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The distribution pattern of the connection length in the divertor region of Heliotron J was calculated by the field line tracing method. A multifold layer structure, characterized by the range of connection length, was revealed to interpret the response of the transport of the lower‐charged impurity ions to the divertor structure. Impurity transport simulated by the EMC3‐EIRENE code shows that lower‐charged impurity ions tend to concentrate in the first multifold layer. This result is consistent with the line‐integral extreme ultraviolet spectroscopy measurement, which implies that the impurity's response to the divertor topological structure needs to be considered in interpreting the spectroscopy result. [ABSTRACT FROM AUTHOR]

Yoichi Nishii,1 Kazuki Furuhashi,1 Saki Nakamura,1 Miho Nishio,1 Yuki Nakamura,1 Kengo Ushiro,1 Kentaro Ito,1 Tadashi Sakaguchi,1 Yuta Suzuki,1 Kentaro Fujiwara,1 Taro Yasuma,2 Tetsu Kobayashi,3 Corina D’Alessandro-Gabazza,2 Esteban C Gabazza,2 Osamu Taguchi,1 Osamu Hataji1 1Respiratory Center, Matsusaka Municipal Hospital, Matsusaka, Mie, Japan; 2Department of Immunology, Faculty and Graduate School of Medicine, Mie University, Tsu-city, Mie, Japan; 3Department of Pulmonary and Critical Care Medicine, Faculty and Graduate School of Medicine, Mie University, Tsu-city, Mie, JapanCorrespondence: Esteban C GabazzaDepartment of Immunology, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu-city, Mie, 514-8507, JapanTel +81 59 231 5017Fax +81 59 231 5225Email gabazza@doc.medic.mie-u.ac.jpIntroduction: Many patients with nontuberculous mycobacteria pulmonary disease are asymptomatic. The disease diagnosis is confirmed in only a small proportion of patients with radiological findings suspicious for nontuberculous mycobacteria pulmonary disease. Thus, many patients remained undiagnosed. Here, we evaluated the diagnostic value of digital polymerase chain reaction (PCR) in nontuberculous mycobacteria pulmonary disease.Methods: We prospectively evaluated 123 patients with radiological findings suspicious for nontuberculous mycobacteria pulmonary disease. Digital PCR was performed using bronchial lavage fluid, sputum, saliva, blood, and urine.Results: The culture of bronchial washing fluid was positive for nontuberculous mycobacteria in 53 patients and negative in 70. The positive detection rate of nontuberculous mycobacteria by digital PCR in patients with positive culture (n = 53) was as follows: bronchial lavage fluid 100%, sputum 62.9%, saliva 41.5%, blood 7.5%, and urine 3.8%. All patients with two or more positive partitions for nontuberculous mycobacteria in the digital PCR of bronchial lavage fluid showed nontuberculous mycobacteria growth in the bronchial lavage fluid culture. The digital PCR analysis of the bronchial lavage fluid showed a high sensitivity (100%), specificity (85.7%), positive predictive value (84.1%), negative predictive value (100%), and a high concordance rate (91.9%) with the bronchial lavage fluid culture results. In addition, the culture of bronchial lavage fluid was positive for nontuberculous mycobacteria in patients with two or more positive partitions in the digital PCR of sputum and saliva with a combined positive predictive value of 81.1%.Conclusion: Digital PCR analysis of nontuberculous mycobacteria in bronchial lavage fluid shows a high concordance rate with the bronchial lavage fluid culture results and a high positive predictive value using both sputum and saliva, suggesting the potential usefulness of dPCR for diagnosis of nontuberculous mycobacteria pulmonary disease in clinical practice.Keywords: digital PCR, nontuberculous mycobacteria pulmonary disease, diagnosis, bronchial lavage fluid culture, bronchoscopy

