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The efficacy of unrelated transplantation for patients with ALL who lack an HLA-matched sibling remains unclear. We performed a decision analysis to determine the efficacy of myeloablative transplantation from a genetically HLA-A, -B, -DRB1 allele-matched unrelated donor for patients with Ph chromosome-negative ALL aged 21-54 years. The transition probabilities were estimated from the Japan Adult Leukemia Study Group studies (ALL93; n=80, ALL97; n=82), and the Japan Marrow Donor Program database (transplantation in first CR (CR1): n=177). The primary outcome measure was the 10-year survival probability with or without quality of life (QOL) adjustment. Subgroup analyses were performed according to risk stratification based on the WBC count and cytogenetics, and according to age stratification. In all patients, unrelated transplantation in CR1 was shown to be superior in analyses both with and without QOL adjustment (40.8 vs 28.4% and 43.9 vs 29.0%, respectively). A similar tendency was observed in all subgroups. The decision model was sensitive to the probability of leukemia-free survival following chemotherapy and the probability of survival after transplantation in standard-risk and higher-aged patients. Unrelated transplantation in CR1 improves the long-term survival probability in patients who lack an HLA-matched sibling. However, recent improvements in treatment strategies may change this result. [ABSTRACT FROM AUTHOR]

High incidences of human herpesvirus (HHV)-6 encephalitis have recently been reported from several Japanese SCT centers. To evaluate the effect of low-dose foscarnet (PFA) in preventing HHV-6 infection among recipients of unrelated BM or cord blood (CB), we examined consecutive cohorts without prophylaxis against HHV-6 (Cohort 1, n=51) and with PFA prophylaxis (Cohort 2, PFA 50 mg/kg/day for 10 days after engraftment, n=67). Plasma real-time PCR assay was performed weekly. High-level reactivation defined as HHV-6 DNA104 copies/mL by day 70 was the primary endpoint. No significant reduction of high-level reactivation was seen in Cohort 2 (19.4%) compared with Cohort 1 (33.8%, P=0.095). A trend was identified toward fewer high-level HHV-6 reactivations in Cohort 2 among recipients of unrelated BM (P=0.067), but no difference in incidence was observed among CB recipients (P=0.75). Breakthrough HHV-6 encephalitis occurred following PFA prophylaxis in three patients, and incidence of HHV-6 encephalitis did not differ between Cohort 1 (9.9%) and Cohort 2 (4.5%, P=0.24). In conclusion, 50 mg/kg/day of PFA does not effectively suppress HHV-6 reactivation and cannot prevent all cases of HHV-6 encephalitis. To effectively prevent HHV-6 encephalitis, alternative approaches based on the pathogenesis of HHV-6 encephalitis will probably be required. [ABSTRACT FROM AUTHOR]

To investigate new particle formation (NPF) events in urban and forest environments, number size distributions of ultrafine particles were measured at an urban site and a deciduous forest site in Sapporo, Northern Japan, during the summers of 2011 and 2010, respectively. The burst of nucleation mode particles at the urban site typically started in the morning (07:00-11:30 local time, LT) with simultaneous increases in SO2 and O3 concentrations and the UV index under clear (sunny) weather conditions. The growth rates of nucleated particles at the urban site ranged from 5.0 to 7.8 nm h-1 with an average of 6.3 ± 1.1 nm h-1. NPF events at the urban site were separated into events with or without subsequent particle growth after the burst of nucleation mode particles. This division was found to relate to prevailing wind direction because the subsequent growth of freshly nucleated particles typically occurred when wind direction shifted to northwesterly (from residential and public park areas), whereas it did not occur under southeasterly winds (from the downtown area). During the periods with NPF events, elevated concentrations of non-methane hydrocarbons (NMHC) were obtained under conditions of northwesterly winds when compared to southeasterly winds, whereas no difference in SO2 levels was recorded. These results suggest that variations in NMHC concentration may play an important role in the growth of freshly nucleated particles at the urban site. The burst of nucleation mode particles at the forest site typically started around noon (10:30-14:30 LT), which was 3-4 h later than that at the urban site. Interestingly, at the forest site the burst of nucleation mode particles usually started when air masses originating from urban Sapporo arrived at the forest site. The present study indicates that the inflow of these urban air masses acted as a trigger for the initiation of the burst of nucleation mode particles in the deciduous forest. [ABSTRACT FROM AUTHOR]

Clinical studies using genetic randomization cannot accurately answer whether adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) who have a human leukocyte antigen (HLA)-matched sibling should undergo allogeneic hematopoietic stem cell transplantation (HSCT) or chemotherapy in first remission, as, in these studies, patients without a sibling donor undergo alternative donor transplantation or chemotherapy alone after a relapse. Therefore, we performed a decision analysis to identify the optimal strategy in this setting. Transition probabilities and utilities were estimated from prospective studies of the Japan Adult Leukemia Study Group, the database of the Japan Society for Hematopoietic Cell Transplantation and the literature. The primary outcome measure was the 10-year survival probability with or without quality of life (QOL) adjustments. Subgroup analyses were performed according to risk stratification on the basis of white blood cell count and cytogenetics, and according to age stratification. In analyses without QOL adjustments, allogeneic HSCT in first remission was superior in the whole population (48.3 vs 32.6%) and in all subgroups. With QOL adjustments, a similar tendency was conserved (44.9 vs 31.7% in the whole population). To improve the probability of long-term survival, allogeneic HSCT in first remission is recommended for patients who have an HLA-matched sibling. [ABSTRACT FROM AUTHOR]

Apart from its unique lesion distribution pattern, the opticospinal form of multiple sclerosis (OSMS) is distinct among Japanese patients who satisfy the diagnostic criteria of MS. OSMS has been suggested to be strongly associated with HLA-DPB1*0501 in Japanese. However, association of DPB1*0301 with non-OSMS and lack of DPB1*0301 in OSMS were also reported. To verify the role of DPB1*0501 and DPB1*0301 in Japanese MS patients we determined the frequencies of these alleles in 26 patients with OSMS, 167 with non-OSMS and 156 normal subjects, who were all residents of Hokkaido, the northernmost island of Japan. All (100%) OSMS were negative for DPB1*0301 while 32 (19%) of the non-OSMS were positive for the allele. In DPB1*0301-negatives, the frequencies of DPB1*0501 in OSMS (85%) and non-OSMS (82%) were similar, but both were higher than in the controls (66%). In DPB1*0301-positives, the frequency of DPB1*0501 was low but similar in non-OSMS (12/32; 38%) and controls (6/14; 43%). Periventricular white matter lesions (PVL) were noted in 31 of 32 (97%) DPB1*0301-positive non-OSMS patients but in only 22 out of 135 (16%) DPB1*0301-negative non-OSMS patients and two out of 26 (8%) OSMS patients. Our findings indicate that DPB1*0501 plays an important role in the development of MS in general, but not in OSMS. The strong association of DPB1*0501 with OSMS may be due to the over-representation of the DPB1*0301 allele among individuals in the non-OSMS group. In addition, DPB1*0301 might be relevant to the development of periventricular lesions in Japanese patients with MS. [ABSTRACT FROM AUTHOR]

