Search

Hiromu Tanaka,1 Takanori Asakura,1 Jun Kikuchi,2 Makoto Ishii,1 Ho Namkoong,3 Yuko Kaneko,2 Koichi Fukunaga,1 Naoki Hasegawa3 1Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan; 2Division of Rheumatology, Department of Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan; 3Department of Infectious Diseases, Keio University School of Medicine, Shinjuku-ku, Tokyo, JapanCorrespondence: Takanori AsakuraDivision of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, JapanTel +81-3-3353-1211Fax +81-3-3353-2502Email takanori.asakura@keio.jpBackground: Nontuberculous mycobacterial pulmonary disease (NTM-PD) often develops in patients with rheumatoid arthritis (RA), especially during immunosuppressive treatment, including biological disease-modifying antirheumatic drugs. NTM-PD is associated with airway lesions such as bronchiectasis, which is frequently seen in RA patients. Distinguishing which diseases cause the pulmonary lesion is difficult. However, there are limited reports of the development of RA during the follow-up of NTM-PD and how biological agents should be administered in these conditions, especially with cavitary lesions.Case Presentation: A 62-year-old woman with hemosputum was referred to our hospital, where she was diagnosed with Mycobacterium avium pulmonary disease. She began treatment with several antibiotics, including clarithromycin, ethambutol, rifampicin, and amikacin. In the course of treatment, M. avium became macrolide-resistant. Five years after beginning antibiotic treatment, she felt arthralgia in the fingers and wrists and had a high titer of rheumatoid factor and anticitrullinated peptide antibody, with which we diagnosed RA. Methotrexate, prednisolone, and iguratimod were subsequently administered, but the activity of RA gradually worsened. Meanwhile, M. avium changed to a macrolide-susceptible strain, her sputum smear results remained almost negative, and the NTM-PD disease was well controlled with antimicrobial therapy, despite her having cavitary lesions. Therefore, we started using CTLA4-Ig (abatacept). RA symptoms were substantially ameliorated. The pulmonary lesions and NTM-PD worsened mildly, but her pulmonary symptoms were stable.Conclusion: Physicians should be mindful of the etiologies of bronchiectasis, including RA, even in patients with a long-term history of treatment for bronchiectasis and NTM-PD. When NTM-PD is well controlled, even with remaining cavitary lesions, abatacept may be an option for patients with RA based on a comprehensive assessment of disease progression using NTM sputum smear/culture, computed tomography findings, and treatment response.Keywords: rheumatoid arthritis, nontuberculous mycobacterial infection, cavitary lesion, biological agent, bronchiectasis

Asami Nagaoka-Takatori,1 Madoka Ishii,1 Koremasa Hayama,1 Daisuke Obinata,2 Kenya Yamaguchi,2 Satoru Takahashi,2 Hideki Fujita1 1Division of Cutaneous Science, Department of Dermatology, Nihon University School of Medicine, Tokyo, 173-8610, Japan; 2Department of Urology, Nihon University School of Medicine, Tokyo, 173-8610, JapanCorrespondence: Hideki FujitaDivision of Cutaneous Science, Department of Dermatology, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo, 173-8610, JapanTel +81-3-3972-8111 (ext. 2502)Fax +81-3-5995-9841Email fujita.hideki@nihon-u.ac.jpAbstract: A 50-year-old Japanese woman presented with a 4-day history of multiple purpura on her extremities and myalgia. She had been receiving nivolumab therapy for stage IV renal cell carcinoma for 18 months. Nivolumab was temporarily discontinued due to liver dysfunction and resumed 3 months before. Biopsy specimen revealed leukocytoclastic vasculitis, and direct immunofluorescence showed deposition of IgA and C3 in the vessel walls of the upper dermis. Based on these findings, a diagnosis of IgA vasculitis was made. She was treated with 20 mg/day of oral prednisolone, which resulted in the complete disappearance of purpura and myalgia. Although the patient needed temporary cessation of nivolumab therapy, she experienced no recurrence of purpura or myalgia, and the dose of prednisolone was gradually tapered to 5 mg/day. Although nivolumab can lead to various immune-related adverse events, vasculitis is rare. To the best of our knowledge, this is the second case of IgA vasculitis during nivolumab therapy.Keywords: immune checkpoint inhibitors, leukocytoclastic vasculitis, PD-1, purpura