Hiroshi Saito,1 Yuya Nakamura,2,3 Masahiro Inagaki,2,4 Shiho Yamadera,5 Hideo Misawa,2,3 Naoki Sato,2,6 Tatsunori Oguchi,2 Takae Inagaki,7 Yuya Tsuji,2 Mayumi Tsuji,2 Isao Ohsawa,3 Hiromichi Gotoh,3 Yuji Kiuchi2 1JA Hiroshima Genneral Hospital, Hatsukaichi City, Hiroshima, Japan; 2Department of Pharmacology, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan; 3Saiyu Soka Hospital, Soka City, Saitama, Japan; 4Faculty of Arts and Sciences at Fujiyoshida, Showa University, Fujiyoshida City, Yamanashi, Japan; 5Department of Hospital Pharmaceutics, Showa University School of Pharmacy, Shinagawa-ku, Tokyo, Japan; 6Department of Research Center, Tanabe Pharmacy Inc., Chuo-ku, Tokyo, Japan; 7Graduate School of Nursing and Rehabilitation Science, Yokohama City, Kanagawa, JapanCorrespondence: Yuya Nakamura Email y.nakamura@med.showa-u.ac.jpPurpose: Lipopolysaccharides (LPS) induce inflammation by binding to the Toll-like receptor (TLR) 4 complex, including LPS-binding protein (LBP). The anti-inflammatory effects of linagliptin in LPS-induced inflammation in the TLR4-independent pathway have not been examined before. We examined the anti-inflammatory effects of linagliptin in the TLR4- and the LBP-independent pathway.Methods: U937 cells were cultured in the medium supplemented with 10% fetal bovine serum (FBS) and treated with 100 nM phorbol myristate acetate for 48 h. Cells were then left untreated or were treated with 10 μg/mL anti-TLR4 antibodies alone or in combination with linagliptin for 1 h in media supplemented with or without 10% FBS. The cells were divided into 5 groups: a) control cells (untreated) b) cells treated with LPS c) cells treated with 10 μg/mL anti-TLR4 antibodies d) cells treated with LPS and 10 μg/mL anti-TLR4 antibodies and e) cells treated with LPS, 10 μg/mL anti-TLR4 antibodies, and linagliptin. The LPS concentrations used were 50 pg/mL or 100 pg/mL for cells treated in the presence of 10% FBS and 100 pg/mL or 1 μg/mL for cells treated in the absence of FBS. Linagliptin concentrations of 1 nM, 10 nM, and 100 nM were used for treatment. The supernatants were analyzed for interleukin (IL)-6 production after 24 h of various treatments.Results: LPS increased IL-6 production compared to the untreated control cells, and anti-TLR4 antibody suppressed LPS-induced increased IL-6 levels. Linagliptin suppressed LPS-induced IL-6 production in a concentration-dependent manner in the presence of FBS. However, only 100 nM linagliptin could suppress LPS-induced IL-6 production in the absence of FBS.Conclusion: Concentration-dependent and -independent inflammatory suppression was observed following linagliptin treatment after LPS induction in an experimental model of TLR4 inhibition by anti-TLR4 antibodies. Our results showed that linagliptin may inhibit inflammation through multiple mechanisms centered around the TLR-4-mediated pathway.Keywords: lipopolysaccharide, U937 cells, fetal bovine serum, anti- toll-like receptor 4 antibody, interleukin-6

Masaki Nakano,1,* Haruka Yui,1,* Shingo Kikugawa,2 Ryosuke Tokida,3 Noriko Sakai,4 Naoki Kondo,5 Naoto Endo,5 Hirotaka Haro,6 Hiroki Shimodaira,1 Takako Suzuki,1,7 Hiroyuki Kato,1 Jun Takahashi,1 Yukio Nakamura1 1Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Nagano, 390-8621, Japan; 2DNA Chip Research Inc., Minato-ku, Tokyo, 105-0022, Japan; 3Rehabilitation Center, Shinshu University Hospital, Matsumoto, Nagano, 390-8621, Japan; 4Department of Orthopaedic Surgery, New Life Hospital, Obuse, Nagano, 381-0295, Japan; 5Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata, 951-8510, Japan; 6Department of Orthopaedic Surgery, University of Yamanashi Graduate School of Medicine, Chuo, Yamanashi, 409-3898, Japan; 7Department of Human Nutrition, Faculty of Human Nutrition, Tokyo Kasei Gakuin University, Chiyoda-ku, Tokyo, 102-8341, Japan*These authors contributed equally to this workCorrespondence: Yukio NakamuraDepartment of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, JapanTel +81-263-37-2659Fax +81-263-35-8844Email yxn14@aol.jpObjective: Osteoarthritis (OA) is a common and degenerative joint disorder in the elderly. A greater importance of understanding the relationship between genetic factors and OA prevalence has emerged with population aging. We therefore