The Aerodyne Aerosol Mass Spectrometer (AMS) provides size-resolved chemical composition of non-refractory (vaporized at 600°C under vacuum) submicron aerosols with a time resolution of the order of minutes. Ambient measurements were performed in Tokyo between February 2003 and February 2004. We present intercomparisons of the AMS with a Particle-Into-Liquid Sampler combined with an Ion Chromatography analyzer (PILS-IC) and a Sunset Laboratory semi-continuous thermal-optical carbon analyzer. The temperature of the AMS inlet manifold was maintained at > 10 C above the ambient dew point to dry particles in the sample air (relative humidity (RH) in the inlet [ABSTRACT FROM AUTHOR]

The thin gap chambers (TGCs) are used for the muon trigger system in the end-cap regions of the ATLAS detector. The TGC mass production phase at High Energy Accelerator Research Organization (KEK) started in January 2001. As the anode-cathode distance is small, 1.4 mm, chamber flatness is essential to achieve a uniform gas gain over the chamber. In order to perform a stable production with high quality we developed a chamber closing system. When we glue two half-chambers together, we sandwich them between a granite table and an aluminum honeycomb panel to keep the chamber flat from both sides. By using silk screens, we control the quantity of epoxy adhesive that affects the chamber thickness. Due to these developments, we can achieve the flatness of less than 100 μm. Uniformity of detection efficiency of the TGC is measured with a cosmic-ray test bench at Kobe University. So far we have tested 300 TGCs. Position dependence of the efficiency is measured with a granularity of 5 mm × 5 mm. The average efficiency over the tested chambers is achieved to be 99% excluding the wire supports and spacers. [ABSTRACT FROM AUTHOR]

Objective: To provide scientific evidence supporting the efficacy of forest bathing as a natural therapy by investigating its physiological benefits using biological indicators in outdoor settings. Study design: Within-group comparisons were used to examine psychological and physiological responses to exposure to real forest and urban environments. Methods: Young Japanese male adults participated in a 3-day, 2-night field experiment. Physiological responses as well as self-reported psychological responses to forest and urban environmental stimuli were measured in real settings. The results of each indicator were compared against each environmental stimulus. Results: Heart rate variability analysis indicated that the forest environment significantly increased parasympathetic nervous activity and significantly suppressed sympathetic activity of participants compared with the urban environment. Salivary cortisol level and pulse rate decreased markedly in the forest setting compared with the urban setting. In psychological tests, forest bathing significantly increased scores of positive feelings and significantly decreased scores of negative feelings after stimuli compared with the urban stimuli. Conclusion: Physiological data from this field experiment provide important scientific evidence on the health benefits of forest bathing. The results support the concept that forest bathing has positive effects on physical and mental health, indicating that it can be effective for health promotion. Despite the small sample size in this study, a very clear tendency towards positive physiological and psychological outcomes in forests was observed. [ABSTRACT FROM AUTHOR]

