Department of Cellular Signaling, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan; 3Department of Psychiatry and Behavioral Science, Graduate School of Medicine, Nippon Medical School, Bunkyo-ku, Tokyo, JapanBackground: Treatment of the depressive and manic states in bipolar disorder I (BDI) is a challenge for psychiatrists. Despite the recognized importance of the switch phenomenon, the precise mechanisms underlying this process are yet to be shown. We conducted a naturalistic study in two BDI patients to determine whether biological markers (monoamine metabolites and brain-derived neurotrophic factor [BDNF]) are associated with the switch between depressive and manic states.Case presentation and methods: Blood sampling and mood assessments were performed at 2-week intervals over a period of 2 (Case 1, n=72) and 6 (Case 2, n=183) years. Plasma concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG) and homovanillic acid (HVA) were analyzed by high-performance liquid chromatography with electrochemical detection. Plasma BDNF was assayed by sandwich ELISA (enzyme-linked immunosorbent assay).Results: MHPG had the highest standardized coefficient (β) in the multiple regression analysis. We found a significant positive correlation between Young Mania Rating Scale scores and plasma MHPG levels (Case 1: р=0.429; Case 2: р=0.488), and a significant negative correlation between Montgomery–Asberg Depression Rating Scale scores and MHPG levels (Case 1: р=-0.542; Case 2: р=-0.465). Conversely, no significant correlation was found between the level of BDNF and the presence of a manic or depressive state, and although HVA had a slightly stronger correlation than MHPG, the levels of neither of these were found to significantly correlate with the symptoms.Conclusion: These data suggest that peripheral MHPG levels (which is related to noradrenaline levels in the brain) could be used as a biomarker of mood states in BDI. The noradrenaline level in the brain is likely to reflect the clinical characteristics of the switch process in BDI, and has prognostic significance for the treatment of both manic and depressive states.Keywords: brain-derived neurotrophic factor (BDNF), monoamine, dopamine, homovanilic acid (HVA), depression, pathophysiology, mood disorder

Tomoki Sato,1 Akira Hirata,2 Takanori Mizoguchi31Sato Eye Clinic, Arao City, Kumamoto, 2Hayashi Eye Hospital, Fukuoka, 3Mizoguchi Eye Clinic, Nagasaki, JapanBackground: In this paper, we describe 360° suture trabeculotomy (360°LOT) ab interno and the short-term course in patients who underwent this procedure.Methods: We prospectively studied 12 patients (12 eyes) with open-angle glaucoma who underwent 360°LOT ab interno at the Sato Eye Clinic between February and July 2014. The surgical procedure involved making a 1.7 mm temporal corneal incision, exposing an approximately 15° opening in the inner wall of Schlemm’s canal (nasal side) using a Trabectome with a gonioscope, and inserting a 5-0 nylon suture rounded at the tip into Schlemm’s canal opened via the anterior chamber. The suture was then threaded around Schlemm’s canal, and the tip of the suture that emerged on the other side was then advanced through the opening to make a circumferential incision. Intraocular pressure (IOP), number of anti-glaucoma medications used, complications, and the surgery completion rate were prospectively studied.Results: Mean IOP, which was 19.4 mmHg at baseline, showed a significant decrease at each of the monthly observation points, reaching 13.8 mmHg at 6 months after surgery (P=0.0004, paired t-test). The mean number of anti-glaucoma medications decreased from 3.2 at baseline to 1.1 at 6 months after surgery. IOP spikes ≥30 mmHg were seen in 25% of patients, but there were no other serious complications and the surgery completion rate was 92%.Conclusion: The 360°LOT ab interno procedure preserves the conjunctiva and sclera, and has a high surgery completion rate when using the anterior chamber approach, and could therefore be an effective short-term treatment of open-angle glaucoma.Keywords: non-penetrating surgery, intraocular pressure, Schlemm’s canal, corneal incision, Trabectome

Joji Nishimura,1 Shingo Kakeda,1 Osamu Abe,2 Reiji Yoshimura,3 Keita Watanabe,1 Naoki Goto,3 Hikaru Hori,3 Toru Sato,1 Hidemasa Takao,4 Hiroyuki Kabasawa,5 Jun Nakamura,3 Yukunori Korogi1 1Department of Radiology, University of Occupational and Environmental Health School of Medicine, Fukuoka, Japan; 2Department of Radiology, Graduate School of Medicine, Nihon University, Tokyo, Japan; 3Department of Psychiatry, University of Occupational and Environmental Health School of Medicine, Fukuoka, Japan; 4Department of Radiology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; 5MR Applied Science Laboratory Japan, GE Yokogawa Medical Systems, Hino-shi, Tokyo, Japan Abstract: The aims of this study are to determine how the interval changes of the brain structures in the early stage of first-episode schizophrenia relate to the interval changes in the clinical data, including the clinical symptoms of schizophrenia and catecholaminergic measures (plasma homovanillic acid [HVA] and 3-methoxy-4-hydroxyphenylglycol [MHPG]). Regional brain volumes and fractional anisotropy (FA)/mean diffusivity (MD) with diffusion tensor imaging (DTI) were measured at baseline and 6-month follow-up in a 3T magnetic resonance imaging (MRI) system in a cohort of 16 schizophrenic patients, who were in their first episode at the time of baseline MRI. At the time of baseline and follow-up MRI, all 16 patients underwent evaluations that included a psychopathological assessment (Positive and Negative Syndrome Scale [PANSS]) and peripheral catecholaminergic measures (plasma MHPG or HVA). For interval changes between baseline and follow-up MRI data (morphological change, MD, and FA), the correlation/regression analysis was performed as a series of single regression correlations in Statistical Parametric Mapping 5, with the interval changes in PANSS or plasma HVA and MHPG as the covariates of interest. Positive and inverse correlations contrasts were created, and in this preliminary analysis, a family-wise error-corrected threshold of P