investigated the associations of several bone disease-related genetic variants with the prevalence of OA and osteoporosis in Japanese elderly women from the Obuse study cohort, which was randomly sampled from a basic town resident registry.Methods and Results: In total, 206 female participants (mean ± standard deviation age: 69.7 ± 11.0 years) who completed OA, bone mineral density, and genotype assessments were included. The number of patients diagnosed as having knee/hip OA and osteoporosis was 59 (28.6%) and 30 (14.6%), respectively. Fisher’s exact testing revealed significant relationships between the minor T allele of LDL receptor related protein 5 (LRP5) rs3736228 and the prevalence of knee/hip OA and osteoporosis. The respective odds ratios (ORs) of the TT genotype for knee/hip OA and osteoporosis were 7.28 (95% confidence interval [CI] 2.22– 28.08) and 5.24 (95% CI 0.95– 26.98). An additional subgroup analysis for knee OA revealed that the frequency of the common C allele of methylenetetrahydrofolate reductase (MTHFR) rs1801133 had a statistically significant protective association with the prevalence of knee OA (OR 0.58, 95% CI 0.35– 0.97).Conclusion: In sum, the present study demonstrated significant associations of LRP5 rs3736228 and MTHFR rs1801133 with knee/hip OA and osteoporosis prevalences and knee OA prevalence, respectively, in Japanese elderly women. These results will help further the understanding of OA pathogenesis and related genetic risk factors.Keywords: genetic variant, LRP5, MTHFR, osteoarthritis, osteoporosis

Takashige Momose,1 Yukio Nakamura,2 Masaki Nakano,2 Takashi Maeda,1 Susumu Morioka,3 Atsushi Sobajima,1 Yukio Nakatsuchi,1 Jun Takahashi,2 Masashi Nawata1 1Department of Orthopaedic Surgery, Marunouchi Hospital, Matsumoto, Nagano, 390-8601, Japan; 2Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Nagano, 390-8621, Japan; 3Department of Orthopaedic Surgery, Chikuma Central Hospital, Chikuma, Nagano, 387– 8512, JapanCorrespondence: Yukio NakamuraDepartment of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, JapanTel +81-263-37-2659Fax +81-263-35-8844Email yxn14@aol.jpObjective: This study aimed to evaluate the short- to mid-term clinical results of posterior-stabilized trabecular metal total knee arthroplasty (TKA) with cementless fixation of all components and investigate the radiographic changes of tibial and patellar components and cut bone surfaces over time.Methods: We retrospectively collected the data of 128 knees from 88 consecutive patients who had undergone initial TKA with NexGen LPS-Flex TM implants. A total of 66 knees from 45 patients (mean ± standard deviation age: 70.3 ± 7.5 years) met the selection criteria, which had been employed cementless fixation of all parts and at least 3 years of postoperative follow-up duration. Clinical evaluations included range of motion, conventional knee score, function score, postoperative complications, and revision. For radiological evaluations, the bone contact surface of each implant was divided into 7 zones for tibial component and 2 zones for patellar component. Each region was examined immediately after surgery, at 6 and 12 months, and then every year afterwards.Results: The mean observation period of 45 subjects was 4.2 years. Adequate fixation of tibial components was maintained during follow-up, although the patellar components of 2 knees required revision after repeated falls. No loosening was observed in any implants. The initial gap in tibial components disappeared in all knees, and a reactive line remained in 4 knees. There were no revisions, except for 2 cases, which were ascribed to patellar component fracture caused by repeated falls.Conclusion: Cementless posterior-stabilized trabecular metal TKA appears to be a good surgical option. Longer-term examination for revision cases is required to validate our results.Keywords: cementless fixation, short- to mid-term clinical outcomes, total knee arthroplasty, trabecular metal components

