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Manabu Saito,1,&ast; Hiroshi Uchino,1,&ast; Yoko Iwata,1 Ayako Fuchigami,1 Genki Sato,1 Fukumi Yoshikawa,1 Masahiko Miyagi,1 Taito Miyazaki,2 Yoshihisa Urita,2 Kotaro Aoki,3 Yoshikazu Ishii,3 Kazuhiro Tateda,3 Takahisa Hirose1 1Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Toho University Graduate School of Medicine, Tokyo, Japan; 2Department of General Medicine and Emergency Care, Toho University School of Medicine, Tokyo, Japan; 3Department of Microbiology and Infectious Diseases, Toho University School of Medicine, Tokyo, Japan&ast;These authors contributed equally to this workCorrespondence: Hiroshi Uchino, Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Toho University Graduate School of Medicine, 6-11-1 Omori-nishi, Ota-ku, Tokyo, 143-8541, Japan, Tel +81-3-3762-4151, Fax +81-3-3765-6488, Email h.uchino@med.toho-u.ac.jpPurpose: The severe pathogenic ancient-type COVID-19, SARS-CoV-2/WA-1/2020 was the predominant gene variant in early 2020 in Japan, however, its transmissibility was uncertain. The period before the public commenced using any personal protective equipment (PPE) was evaluating to describe the transmissibility of the SARS-CoV-2/WA-1/2020. We analyzed the secondary attack rate (SAR) among close contacts and the risk factor for SAR.Methods: This retrospective cohort study included a total of 539 patients who were anticipated for the SARS-CoV-2/WA-1/2020 infection at Toho University Medical Center Omori Hospital from February to May 2020. We selected 54 patients with 1) exclude other pathogens infection, 2) include “Three Cs” condition: crowded places between distance< 6 feet, closed spaces indoor and close contact settings involving contact > 15min with a person tested positive for SARS-CoV-2/WA-1/2020 without PPE. We evaluated alternative infection risks: the body mass index (BMI) and diabetes (DM) status (non-DM, pre-DM, and DM) as demographic determinants of transmissibility and infectivity of SARS-CoV2/WA-1/2020 cases during the incubation period.Results: The calculated SAR was 79.3%. BMI was significantly associated with the PCR positivity rate, which was significant in the univariate (CI 95%, 1.02– 1.51; P = 0.03) and multivariate (CI 95%, 1.02– 1.60; P = 0.03) analyses. Comparing the different BMI groups, the highest BMI group (25.5− 35.8 kg/m2) had an elevated risk of SAR compared to the lowest BMI group (14.0– 22.8 kg/m2), with an odds ratio of 1.41 (95% CI, 1.02– 1.59; P = 0.03). There were no significant differences in the risk of SAR among different DM statuses.Conclusion: The transmissibility of SARS-CoV2/WA-1/2020 was high (79.3%) among household members without PPE who had “Three Cs” exposure. Although pre-DM and established DM did not confer a risk for transmissibility, higher BMI was associated with an increased risk of SAR.Trial Registration: UMIN Clinical Trials Registry, UMIN0000 50905.Keywords: obesity, pre-diabetes, SARS-CoV-2 transmission