Poor prognostic factors, such as transfusion dependency and chromosomal risk, need to be considered in the indication of allogeneic hematopoietic cell transplantation (allo-HCT) for patients harboring myelodysplastic syndromes with less than 5% marrow blasts (MDS-Lo). We analyzed the post-transplant outcomes of 1229 MDS-Lo patients who received myeloablative (MAC)(n = 651), reduced-intensity (RIC)(n = 397), and non-myeloablative conditioning (NMAC) regimens (n = 181). The multivariate analysis revealed that the RIC group had better chronic graft-versus-host disease (GVHD)- and relapse-free survival (CRFS) (P = 0.021), and GVHD- and relapse-free survival (GRFS) than the MAC group (P = 0.001), while no significant differences were observed between the NMAC and MAC groups. In the subgroup analysis, the MAC group has better overall survival (P = 0.008) than the RIC group among patients with an HCT-comorbidity index (HCT-CI) score of 0, while the RIC group had better overall survival (P = 0.029) than the MAC group among those with an HCT-CI score ≥3. According to the type of conditioning regimen, total body irradiation 12 Gy-based MAC regimen showed better OS and CRFS than the other MAC regimen, and comparable outcomes to the RIC regimen. In conclusion, the RIC and NMAC regimens are promising options for MDS-Lo patients in addition to the MAC regimen., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Human mpox, which has spread worldwide since May 2022, is characterized by symptoms involving the genital area; however, its treatment methods and clinical course are not completely understood. Furthermore, penile swelling in human mpox can be difficult to differentiate from cellulitis and antibiotic use has been reported in such cases. Herein, we report a case of human mpox in Japan with prominent penile swelling and persistent penile ulcers that improved without specific treatment. The patient was a Japanese man in his 20s with a history of having sexual intercourse with men frequently. He visited Tokyo Metropolitan Toshima Hospital because of a fever and rash in the genital area. Physical examination revealed vesicles on the limbs, penile pigmentation, and significant penile swelling and redness. There were no signs of cellulitis and symptomatic treatment was initiated with outpatient follow-up. After 7 days, an improving trend in penile swelling, redness, and pain was observed. However, a partially black skin ulcer with exudate was observed at the left coronal sulcus of the penis. Therefore, the symptomatic treatment was continued. On illness day 28, the penile swelling completely improved; however, the penile ulcer and pain persisted, and the exudate was observed again. By illness day 63, the pain in his anogenital area had disappeared, and the penile skin ulcer had healed. The following observations were noted in this case: (i) human mpox can improve without specific treatment such as tecovirimat administration and (ii) skin lesions in the genital area may change over time., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest regarding this report., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for adult T-cell leukaemia/lymphoma (ATL). Specific HLAs are associated with outcomes of immunotherapy and allo-HSCT. We hypothesised that individual HLAs would affect the clinical outcomes of ATL patients after allo-HSCT. Using data from a Japanese registry, we retrospectively analysed 829 patients with ATL who received transplants from HLA-identical sibling donors or HLA-A, -B, -C or -DRB1 allele-matched unrelated donors between 1996 and 2015. We evaluated the overall mortality risk of HLA-A, -B and -DR antigens with frequencies exceeding 3%. Outcomes were compared between transplants with or without specific HLA antigens. Of the 25 HLAs, two candidates were identified but showed no statistically significant differences by multiple comparison. HLA-B62 was associated with a lower risk of mortality (hazard ratio [HR], 0.68; 95% confidence interval [CI]: 0.51-0.90; p = 0.008), whereas HLA-B60 was associated with a higher risk of mortality (HR, 1.64; 95% CI: 1.19-2.27; p = 0.003). In addition, HLA-B62 was associated with a lower risk of transplant-related mortality (TRM) (HR, 0.52; 95% CI: 0.32-0.85, p = 0.009), whereas HLA-B60 was associated with a higher risk of grades III-IV acute graft-versus-host disease (HR, 2.63; 95% CI: 1.62-4.27; p < 0.001). Neither HLA influenced relapse. The higher risk of acute GVHD in HLA-B60-positive patients and the lower risk of TRM in HLA-B62-positive patients were consistent with previously obtained results from patients with other haematological malignancies. Consideration of HLA in ATL patients may help to predict risk and outcomes after allo-HSCT., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: NS-87/CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin. NS-87/CPX-351 exerts antileukemic action by maintaining a synergistic molar ratio of cytarabine to daunorubicin of 5:1 within the liposome while in circulation. Patients with high-risk acute myeloid leukemia (AML), which includes therapy-related AML and AML with myelodysplasia-related changes (AML-MRC), have poorer outcomes than those with other AML., Methodology: This open-label phase 1/2 (P1/2) study was conducted in 47 Japanese patients aged 60-75 years with newly diagnosed high-risk AML to evaluate the pharmacokinetics, safety, and efficacy of NS-87/CPX-351., Results: In the 6 patients enrolled in the P1 portion, no dose-limiting toxicities (DLTs) were reported, and 100 units/m 2 during the induction cycle was found to be acceptable. Cytarabine and daunorubicin had a long half-life in the terminal phase (32.8 and 28.7 h, respectively). In the 35 patients enrolled in the P2 portion, composite complete remission (CRc; defined as complete remission [CR] or CR with incomplete hematologic recovery [CRi]) was achieved in 60.0% (90% CI: 44.7-74.0) of the patients. Adverse events due to NS-87/CPX-351 were well tolerated., Outcomes: NS-87/CPX-351 can be considered as a frontline treatment option for Japanese patients with high-risk AML., (© 2024. The Author(s).)

Background and Objectives: Geographical limitations in remote island medical facilities result in excessive wastage of blood products. To address this, we explored the feasibility of a novel blood rotation system, which enables the return and redelivery of blood products to/from the blood bank while ensuring the management of product quality, including temperature control. This study aimed to enhance the supply of blood products to these facilities., Materials and Methods: The Japan Red Cross Nagasaki Blood Center, Nagasaki Goto Chuoh Hospital (NGCH) and Nagasaki University Hospital collaborated to coordinate the transport and supply of red blood cell (RBC) products. Type O, RhD-positive, irradiated RBC products were stored at a precise 4.0 ± 2.0°C in an active transport refrigerator (ATR). After transport from the Japan Red Cross Nagasaki Blood Center to NGCH, RBC products were held for 1 week in the ATR, and unused products were returned. Eligible returned products were reissued to the Nagasaki University Hospital., Results: All the returned RBC products met the redelivery criteria. Among the 103 redelivered RBC preparations, 101 bags (98.1%) were successfully used. NGCH utilized 597 RBC products and discarded 80 samples. The ATR supplied 107 type O RBC bags without any wastage. The overall wastage rate was 10.2% during the study period compared with 24.2% in the same period in the previous year., Conclusion: This innovative supply and operation system ensures a consistent and secure RBC product supply to remote islands while maximizing blood product use., (© 2024 International Society of Blood Transfusion.)