Maude Laberge,1– 3 Caroline Sirois,2– 5 Carlotta Lunghi,3,6 Myriam Gaudreault,7 Yumiko Nakamura,8 Carolann Bolduc,4 Marie-Laure Laroche9,10 1Department of Operations & Decision Systems, Faculty of Administration, Université Laval, Quebec City, Quebec, Canada; 2Vitam, Centre de recherche en santé durable-Université Laval, Quebec, Canada; 3Centre de recherche du CHU de Québec-Université Laval, Quebec City, Quebec, Canada; 4Faculty of Pharmacy, Université Laval, Quebec City, Quebec, Canada; 5Institut National de santé publique du Québec, Quebec City, Quebec, Canada; 6Department of Health Sciences, Université du Québec à Rimouski, Rimouski, Quebec, Canada; 7Faculty of Administration, Université Laval, Quebec City, Quebec, Canada; 8College of Medicine, University of Florida, Gainesville, FL, USA; 9Centre de Pharmacovigilance, de Pharmacoépidémiologie et d’information sur les médicaments, Service de Pharmacologie, Toxicologie et Pharmacovigilance, CHU de Limoges, Limoges, France; 10Laboratoire Vie-Santé, Faculté de Médecine, Université de Limoges, Limoges, FranceCorrespondence: Maude LabergeDepartment of Operations & Decision Systems, Faculty of Administration, Université Laval, 2325 rue de la Terrasse, Bureau 2519, Quebec City, Québec, G1V 0A6, CanadaTel +1 418-656-2131 ext 407670Fax +1 418-656-2180Email Maude.laberge@fsa.ulaval.caPurpose: To conduct a systematic review of the economic impact of interventions intended at optimizing medication use in older adults with multimorbidity and polypharmacy.Methods: We searched Ovid-Medline, Embase, CINAHL, Ageline, Cochrane, and Web of Science, for articles published between 2004 and 2020 that studied older adults with multimorbidity and polypharmacy. The intervention studied had to be aimed at optimizing medication use and present results on costs.Results: Out of 3,871 studies identified by the search strategy, eleven studies were included. The interventions involved different provider types, with a majority described as a multidisciplinary team involving a pharmacist and a general practitioner, in the decision-making process. Interventions were generally associated with a reduction in medication expenditure. The benefits of the intervention in terms of clinical outcomes remain limited. Five studies were cost-benefit analyses, which had a net benefit that was either null or positive. Cost-utility and cost-effectiveness analyses resulted in incremental cost-effectiveness ratios that were generally within the willingness-to-pay thresholds of the countries in which the studies were conducted. However, the quality of the studies was generally low. Omission of key cost elements of economic evaluations, including intervention cost and payer perspective, limited interpretability.Conclusion: Interventions to optimize medication use may provide benefits that outweigh their implementation costs, but the evidence remains limited. There is a need to identify and address barriers to the scaling-up of such interventions, starting with the current incentive structures for pharmacists, physicians, and patients.Keywords: polypharmacy, economic evaluation, potentially inappropriate medication, cost-effectiveness, cost-utility, cost-benefit

Recently, integrated geophysical‐geological surveys in the Nankai subduction zone in Japan have revealed that slow earthquakes repeatedly occur beneath the outer wedge of the forearc. During December 2020 to February 2021, clustered slow earthquakes propagated around the frontal thrust of the accretionary wedge. The frontal thrust ramps up from the basal décollement and slips over trench‐filling sediment along the landward edge of the Nankai trough floor. Here, the Paleo‐Zenisu ridge has been subducted beneath the inner‐outer slope border. In addition, ocean floor topography and geologic structure revealed by seismic reflection surveys completed before 2022 document that the basement of the Philippine Sea Plate beneath the frontal thrust has a seamount and a horst‐like basement high. The northern edge of the basement high is located at the ramp‐up