Ken Takata, Kentaro Uchida, Shotaro Takano, Manabu Mukai, Gen Inoue, Hiroyuki Sekiguchi, Jun Aikawa, Masayuki Miyagi, Dai Iwase, Masashi Takaso Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa, 252-0374, JapanCorrespondence: Kentaro UchidaDepartment of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-Ku Kitasato, Sagamihara City, Kanagawa, 252-0374, JapanTel/Fax +81-042-778-9217Email kuchida@med.kitasato-u.ac.jpPurpose: Obesity is associated with the risk of developing knee osteoarthritis (KOA). Furthermore, synovial basic fibroblast growth factor (bFGF) is linked to the severity of KOA. We previously demonstrated that bFGF and mast cell (MC) marker expression were elevated in the synovial tissues (ST) of KOA patients with obesity. However, it remains unclear whether MCs contribute to bFGF expression and regulation.Patients and Methods: Radiographically diagnosed KOA patients (n=249) were assigned to groups based on the body mass index (BMI) classifications used by the World Health Organization: normal-weight (NW, BMI < 25 kg/m2, n=95), overweight (OW, BMI ≥ 25 and < 30, n=109) and obese (OB, ≥ 30 kg/m2, n=45). BFGF expression in the ST was examined using quantitative polymerase chain reaction and compared across the BMI groups. Additionally, BFGF and interleukin (IL) 13 expression were examined in freshly extracted MC-rich (THY-1-, CD3-, CD14-, and CD19-) and MC-poor (THY-1+, CD3+, CD14+, or CD19+) fractions from ST. Moreover, regulation of BFGF expression by IL-13 was studied in CD14-negative (fibroblast-rich) and CD14-positive (M&phis;-rich) and cells in culture.Results: BFGF expression was significantly higher in OB than in NW patients. Furthermore, although IL13 was significantly higher in the MC-rich than the MC-poor fraction, BFGF expression was comparable. Recombinant human IL-13 stimulated expression of BFGF in synovial fibroblast cells.Conclusion: BFGF expression is higher in the ST of KOA patients with obesity. Increased numbers of MCs may contribute to the elevated BFGF expression through IL-13 in KOA patients with obesity.Keywords: obesity, mast cell, osteoarthritis, BFGF, IL13, synovial tissues

Kaori Hisanaga,1 Hiroshi Uchino,1 Naoko Kakisu,1 Masahiko Miyagi,1 Fukumi Yoshikawa,1 Genki Sato,1 Kazutoshi Isobe,2 Kazuma Kishi,2 Sakae Homma,3 Takahisa Hirose1 1Division of Diabetes, Metabolism and Endocrinology, Department of Medicine, Toho University Graduate School of Medicine, Tokyo, Japan; 2Department of Respiratory Medicine, Toho University Graduate School of Medicine, Tokyo, Japan; 3Department of Advanced and Integrated Interstitial Lung Disease Research, School of Medicine, Toho University, Tokyo, JapanCorrespondence: Hiroshi UchinoDivision of Diabetes, Metabolism and Endocrinology, Department of Medicine, Toho University Graduate School of Medicine, 6-11-1 Omori-Nishi, Ota-Ku, Tokyo, 143-8541, JapanTel +81-3-3762-4151Fax +81-3-3765-6488Email h.uchino@med.toho-u.ac.jpBackground: Although immune checkpoint inhibitors (ICIs) are promising in the treatment of advanced cancer, their use is associated with immune-related adverse events (irAEs) that affect endocrine organ systems. Although development of irAEs was associated with improved cancer-specific survival, the risk of irAEs is unclear. We investigated the association of pre-ICI comorbidities—including diabetes—with irAEs, overall survival (OS), and progression-free survival (PFS) in advanced lung cancer.Methods: Patients with lung cancer who were treated with ICIs during the period from September 1, 2015 through July 31, 2018 were retrospectively enrolled. All data were collected from the NEPTUNE database of university patients. Hazard ratios were estimated by using Cox regression weighted for propensity scores. Odds ratios were calculated by logistic regression and adjusted for unbalanced variables. The Kaplan–Meier method was used to compare OS, and the generalized Wilcoxon test was used to compare median survival.Results: Among the 88 patients identified, 22 (25.0%) had diabetes (DM) before ICI treatment and 57 (75.0%) did not (non-DM); irAEs developed in 12.2% of patients with DM and in 9.1% of patients in non-DM (p=0.87). Diabetes status was not associated with irAE risk in relation to baseline characteristics (age, sex, TNM staging, thyroid and renal function) or in propensity score–matched analysis (age, TNM staging). During a mean follow-up of 30 months, OS and cancer-specific PFS were significantly higher in patients who developed irAEs (Kaplan–Meier estimates, p=0· 04 and 0· 03, respectively). In propensity score–matched analysis, diabetes was significantly associated with lower OS (multivariate hazard ratio, 0· 36; 95% CI, 0· 13– 0· 98) unrelated to irAEs. Irrespective of irAEs, PFS was also lower among patients with DM than among non-DM patients (Kaplan–Meier estimate, p=0· 04).Conclusion: Pre-existing diabetes was associated with higher mortality in advanced lung cancer, regardless of irAE development during treatment with ICI.Keywords: immune checkpoint inhibitor, diabetes, overall survival, progression-free survival