Background: Disability in ambulation has a critical impact on activities of daily living in patients with multiple sclerosis (MS). The 12-item Multiple Sclerosis Walking Scale (MSWS-12) is a self-reported instrument developed to assess the impact of MS on walking. The scale's 12 items assess various aspects of walking-related tasks during the past 2 weeks. MSWS-12 has been used in multiple clinical studies and translated into several languages. In the present study, we translated the MSWS-12 into Japanese and evaluated its psychometric properties in a cross-sectional study., Methods: The original English MSWS-12 version 2 (v2) was translated into Japanese through a standard procedure. Sixty consecutive Japanese MS patients completed the newly prepared Japanese MSWS-12v2 questionnaire and repeated the test 14 days later. Physical disability was assessed by the Expanded Disability Status Scale (EDSS), Timed 25-foot Walk (T25FW), and 9-hole Peg Test (9HPT). Cognitive performance was evaluated using the Processing Speed Test (PST). Fatigue and health-related quality of life were assessed using the Japanese versions of the Fatigue Severity Scale (FSS) and the Functional Assessment of MS (FAMS)., Results: The mean age of the patients was 42.5 years, with median disease duration of 10 years, and median EDSS of 2.0 (range 0, 6.5). Forty-seven patients (78.3 %) had relapsing-remitting, 9 (15.0 %) had secondary-progressive, and 4 (6.7 %) had primary-progressive phenotypes. The median score of the MSWS-12v2 was 5.95 (interquartile range 0, 50.6). Twenty-seven patients (45 %) scored the lowest possible score (0 points), while one (1.7 %) scored the highest possible score (100 points). Cronbach's alpha was 0.98 (95 % confidence interval [CI] 0.97, 0.98), and the test-retest intraclass correlation was 0.95 (95%CI 0.94, 0.96). MSWS-12v2 score was strongly correlated with EDSS (Spearman's ρ = 0.73 [95%CI 0.58, 0.83]), T25FW (ρ = 0.70 [95%CI 0.55, 0.81]), and total FAMS score (ρ = -0.80 [95%CI -0.88, -0.69]), and moderately correlated with 9HPT (ρ = 0.65 [95%CI 0.47, 0.77] for the dominant hand; ρ = 0.62 [95%CI 0.43, 0.75] for the non-dominant hand), PST (ρ = -0.65 [95%CI -0.78, -0.47]), and FSS (ρ = 0.68 [95%CI 0.52, 0.80]). Among the subcomponents of FAMS, the mobility subcomponent showed the most robust correlation with MSWS-12v2 score (ρ = -0.91 [95%CI -0.94, -0.81]). In patients with minimal or no objective disability (EDSS < 3.0, n = 40), only the mobility subcomponent of FAMS was strongly correlated with MSWS-12v2 score (ρ = -0.76 [95% CI -0.87, -0.58]). In contrast, correlations of MSWS-12v2 score with EDSS and T25FW were weak in this subgroup (ρ = 0.28 [95%CI -0.03, 0.55] for EDSS; ρ = 0.25 [95%CI -0.06, 0.52] for T25FW). Response patterns for the single items showed that 32.5 % of the patients with EDSS below 3.0 reported having problems with balance, followed by climbing stairs and standing while doing things (both 25 %)., Conclusion: The Japanese version of the MSWS-12v2 developed in this study is reliable, valid, and helpful for screening walking disability in Japanese MS patients, including those with minimal objective disability., Competing Interests: Declaration of competing interest Yusei Miyazaki has received travel and speaker honoraria from Alexion Pharma, Biogen Japan, Chugai Pharmaceutical Company, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, and Teijin Pharma. Masaaki Niino has received travel and speaker honoraria from Alexion Pharma, Biogen Japan, Chugai Pharmaceutical Company, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, and Takeda Pharmaceutical Company. Naoya Minami has received travel and speaker honoraria from Argenx Japan. The other authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease with a poor prognosis and an unknown cause that generally progresses to pulmonary fibrosis and leads to irreversible tissue alteration. The "Guidelines for the treatment of idiopathic pulmonary fibrosis 2017," specializing in the treatment of IPF for the first time in Japan and presenting evidence-based standard treatment methods suited to the state of affairs in Japan, was published in 2017, in line with the 2014 version of "Formulation procedure for Minds Clinical Practice Guidelines." Because new evidence had accumulated, we formulated the "Guidelines for the treatment of Idiopathic Pulmonary Fibrosis 2023 (revised 2nd edition)." While keeping the revision consistent with the ATS/ERS/JRS/ALAT IPF treatment guidelines, new clinical questions (CQs) on pulmonary hypertension were added to the chronic stage, in addition to acute exacerbation and comorbid lung cancer, which greatly affect the prognosis but are not described in the ATS/ERS/JRS/ALAT IPF guidelines. Regarding the advanced stages, we additionally created expert consensus-based advice for palliative care and lung transplantation. The number of CQs increased from 17 in the first edition to 24. It is important that these guidelines be used not only by respiratory specialists but also by general practitioners, patients, and their families; therefore, we plan to revise them appropriately in line with ever-advancing medical progress., Competing Interests: Declaration of competing interest Masashi Bando received lecture fees from AstraZeneca K.K., Shionogi & Co., Ltd. and Nippon Boehringer Ingelheim Co., Ltd. Sakae Homma received lecture fees from Nippon Boehringer Ingelheim Co., Ltd. and belongs to Endowed departments by Shionogi & Co., Ltd., Chugai Pharmaceutical Co., Ltd., Teijin Pharma Ltd. and Nippon Boehringer Ingelheim Co., Ltd. Hiroshi Date received lecture fees from Covidien Japan Inc. and Johnson & Johnson K.K. and donations from Adachi Co., Ltd., Hogy Medical Co., Ltd. and Taiho Pharmaceutical Co., Ltd. Kazuma Kishi received lecture fees from AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd. and Nippon Boehringer Ingelheim Co., Ltd. and research funding from MSD K. K., Taiho Pharmaceutical Co., Ltd. and Chugai Pharmaceutical Co., Ltd. and donations from Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K. and Nippon Boehringer Ingelheim Co., Ltd. Atsushi Miyamoto received lecture fees from Nippon Boehringer Ingelheim Co., Ltd. Takeo Nakayama received lecture fees from Eli Lilly Japan K.K., Pfizer Japan, Inc. and Janssen Pharmaceutical K.K. and research finding from I&H Co., Ltd., Cocokarafine Group Co., Ltd. And Konica Minolta, Inc. and donations from Cancerscan Inc. and Yuyama Manufacturing Co., Ltd. Arata Azuma received lecture fees from Taiho Pharmaceutical Co., Ltd., Toray Industries, Inc. and Nippon Boehringer Ingelheim Co., Ltd. Yasuhiro Kondoh received lecture fees from Nippon Boehringer Ingelheim Co., Ltd., Bristol-Myers Squibb K.K. and Janssen Pharmaceutical K.K. Takeshi Johkoh received lecture fees from Nippon Boehringer Ingelheim Co., Ltd. Yasuhiko Nishioka received lecture fees from MSD K. K., AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd. and Nippon Boehringer Ingelheim Co., Ltd. and research funding from Taiho Pharmaceutical Co., Ltd., TMS Co., Ltd., Chugai Pharmaceutical Co., Ltd. and Bonac Corporation and donations from Asahi Kasei Pharma Corporation, Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd. and Eli Lilly Japan K.K. Junya Fukuoka received research funding from National Institute of Advanced Industrial Science and Technology and Future Corporation. Yasunari Miyazaki received donations from Chugai Pharmaceutical Co., Ltd. and Nippon Boehringer Ingelheim Co., Ltd. and lecture fees from AstraZeneca K.K. and Nippon Boehringer Ingelheim Co., Ltd. Ichiro Yoshino received lecture fees from MSD K. K., AstraZeneca K.K., Intuitive Surgical G.K., Ono Pharmaceutical Co., Ltd., Covidien Japan Inc., Johnson & Johnson K.K., Daiichi Sankyo Company, Ltd., Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co. and Eli Lilly Japan K.K. and donations from Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Eli Lilly Japan K.K. and Pfizer Japan, Inc. Takafumi Suda received lecture fees from AstraZeneca K.K. and Nippon Boehringer Ingelheim Co., Ltd. and research funding from Chugai Pharmaceutical Co., Nippon Boehringer Ingelheim Co. and Bristol-Myers Squibb K.K. and donations from Shionogi & Co., Ltd. and Chugai Pharmaceutical Co. Yoshihito Goto, Susumu Sakamoto and Hiroyoshi Yamauchi have no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background/objectives: Obesity, defined by body mass index (BMI), is a well-known risk factor for the severity of coronavirus disease 2019 (COVID-19). Adipose tissue distribution has also been implicated as an important factor in the body's response to infection, and excess visceral fat (VF), which is prevalent in Japanese, may contribute significantly to the severity. Therefore, this study aimed to evaluate the association of obesity and VF with COVID-19 severe illness in Japan., Subjects/methods: This retrospective cohort study involved 550 COVID-19 patients admitted to a tertiary care hospital with BMI and body composition data, including VF. The primary endpoint was severe illness, including death, due to COVID-19 during hospitalization. Logistic regression analysis was applied to examine the quartiles of BMI and VF on severe illness after adjusting for covariates such as age, sex, subcutaneous fat, paraspinal muscle radiodensity, and comorbidities affecting VF (COPD, cancer within 5 years, immunosuppressive agent use)., Results: The median age was 56.0 years; 71.8% were males. During hospitalization, 82 (14.9%) experienced COVID-19 severe illness. In the multivariate logistic regression analysis, Q4 of BMI was not significantly associated with severe illness compared to Q1 of BMI (OR 1.03; 95% CI 0.37-2.86; p = 0.95). Conversely, Q3 and Q4 of VF showed a higher risk for severe illness compared to Q1 of VF (OR 2.68; 95% CI 1.01-7.11; p = 0.04, OR 3.66; 95% CI 1.30-10.26; p = 0.01, respectively). Stratified analysis by BMI and adjusted for covariates showed the positive association of VF with severe illness only in the BMI < 25 kg/m 2 group., Conclusions: High BMI was not an independent risk factor for COVID-19 severe illness in hospitalized patients in Japan, whereas excess VF significantly influenced severe illness, especially in patients with a BMI < 25 kg/m 2 ., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