position of the frontal thrust. The 2020–2021 clustered slow earthquakes started at the Paleo‐Zenisu ridge and propagated to the topographic highs beneath the deformation front. Considering that the relative plate convergence between the upper Amurian Plate of the Nankai forearc and the subducting Philippine Sea Plate is ∼6.0 cm/year, the basement high at the deformation front has uplifted the frontal crest of the wedge at an average rate of 2.7–5.7 mm/year for several tens to hundred thousand years. These rates are among some of the highest rock uplift rates measured in the world. The slow earthquakes in the off‐Kumano Nankai Trough in 2020–2021 are a snapshot of a "living" Nankai frontal thrust during the megathrust interseismic period. Plain Language Summary: Slow earthquakes family: slow slips, very low frequency earthquakes, and tremors are significant events for understanding the interseismic dynamics between large earthquakes along the convergent plate boundary in the ocean. Slow earthquakes took place during December 2020 to February 2021 in the Nankai Trough in Japan and propagated along the frontal edge of the upper plate. Seismic reflection surveys revealed that seamount‐like and horst‐like basement highs exist beneath the front, collide with the upper plate, and uplift trench filling sediments by a ramp thrust. Even the incipient plate boundary of the décollement is initiated within the sediments beneath the Nankai Trough. Such a deformation feature around the front is a source candidate for the slow earthquakes. The uplift rate of the frontal crest of the upper plate presents the same order of a few to several mm/year as that of the foreland of the Himalayan Mountain belt. The slow earthquakes in the off‐Kumano Nankai Trough in 2020–2021 appear the first snapshot of a "living" Nankai frontal thrust during inter‐large seismic period. Key Points: Between 2020 and 2021, slow earthquakes propagated around the frontal thrust of the accretionary wedge in the Nankai Trough off KumanoSeamount and horst‐like basement highs beneath the frontal thrust cause uplift and are associated with the slow earthquake eventsThe average uplift rate of the frontal crest is 2.7–5.7 mm/year, approximately the same order as that of the Himalayan foreland [ABSTRACT FROM AUTHOR]

Manami Kinjo, Kazuki Masuda, Yu Nakamura, Satoru Taguchi, Mitsuhiro Tambo, Takatsugu Okegawa, Hiroshi Fukuhara Department of Urology, Kyorin University School of Medicine, Tokyo 181-8611, JapanCorrespondence: Manami Kinjo Tel +81 422 47 5511Fax +81 422 42 8431Email kinjo_1702@yahoo.co.jpPurpose: Urinary incontinence (UI) is a common health-related problem in the female population and has a negative impact on many aspects of patients’ quality of life including mental problems. This study evaluated the mental effects of mid-urethral sling (MUS) surgery in female patients with stress UI or stress UI-dominant mixed UI.Patients and Methods: Women with stress UI or stress UI-dominant mixed UI who underwent MUS surgery and were enrolled in this study and followed up for 12 months. The International Consultation of Incontinence Questionnaire-Short Form (ICIQ-SF) and the Hospital Anxiety and Depression Scale (HADS) at baseline and 12 months after the MUS to evaluate the efficacy of the surgery.Results: At baseline, proportions of the patients with anxiety (HADS-Anxiety score of ≥ 8) and depression (HADS-Depression score of ≥ 8) were 21.6% (22/102) and 24.5% (25/102), respectively. At 12 months postoperatively, the median ICIQ-SF score, HADS-Anxiety score, and HADS-Depression score were significantly improved compared with their baseline values (p< 0.001 for ICIQ-SF and HADS-Depression, p=0.011 for HADS-Anxiety). At 12 months postoperatively, changes in the ICIQ-SF and HADS-A scores showed a moderate correlation (r = 0.578, p < 0.001), and changes in the ICIQ-SF and HADS-D scores had a strong correlation (r = 0.838, p < 0.001).Conclusion: This study demonstrated that MUS surgery significantly improved UI, anxiety, and depression with significant correlations in their symptoms. This suggests that improvement of the patients’ UI helped to relieve their symptoms of anxiety and depression.Keywords: urinary incontinence, anxiety, depression, mid-urethral sling surgery