Ken Takata,1 Kentaro Uchida,1,2 Manabu Mukai,1 Shotaro Takano,1 Jun Aikawa,1 Dai Iwase,1 Hiroyuki Sekiguchi,2 Masayuki Miyagi,1 Gen Inoue,1 Masashi Takaso1 1Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa 252-0374, Japan; 2Shonan University of Medical Sciences Research Institute, Chigasaki City, Kanagawa 253-0083, JapanCorrespondence: Kentaro Uchida Tel/Fax +81-42-778-9217Email kuchida@med.kitasato-u.ac.jpPurpose: The mechanisms governing evidence that obesity is a risk factor for osteoarthritis (OA) are not well understood. We previously reported an increase in mast cell (MC) marker expression in the osteoarthritic synovial membrane (SM) of patients with obesity. We hypothesized that an enzyme produced by MC, β-tryptase, may be increased in the SM of obese patients with knee OA and contribute to synovial inflammation. This study investigated the expression of the β-tryptase encoding gene, TPSB2, in the SM of obese patients with knee OA and β-tryptase-mediated regulation of IL-1β in synovial cells.Patients and Methods: A total of 216 patients radiographically diagnosed with knee OA were grouped according to the World Health Organization’s body mass index classifications: normal weight (NW; < 25 kg/m2), overweight (OW; 25– 29.99 kg/m2) and obese (OB; ≥ 30 kg/m2). Quantitative polymerase chain reaction was conducted to examine TPSB2 expression in the SM among the three groups. We also examined TPSB2 and IL1B expression in MC-rich (CD3-CD14-CD19-CD90-) and MC-poor (CD3+, CD14+, CD19+, or CD90+) fractions freshly isolated from synovial tissue. Further, the effect of β-tryptase on IL1B expression was investigated in cultured CD14-positive (macrophage-rich fraction) and CD14-negative (fibroblast-rich fraction) cells.Results: There was significantly elevated TPSB2 expression in the OW and OB groups compared to the NW group. The MC-rich fraction had significantly higher levels of TPSB2, CD117 and CD203c than the MC-poor fraction. Recombinant human β-tryptase stimulated IL1B expression in both the synovial fibroblast and macrophage fractions.Conclusion: Obese patients with knee OA showed elevated TPSB2 expression in the SM. Tryptase may play a role in synovial inflammation in obese patients with OA.Keywords: obese, mast cell, osteoarthritis, tryptase, synovial membrane

Shotaro Takano*, Kentaro Uchida*, Gen Inoue, Atsushi Minatani, Masayuki Miyagi, Jun Aikawa, Dai Iwase, Kenji Onuma, Manabu Mukai, Masashi Takaso Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara, Japan *These authors contributed equally to this work Background: Recent studies suggest that the vasodilatory neuropeptide calcitonin gene-related peptide (CGRP) is localized in the synovial tissue and may be involved in the pathology of hip and knee osteoarthritis (OA). However, the regulation and relationship between pain and CGRP expression levels in the synovial tissue of human OA patients are not fully understood.Methods: Synovial tissues were harvested from 74 participants with radiographic knee OA (unilateral Kellgren/Lawrence grades 3–4) during total knee arthroplasty. CGRP-expressing cells in the resected tissue were identified by immunohistochemical analyses. To examine CGRP expression levels, CD14-positive (CD14+) (macrophage-rich cell fraction) and CD14-negative (CD14−; fibroblast-rich cell fraction) cells were isolated from the synovial tissue. To investigate the involvement of prostaglandin E2 (PGE2) in the regulation of CGRP expression, cultured CD14− and CD14+ cells were stimulated with PGE2. In addition, CGRP expression levels in the synovial tissue of OA patients with strong/severe (visual analog scale [VAS]≥6) and mild/moderate pain (VAS

Light scattering in columnar micropores by nematic liquid crystals is caused by the mismatched refractive indices of alumina and liquid crystals and the distribution of the refractive index within the liquid crystals. The crystals are embedded in the micropores of approximately 2000 amstrong units in diameter. Temperature and electric field negatively affect transmittance.