We conducted a multicenter, prospective observational study of acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML) in Japan. From August 2011 to January 2016, we enrolled 6568 patients. Herein, we report the results for MDS (n = 2747) and CMML (n = 182). The percentage of patients aged 65 years or older was 79.5% for MDS and 79.7% for CMML. The estimated overall survival (OS) rate and cumulative incidence of AML evolution at 5 years were 32.3% (95% confidence interval: 30.2-34.5%) and 25.7% (23.9-27.6%) for MDS, and 15.0% (8.9-22.7%) and 39.4% (31.1-47.6%) for CMML. Both diseases were more common in men. The most common treatment for MDS was azacitidine, which was used in 45.4% of higher-risk and 12.7% of lower-risk MDS patients. The 5-year OS rate after treatment with azacitidine was 12.1% (9.5-15.1%) for of higher-risk MDS patients and 33.9% (25.6-42.4%) for lower-risk patients. The second most common treatment was erythropoiesis-stimulating agents, given to just 20% of lower-risk patients. This is the first paper presenting large-scale, Japanese data on survival and clinical characteristics in patients with MDS and CMML., (© 2023. Japanese Society of Hematology.)

This report covers acute myeloid leukemia (AML) results from a multicenter, prospective observational study of AML, myelodysplastic syndromes, and chronic myelomonocytic leukemia in Japan. From August 2011 to January 2016, 3728 AML patients were registered. Among them, 42% were younger than 65, and the male-to-female ratio was 1.57:1. With a median follow-up time of 1807 days (95% confidence interval [CI]: 1732-1844 days), the estimated 5-year overall survival (OS) rate in AML patients (n = 3707) was 31.1% (95% CI: 29.5-32.8%). Trial-enrolled patients had a 1.7-fold higher OS rate than non-enrolled patients (5-year OS, 58.9% [95% CI: 54.5-63.1%] vs 35.5% [33.3-37.8%], p < 0.0001). Women had a higher OS rate than men (5-year OS, 34% [95% CI; 31.4-36.7%] vs 27.7% [25.7-29.7%], p < 0.0001). The OS rate was lower in patients aged 40 and older than those under 40, and even lower in those over 65 (5-year OS for ages < 40, 40-64, 65-74, ≥ 75: 74.5% [95% CI; 69.3-79.0%] vs 47.5% [44.4-50.6%] vs 19.3% [16.8-22.0%] vs 7.3% [5.5-9.4%], respectively). This is the first paper to present large-scale data on survival and clinical characteristics in Japanese AML patients., (© 2023. Japanese Society of Hematology.)

We conducted a multicenter survey of emergency room nurses to obtain information that would be useful for the establishment of pharmacist services in emergency rooms. Notably, 199 valid responses were obtained from 12 hospitals. The most common expectation from pharmacists in the emergency room was "drug management" (70.9%), followed by "providing information to physicians regarding the patient's medication history" (59.3%), and "auditing of dosage and interaction" (57.3%). The working arrangements that the survey respondents wanted regarding pharmacists in emergency rooms were: 24 h pharmacist (41.7% wanted this arrangement), day-shift pharmacist (24.6% wanted this arrangement), 24 h on-call (17.1% wanted this arrangement), day-shift on-call (5.0% wanted this arrangement), telephone support (11.1% wanted this arrangement), and 0.5% said that there was no need for pharmacists. In the analysis of factors affecting nurse satisfaction, day-shift pharmacist was a significant factor. We hope that the results of this survey will be used as a guide for the development of emergency room pharmacist services tailored to the unique characteristics and actual working conditions of each hospital.