The impact of resolving western boundary currents and mesoscale eddies on a carbon circulation simulation for the North Pacific Ocean is investigated to evaluate the merits of using high‐resolution ocean biogeochemical models for climate projections. Simulations by a 100‐km resolution global ocean biogeochemical model with and without embedding a 10‐km resolution model in the North Pacific Ocean are compared. The major improvement in the high‐resolution simulation is the representation of the Kuroshio, its extension current, and the recirculation gyres formed to its south and north, resulting in a proper representation of the North Pacific subtropical mode water (STMW) and an increase in storage of the anthropogenic CO2 (Canth) in STMW by about two‐thirds. The larger storage rate in STMW is caused by supply of a larger amount of warm surface water containing rich Canth to the formation region by the intensified Kuroshio. A huge buoyancy loss from this warm water results in the increased formation of STMW that occupies a vast area in the western subtropical gyre. The surface uptake of Canth in the formation region of STMW is slightly increased but is largely comparable to that of the low‐resolution model. Moreover, there is no structural difference in Canth uptake in other parts of the subtropical region. Thus, the improvement of Canth distribution can be understood as a redistribution of water mass in the subtropical gyre by the improved circulation. The present assessment motivates the use of a high horizontal resolution ocean model in next‐generation projection experiments with carbon cycles. Plain Language Summary: Accurately representing absorption and accumulation of anthropogenic CO2 (Canth) by the ocean in Earth system models is important to reliably project future climate change. This study investigates the impact of realistically expressing the Kuroshio, which is not expressed adequately in the majority of current Earth system models, on a carbon circulation simulation for the North Pacific Ocean. Two simulations differing in the horizontal grid spacing, about 100 and 10 km, are compared. The intensified Kuroshio in the fine resolution model results in an improved oceanic structure for the upper 500‐m depths in the western North Pacific Ocean, and more Canth is accumulated there, which is closer to observations. Budget analysis suggests that source for the increased Canth accumulation is not local surface flux but a supply of Canth‐rich surface water from low latitudes by the intensified Kuroshio. Such improvements would give more fidelity to projections of regional subsurface water acidification rate. Overall, the use of a fine horizontal resolution ocean model can be recommended in next‐generation projection experiments with carbon cycles for the North Pacific Ocean. Key Points: Storage of anthropogenic carbon in the western North Pacific Ocean is improved by using a 10‐km horizontal resolution ocean modelImprovement in the formation and distribution of the North Pacific subtropical mode water is a keyUse of 10‐km class high horizontal resolution ocean models is recommended as part of Earth system models with carbon cycles [ABSTRACT FROM AUTHOR]

Spatiotemporal variations in air‐sea CO2 fluxes in the Kuroshio region were evaluated using measurements made by voluntary cargo ships and research vessels. The data were re‐gridded to produce a 1° × 1° horizontal grid and 0.1‐year timesteps. Spatial clustering showed that the area north of approximately 30°N was the strongest atmospheric CO2 sink. The spatial differences were largest in winter and insignificant in summer. The oceanic CO2 uptake in the Kuroshio region increased from 2000 to 2019. Changes in the wind speed and total alkalinity affected the decadal increase in CO2 absorption. The spatial distributions of the air‐sea CO2 fluxes were affected by the Kuroshio large meander (KLM). This effect was likely caused by the change in seawater fCO2 via the change in the Kuroshio Extension Path during the KLM period. The Fourier regression technique used in the data analysis was expected to facilitate analyses of the carbonate system in coastal waters, where comprehensive on‐site measurements and satellite analyses are difficult. Plain Language Summary: We analyzed oceanic CO2 uptake in the Kuroshio region using measurements from cargo ships and research vessels. The regression technique used in this study improved the spatiotemporal resolution of the data and is expected to be widely applicable for the analysis of other seawater carbonate systems, especially in coastal areas where comprehensive measurements and satellite analysis are difficult. CO2 absorption was particularly high in the area north of approximately 30°N. The differences between CO2 absorption in that area and other areas were largest in winter and small in summer. The CO2 absorption increased between 2000 and 2019. Changes in wind speed and alkalinity affected the increase in CO2 absorption. The areal differences in CO2 absorption were affected by the Kuroshio large meander. This effect was probably the result of the change of the Kuroshio path during the Kuroshio large meander. Key Points: Spatiotemporal variations in carbonate parameters and air‐sea CO2 fluxes in the Kuroshio region were analyzed by Fourier regressionOceanic CO2 uptake increased between 2000 and 2019. Changes in wind speed and total alkalinity affected the increase rate in CO2 uptakeThe Kuroshio large meander affects the spatial distribution of air‐sea CO2 fluxes by change in the Kuroshio Extension path [ABSTRACT FROM AUTHOR]