Tatsuya Ogawa, 1 Yosuke Ishitsuka, 1 Yoshiyuki Nakamura, 1 Naoko Okiyama, 1 Rei Watanabe, 1, 2 Yasuhiro Fujisawa, 1 Manabu Fujimoto 1, 2 1Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan; 2Department of Dermatology, Osaka University Graduate School of Medicine, Suita, Osaka, JapanCorrespondence: Yosuke IshitsukaDepartment of Dermatology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, JapanTel +81-29-853-3128Fax +81-29-853-3217Email yosuke.ishitsuka@md.tsukuba.ac.jpIntroduction: The stratum corneum protects against the entry of pathogens, allergens, and irritants while preventing dehydration. The Kelch-like erythroid cell-derived protein with cap-n-collar homology-associated protein 1 (KEAP1)/NF-E2-related factor 2 (NRF2) system maintains skin barrier homeostasis. Aggregated evidence suggests that NRF2-mediated antioxidative response is hardwired into the stratified squamous epithelia. Honey and chamomile have long been regarded as natural antioxidants. Nonetheless, it is still unclear whether they activate the KEAP1/NRF2 system in the epidermis and could promote epidermal barrier recovery.Methods: To address the abovementioned issue, we explored the antioxidative property of honey/chamomile extract by using non-cell-based KEAP1-inhibition assay and cultured human epidermal keratinocytes.Results: Herein we report that the extract inhibited KEAP1-NRF2 interaction and induced keratinocyte production of antioxidant small proline-rich protein.Conclusion: Our results may offer an opportunity to develop cosmetic products that boost NRF2-mediated antioxidative/antiaging, epidermis-intrinsic bio-responses.Keywords: NRF2, honey, chamomile, keratinocyte

Takashi Ono,1,2 Katsuhito Kinoshita,1 Takuya Iwasaki,1 Yosai Mori,1 Ryohei Nejima,1 Yasuko Nakamura,3 Shiro Amano,4 Makoto Aihara,2 Kazunori Miyata1 1Miyata Eye Hospital, Miyakonojo, Miyazaki, Japan; 2Department of Ophthalmology, The University of Tokyo, Tokyo, Japan; 3Kagoshima Miyata Eye Clinic, Kagoshima, Japan; 4Inouye Eye Hospital, Tokyo, JapanCorrespondence: Takashi OnoMiyata Eye Hospital, 6-3, Kuraharacho, Miyakonojo, Miyazaki 885-0051, JapanTel +81-986-22-1441Fax +81-986-24-2174Email taono-tky@umin.ac.jpPurpose: To investigate the clinical courses of patients with corneal endothelial dysfunction due to Gomphocarpus physocarpus milky latex-induced injury.Patients and methods: In this retrospective case series, we included consecutive patients who visited Miyata Eye Hospital or Kagoshima Miyata Eye Clinic between October 2010 and August 2017 and had corneal edema caused by G. physocarpus milky latex-induced injury. Patient information and data on central corneal thickness (CCT), corneal endothelial cell density (ECD), best-corrected visual acuity (BCVA), and treatment were retrospectively reviewed.Results: Five eyes of four patients were included. The mean age was 79.0 ± 7.1 years. All patients complaining of symptoms visited the hospital 1 or 2 days after the injury. All patients had corneal edema; two of the five eyes showed hyperemia, whereas none showed corneal epithelial defect or blepharitis. The mean CCT was 699.8 ± 95.9 μm at the first visit and decreased to 563.2 ± 74.0 μm 1 week after the injury with treatment with topical steroids and antibiotics. The mean ECD and BCVA were 2695.8 ± 191.3 cells/mm2 and 0.22 ± 0.19 at the first visit and 2826.0 ± 132.9 cells/mm2 and 0.10 ± 0.09 one week after the injury, respectively.Conclusion: G. physocarpus caused transient dysfunction of the corneal endothelium and thereby, corneal edema. Accurate diagnosis with history taking is important to ascertain the types of plants the patient has touched and to exclude other possible diagnoses.Keywords: Asclepias physocarpus, corneal endothelial dysfunction, corneal edema, plant toxin