Considering recently published two guidelines for the diagnosis of hypersensitivity pneumonitis (HP), the Japanese Respiratory Society (JRS) has now published its own Japanese clinical practice guide for HP. Major types of HP in Japan include summer-type, home-related, bird-related, farmer's lung, painter's lung, humidifier lung, and mushroom grower's lung. Identifying causative antigens is critical for increasing diagnostic confidence, as well as improving prognosis through appropriate antigen avoidance. This guide proposes a comprehensive antigen questionnaire including the outbreak sources reported in Japan. Drawing on the 2021 CHEST guideline, this guide highlights the antigen identification confidence level and adaptations for environmental surveys. The detection of specific antibodies against causative antigens is an important diagnostic predictor of HP. In Japan, the assessments of bird-specific IgG (pigeons, budgerigars) and the Trichosporon asahii antibody are covered by medical insurance. Although this guide adopts the 2020 ATS/JRS/ALAT guideline diagnostic criteria based on the combination of imaging findings, exposure assessment, bronchoalveolar lavage lymphocytosis, and histopathological findings, it added some annotations to facilitate the interpretation of the content and correlate the medical situation in Japan. It recommends checking biomarkers; seasonal changes in the KL-6 concentration (increase in winter for bird-related HP/humidifier lung and in summer for summer-type HP) and high KL-6 concentrations providing a basis for the suspicion of HP. Antigen avoidance is critical for disease management of HP. This guide also addresses the pharmacological management of HP, highlighting the treatment strategy for fibrotic HP including combination therapies with anti-inflammatory/immunosuppressive and antifibrotic drugs., Competing Interests: Conflict of Interest Hiromi Tomioka received lecture fees from Nippon Boehringer Ingelheim Co., Ltd. Yasunari Miyazaki received research grants from Nippon Boehringer Ingelheim Co., Ltd. and Chugai Pharmaceutical Co., Ltd. and lecture fees from Nippon Boehringer Ingelheim Co., Ltd. and Astra Zeneca Co., Ltd. Yoshikazu Inoue received lecture fees from Nippon Boehringer Ingelheim Co., Ltd. Hiroyuki Sano received lecture fees from AstraZeneca Co., Ltd., Glaxo Smith Kline Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd. and Novartis Pharma Co., Ltd.. Takeshi Johkoh received lecture fees from Nippon Boehringer Ingelheim Co., Ltd. Takeshi Hisada received lecture fees from AstraZeneca Co., Ltd. Junya Fukuoka received honoraria from National Institute of Advanced Industrial Science and Technology and Future Corporation. Yuki Iijima received a research grant from Shionogi & Co.,Ltd. Masahiro Ishizuka received a research grant from GlaxoSmithKline Co.,Ltd. Tsukasa Okamoto received endowments from Nippon Boehringer Ingelheim Co., Ltd., Chugai Pharmaceutical Co., Ltd., Wako Filter Technology Co.,Ltd., and Car Conveni Club Co.,Ltd. Toshiaki Kikuchi received lecture fees from AstraZeneca Co.,Ltd., Chugai Pharmaceutical Co.,Ltd and Nippon Boehringer Ingelheim Co., Ltd and a research grant from Astra Zeneca Co.,Ltd. and endowments from Ono Pharmaceutical Co.,Ltd, Shionogi & Co.,Ltd., Chugai Pharmaceutical Co., Ltd. and Nippon Eli Lilly Co.,Ltd. Noriho Sakamoto a research grant from PPD-SNBL Co., Ltd.. Noboru Hattori received lecture fees from Astra Zeneca Co.,Ltd, Glaxo Smith Kline Co.,Ltd., Shionogi & Co.,Ltd., Chugai Pharmaceutical Co.,Ltd and Nippon Boehringer Ingelheim Co., Ltd. and endowments from Ono Pharmaceutical Co.,Ltd, Taiho Pharmaceutical Co.,Ltd and Nippon Eli Lilly Co.,Ltd.. Hiroshi Mukae received lecture fees from Astellas Pharma Inc., Astra Zeneca Co.,Ltd., MSD Co.,Ltd., Kyorin Pharmaceutical Co.,Ltd., Shionogi & Co.,Ltd., Daiichi Sankyo Co.,Ltd., Taisho Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd and Pfizer Co., Ltd. and research grants from Otsuka Pharmaceutical Co., Ltd., Shionogi & Co.,Ltd. and Nippon Boehringer Ingelheim Co., Ltd. and endowments from Astellas Pharma Inc., Kyorin Pharmaceutical Co.,Ltd., Shionogi & Co.,Ltd., Daiichi Sankyo Co.,Ltd., Taisho Pharmaceutical Co., Taiho Pharmaceutical Co.,Ltd, Chugai Pharmaceutical Co.,Ltd, FUJIFILM Toyama Chemical Co.,Ltd, and Meiji Seika Pharma Co.,Ltd. Masao Yamaguchi received lecture fees from AstraZeneca Co.,Ltd. Yoshihiro Nishimura received lecture fees from Astra Zeneca Co.,Ltd., Glaxo Smith Kline Co.,Ltd., Novartis Pharma Co.,Ltd. and Nippon Boehringer Ingelheim Co., Ltd and research grants from Teijinn Pharma Co., Ltd and endowments from Glaxo Smith Kline Co.,Ltd., Taiho Pharmaceutical Co.,Ltd, Chugai Pharmaceutical Co.,Ltd and Nippon Eli Lilly Co.,Ltd. Masayuki Hanaoka received lecture fees from AstraZeneca Co., Ltd. and Nippon Boehringer Ingelheim Co., Ltd and endowments from Bayer Pharma Co., Ltd.. Masashi Bando received lecture fees from AstraZeneca Co., Ltd. Shionogi & Co.,Ltd. and Nippon Boehringer Ingelheim Co., Ltd. Ryoko Egashira, Tetsuji Kawamura, Tamiko Takemura, Naohiko Inase, Masaru Ejima, Horoshi Ohnishi, Ryo Okuda, Susumu Sakamoto, Tsuyoshi Shirai, Kozo Suhara, Reoto Takei, Tomoya Tateishi, Kentaro Tanaka, Toshiharu Tsutsui, Yoshihisa Nukui, Haruhiko Furusawa, Yasushi Horimasu, Akemi Matsuo, Takashi Yamana, Yasuyuki Yoshizawa and Masahiro Kaneko have no conflicts of interest., (© 2023 Published by Elsevier B.V. on behalf of The Japanese Respiratory Society.)

In diurnal and nocturnal organisms, daily activity is regulated by the perception of environmental stimuli and circadian rhythms, which enable organisms to maintain their essential behaviors. The Japanese sand lances genus Ammodytes are coastal marine fish that exhibit unique nocturnal sand burrowing behavior. To elucidate the extrinsic and intrinsic regulation of this behavior and its endocrinological basis, we conducted a series of rearing experiments under various light conditions and hormone administrations. Under a light-dark photoperiod, the fish showed three types of behavior: sand buried, head-exposed from sand, and swimming/feeding. During the transition from dark to light periods, the fish first showed head exposure, followed by swimming and foraging, and buried themselves in the sand immediately after shifting to the dark period. Under constant light conditions, fish exhibited swimming behavior during the period corresponding to the acclimated light period. In addition, swimming did not occur under constant dark conditions but head exposure was observed at the time of the dark-light transition during acclimation. These observations indicate that the essential behavior of sand lances is regulated by both light and circadian rhythms. Subsequently, a melatonin-containing diet promoted the onset of burrowing in 10 to 120 min in a dose-dependent manner at 0.3-128 µg/g-diet, suggesting the direct behavioral regulation by this hormone. These findings suggest that the behavior of sand lances is strictly regulated by an intrinsic mechanism and that melatonin is a regulatory endocrine factor that induces burrowing behavior.