Masaki Miyazaki,1 Hidetoshi Nakamura,1,2 Saeko Takahashi,1 Shotaro Chubachi,1 Mamoru Sasaki,1 Mizuha Haraguchi,1 Hideki Terai,1 Makoto Ishii,1 Koichi Fukunaga,1 Sadatomo Tasaka,1 Kenzo Soejima,1 Koichiro Asano,3 Tomoko Betsuyaku1 On behalf of the Keio COPD Comorbidity Research (K-CCR) group 1Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, 2Department of Respiratory Medicine, Saitama Medical University, Saitama, 3Division of Pulmonary Medicine, Department of Medicine, Tokai University School of Medicine, Kanagawa, Japan Background: Triple combination therapy involving long-acting muscarinic antagonists long-acting β2 agonists, and inhaled corticosteroids has recently become an option for maintenance treatment of COPD. Some add-on clinical trials have reported the benefits of these combinations. However, the process to step up to triple therapy varies for individual cases.Methods: Keio University and affiliated hospitals conducted an observational COPD cohort study, recruiting patients diagnosed as having COPD by pulmonary physicians and those referred for investigation of possible COPD. Their prescription history and clinical course were retrospectively analyzed based on the physicians’ medical records and patient questionnaires. This study was registered with UMIN (UMIN000003470, April 10, 2010).Results: A total of 95 of the 445 COPD patients (21%) were treated with inhaled corticosteroids/long-acting β2 agonists/long-acting muscarinic antagonists as maintenance therapy, including 12 in COPD Grade I, 31 in Grade II, 38 in Grade III, and 14 in Grade IV, based on the Global Initiative for Chronic Obstructive Lung Disease spirometric grading. For more than half of the patients on triple therapy, the treatment had been intensified due to unsatisfactory improvement of symptoms, and 32% were treated with triple therapy due to comorbid asthma. In contrast, there were COPD patients whose therapy was maintained after starting with triple therapy because of their serious conditions or concurrent exacerbation at diagnosis (8%).Conclusion: Triple therapy was often prescribed in the real-life management of COPD, even in patients whose airflow limitation was not severe. To better control symptoms was the major reason for choosing triple therapy, regardless of the severity of COPD, in Japan. Keywords: chronic obstructive pulmonary disease, inhaled corticosteroids, long-acting muscarinic antagonists, long-acting β2 agonists, triple therapy