Background: Convalescent plasma is a potential therapeutic option for patients with coronavirus disease 2019 (COVID-19). Despite its use for treating several viral infections, we lack comprehensive data on its efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)., Methods: We conducted a multicenter, open-label, randomized controlled trial of convalescent plasma therapy with high neutralizing activity against SARS-CoV-2 in high-risk patients within five days after the onset of COVID-19 symptoms. The primary endpoint was the time-weighted average change in the SARS-CoV-2 viral load in nasopharyngeal swabs from days 0-5., Results: Between February 24, 2021, and November 30, 2021, 25 patients were randomly assigned to either convalescent plasma (n = 14) or standard of care (n = 11) groups. Four patients discontinued their allocated convalescent plasma, and 21 were included in the modified intention-to-treat analysis. The median interval between the symptom onset and plasma administration was 4.5 days (interquartile range, 3-5 days). The primary outcome of the time-weighted average change in the SARS-CoV-2 viral load in nasopharyngeal swabs did not significantly differ between days 0-5 (1.2 log 10 copies/mL in the convalescent plasma vs. 1.2 log 10 copies/mL in the standard of care (effect estimate, 0.0 [95% confidence interval, -0.8-0.7]; P = 0.94)). No deaths were observed in either group., Conclusions: The early administration of convalescent plasma with high neutralizing activity did not contribute to a decrease in the viral load within five days compared with the standard of care alone., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2023 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: The Processing Speed Test (PST), a validated iPad®-based cognitive screening test for MS, has been applied to the cognitive assessment of Japanese MS patients using US normative data., Methods: To develop PST normative data from Japanese healthy volunteers and compare the PST score distribution between Japanese and US healthy volunteers, 254 healthy Japanese-speaking volunteers were enrolled and stratified by age (20-65 years). Potential participants with a Mini-Mental State Examination score < 27 were excluded. PST raw scores (total correct) were from the Japan cohort and compared with age-restricted US normative data and propensity score-matched data created by matching sex, age, and educational level from a published study of 428 healthy participants. PST score distributions and standardized z-scores were compared using t-test and Kolmogorov-Smirnov test statistics., Results: The mean age of the Japan cohort was 44.1 years. The PST scores of Japanese volunteers were significantly different from those of the age-restricted (mean ± SD 61.8 ± 10.1 vs 53.7 ± 10.8; p < 0.001) and the propensity score-matched US cohort (62.1 ± 10.1 vs 53.3 ± 10.6; p < 0.001)., Conclusion: Regression analyses centered on US normative data could underestimate disease severity in Japanese MS patients, suggesting that separate normative data should be considered for each population sample., Competing Interests: Declaration of Competing Interest MN has received consultant fees from Biogen; and travel and/or speaker honoraria from Biogen, Takeda, Mitsubishi Tanabe, Chugai, Alexion, and Novartis, YM has nothing to disclose, AA and ME were former employees of Biogen, NB, MK, IC, CdM, and JRW are employees of and may hold stock/stock options in Biogen, SMR has authored IP around the MS PATHS software; is a stockholder and scientific officer of Qr8 Health; and has received royalties and grant funding from Biogen, National MS Society, Department of Defense, and NIH., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

A new species of fish-parasitic isopod in the family Cymothoidae is described from the Izu Islands, Japan. Mothocya kaorui n. sp. is reported from the gill cavities of the keeled needlefish, Platybelone argalus platyura (Bennett). Despite its unique morphological characters, such as completely article-fused antennules, mitochondrial DNA analysis indicated that it belongs to Mothocya Costa. The new species is clearly distinguished from all other species of Mothocya by having completely fused, stout antennules and partially fused, slender antennae; maxilla mesial lobe with 3 or 4 recurved robust setae, lateral lobe with 4-6 recurved robust setae; maxilliped with 5-8 robust setae on article 3; coxae 2 and 3 wide; black subtriangular pleotelson; and black uropods., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: P2Y12 inhibitor monotherapy without aspirin immediately after percutaneous coronary intervention (PCI) has not been tested in East Asian patients, so in this study we aimed to assess the safety and feasibility of reduced dose (3.75 mg/day) prasugrel monotherapy in Japanese patients presenting with chronic coronary syndrome (CCS).Methods and Results: ASET-JAPAN is a prospective, multicenter, single-arm pilot study that completed enrolment of 206 patients from 12 Japanese centers in September 2022. Patients with native de-novo coronary lesions and a SYNTAX score <23 were treated exclusively with biodegradable-polymer platinum-chromium everolimus-eluting stent(s). Patients were loaded with standard dual antiplatelet therapy (DAPT) and following successful PCI and optimal stent deployment, they received low-dose prasugrel (3.75 mg/day) monotherapy for 3 months. The primary ischemic endpoint was a composite of cardiac death, spontaneous target-vessel myocardial infarction, or definite stent thrombosis. The primary bleeding endpoint was Bleeding Academic Research Consortium (BARC) type 3 or 5. At 3-month follow-up, there were no primary bleeding or ischemic events, or any stent thrombosis., Conclusions: This pilot study showed the safety and feasibility of prasugrel monotherapy in selected low-risk Japanese patients with CCS. This "aspirin-free" strategy may be a safe alternative to traditional DAPT following PCI.