Jinichi Hirano,1,2 Koichiro Watanabe,3 Takefumi Suzuki,1,4 Hiroyuki Uchida,1 Ryosuke Den,5 Taishiro Kishimoto,1 Takashi Nagasawa,5 Yusuke Tomita,4 Koichiro Hara,6 Hiromi Ochi,7 Yoshimi Kobayashi,1 Mutsuko Ishii,1 Akane Fujita,1 Yoshihiko Kanai,1 Megumi Goto,1 Hiromi Hayashi,1 Kanako Inamura,1 Fumiko Ooshima,1 Mariko Sumida,1 Tomoko Ozawa,1 Kayoko Sekigawa,1 Maki Nagaoka,1 Kae Yoshimura,1 Mika Konishi,1 Ataru Inagaki,1 Takuya Saito,8 Nobutaka Motohashi,9 Masaru Mimura,1 Yoshiro Okubo,8 Motoichiro Kato,11Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan; 2Ohizumi Hospital, Tokyo, Japan; 3Department of Psychiatry School of Medicine, Kyorin University, Tokyo, Japan; 4Inokashira Hospital, Tokyo, Japan; 5Komagino Hospital, Tokyo, Japan; 6Asai Hospital, Chiba, Japan; 7Kurumegaoka Hospital, Tokyo, Japan; 8Department of Psychiatry School of Medicine, Nippon Medical School, Tokyo, Japan; 9Department of Psychiatry, School of Medicine, University of Yamanashi, Yamanashi, JapanObjective: The use of an algorithm may facilitate measurement-based treatment and result in more rational therapy. We conducted a 1-year, open-label study to compare various outcomes of algorithm-based treatment (ALGO) for schizophrenia versus treatment-as-usual (TAU), for which evidence has been very scarce.Methods: In ALGO, patients with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, fourth edition) were treated with an algorithm consisting of a series of antipsychotic monotherapies that was guided by the total scores in the positive and negative syndrome scale (PANSS). When posttreatment PANSS total scores were above 70% of those at baseline in the first and second stages, or above 80% in the 3rd stage, patients proceeded to the next treatment stage with different antipsychotics. In contrast, TAU represented the best clinical judgment by treating psychiatrists.Results: Forty-two patients (21 females, 39.0 ± 10.9 years-old) participated in this study. The baseline PANSS total score indicated the presence of severe psychopathology and was significantly higher in the ALGO group (n = 25; 106.9 ± 20.0) than in the TAU group (n = 17; 92.2 ± 18.3) (P = 0.021). As a result of treatment, there were no significant differences in the PANSS reduction rates, premature attrition rates, as well as in a variety of other clinical measures between the groups. Despite an effort to make each group unique in pharmacologic treatment, it was found that pharmacotherapy in the TAU group eventually became similar in quality to that of the ALGO group.Conclusion: While the results need to be carefully interpreted in light of a hard-to-distinguish treatment manner between the two groups and more studies are necessary, algorithm-based antipsychotic treatments for schizophrenia compared well to treatment-as-usual in this study.Keywords: algorithm, open-label clinical trial, measurement-based treatment, schizophrenia, treatment-as-usual

Hiroyuki Kawaji,1 Masaji Ishii,1 Yasunobu Tamaki,1 Kan Sasaki,2 Michiaki Takagi,21Department of Orthopaedic Surgery, Saiseikai Yamagata Saisei Hospital, 2Department of Orthopaedic Surgery, Yamagata University Faculty of Medicine, Yamagata, JapanAbstract: Fatal pulmonary thromboembolism is the most serious complication following surgery. Patients undergoing major orthopedic surgeries, including total hip replacement, total knee replacement, and hip fracture surgery, represent a group at particularly high risk of venous thromboembolism. Therefore, prophylaxis for thromboembolic events has been of great concern to surgeons. Edoxaban is a novel, orally available, and highly specific and direct factor Xa inhibitor. This new agent was approved for the prevention of venous thromboembolism in patients undergoing major orthopedic surgery, including total hip replacement, total knee replacement, and hip fracture surgery, by the Japanese Ministry of Health, Labor, and Welfare in 2011. Preclinical and Phase I clinical trials demonstrated several promising properties. Its rapid absorption and short life-time in blood are known. Edoxaban inhibits factor Xa activity directly and selectively. It also has a strong antithrombotic effect without any influence of food intake. Coagulation monitoring is not required. Edoxaban has predictable linear pharmacokinetic and pharmacodynamic profiles. Phase II and III clinical trials have been completed to examine its efficacy and safety in patients undergoing major orthopedic surgery. In these clinical trials, oral administration of edoxaban showed efficacy superior to that of oral placebo or subcutaneously administered dalteparin or enoxaparin. Edoxaban can be regarded as a first choice to prevent venous thromboembolism after major orthopedic surgery.Keywords: edoxaban, thromboprophylaxis, venous thromboembolism, total hip replacement, total knee replacement, hip fracture surgery