Aims: To elucidate the influence of the time-intervals between the onset and arrival (TIME 1), onset and delivery (TIME 2), and the decision to deliver and delivery (TIME 3) on severe adverse outcomes of offspring born to mothers complicated by placental abruption outside the hospital., Methods: This is a multicenter nested case-control study about placental abruption at Fukui Prefecture, a regional area in Japan, through 2013 to 2017. Multiple pregnancy, fetal or neonatal congenital abnormality, and unknown detailed information at onset of placental abruption were excluded. A composite of perinatal death and cerebral palsy or death at 18-36 months of corrected age was defined as the adverse outcome. The relationship between time-intervals and the adverse outcome was analyzed., Results: The 45 subjects for analysis were divided into two groups, including a group with and without adverse outcome (poor, n = 8; and good, n = 37). TIME 1 was longer in the poor group (150 vs. 45 min, p < 0.001). A subgroup analysis targeted to 29 cases with preterm birth at the third trimester indicates that TIME 1 and TIME 2 were longer in the poor group (185 vs. 55 min, p = 0.02; and 211 vs. 125 min, p = 0.03), while TIME 3 was shorter in the poor group (21 vs. 53 min, p = 0.01)., Conclusions: Long time-intervals between onset and arrival or onset and delivery may be correlated with perinatal death or cerebral palsy in surviving infants affected by placental abruption., (© 2023 Japan Society of Obstetrics and Gynecology.)

Background: Three epidemiological small-scale studies on hypersensitivity pneumonitis (HP) have been performed in Japan to date. Herein, we aimed to clarify the clinical characteristics of various types of HP diseases using a large nationwide database in Japan., Methods: We used the Japanese Diagnostic Procedure Combination database that includes data from 1,031 participant hospitals. Patients with HP from 2011 to 2017 were identified using International Classification of Diseases 10th Revision codes. We analyzed patient characteristics, the yearly transition of the number of HP cases, rate per one million hospitalizations, geographical distribution, seasonality, and risk factors for in-hospital mortality., Results: In total, 3,634 patients with HP were identified, including summer-type HP (SHP) (n = 490), bird fancier's lung (BFL) (n = 199), ventilation pneumonitis (n = 106), farmer's lung (n = 48), and unspecified HP (n = 2761). The length of hospital stay was significantly longer in patients with BFL (19 days) than in patients with SHP (15 days). SHP was more prevalent in the southwestern region of Japan, and hospitalization occurred mainly in summer (37.8%) and fall (37.3%). Ventilation pneumonitis was predominant in winter (28.6%) and spring (38.7%). In-hospital mortality was significantly associated with old age (p < 0.001), low body mass index (p = 0.016), severe dyspnea (p < 0.001), and BFL diagnosis on admission (p = 0.031)., Conclusions: This study revealed the clinical characteristics of SHP and BFL, including the frequency of causative antigens, geographical distribution, seasonality, and risk factors for mortality, which may help in diagnosing HP and identifying causative antigens., Competing Interests: Conflict of Interest This study has received a Grant-in-Aid for Research on Policy Planning and Evaluation from the Ministry of Health, Labour and Welfare, Japan (20AA2005). Tsukasa Okamoto has received grants from Konica Minolta, Boehringer Ingelheim, Chugai, Kuramochi Clinic and Wako Filter Technology. Yasunari Miyazaki has received grants, consulting fees and payment for lectures and expert testimony from Thermo Fisher Scientific Inc. Shohei Yamashita, Tatsuo Kawahara, Tomoya Tateishi, Tatsuhiko Anzai, Kunihiko Takahashi and Kiyohide Fushimi have no conflict of interest to declare., (Copyright © 2023 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Objectives: Isavuconazole is a convenient triazole antifungal agent with a broad antifungal spectrum. A randomized, open-label study (ClinicalTrials.gov, NCT03471988) was conducted to evaluate the efficacy and safety of isavuconazole in Japanese patients with deep-seated mycoses., Patients and Methods: In Cohort A, patients with aspergillosis (chronic pulmonary aspergillosis and invasive aspergillosis) were randomized in a 2:1 ratio to isavuconazole or voriconazole, and in Cohort B, patients with cryptococcosis and mucormycosis were assigned to isavuconazole for up to 84 days of treatment. The overall outcome was evaluated according to the clinical, radiological, and mycological responses at Days 42 and 84 and at the end of treatment (EOT)., Results: A total of 103 participants were enrolled and received the study drug. The overall response rate of patients with chronic pulmonary aspergillosis in the isavuconazole (52 patients) and voriconazole (27 patients) groups was 82.7% and 77.8% at EOT, respectively. The response rate in patients with cryptococcosis (10 patients, isavuconazole group only) was 90.0%. One of three participants with invasive aspergillosis and one of three participants with mucormycosis responded in the isavuconazole group. In the safety evaluation, the incidence of adverse events in participants with chronic pulmonary aspergillosis was similar in both groups. Adverse drug reactions were reported in 32 (61.5%) patients receiving isavuconazole and 23 (85.2%) patients receiving voriconazole., Conclusions: Isavuconazole showed efficacy and safety in Japanese patients with chronic pulmonary aspergillosis and cryptococcosis, for which the drug is not currently indicated., Competing Interests: Declaration of competing interest K.I. has received financial support for the present manuscript from Asahi Kasei Pharma Corporation; grants, consulting fees, and honoraria from Asahi Kasei Pharma Corporation, and honoraria from Pfizer, outside the submitted work. T.T. has received non-financial support for the present manuscript from Asahi Kasei Pharma Corporation; grants from MSD, Sumitomo Dainippon Pharma, Takeda Pharmaceutical, and Shionogi Pharma; honoraria from Sumitomo Dainippon Pharma, Pfizer, Kyorin Pharmaceutical, Fisher & Paykel Healthcare, and MSD; and participated on the advisory boards of GlaxoSmithKline, Roche Diagnostics, and Pfizer, outside the submitted work. T.M. has received non-financial support for the present manuscript from Asahi Kasei Pharma Corporation; grants from Asahi Kasei Pharma Corporation, Pfizer, MSD, Astellas Pharma, Otsuka Pharmaceutical, Taisho Pharmaceutical, Daiichi Sankyo, Teijin Pharma, Mitsubishi Tanabe Pharma, Shionogi Pharma, Kyowa Kirin, Chugai Pharmaceutical, and AbbVie; consulting fees from Asahi Kasei Pharma Corporation, Pfizer, and Kyorin Pharmaceutical; honoraria and support for attending meetings from Asahi Kasei Pharma Corporation, Pfizer, MSD, Astellas Pharma, Sumitomo Dainippon Pharma, Janssen Pharmaceutical, AstraZeneca, GlaxoSmithKline, Taisho Pharmaceutical, Daiichi Sankyo, Meiji Seika Pharma, Eli Lilly, Novartis Pharma, Boehringer Ingelheim, Shionogi Pharma, Takeda Pharmaceutical, Gilead Sciences, Insmed, and Sanofi; and drugs and medical writing services from Pfizer and MSD, outside the submitted work. K.K. was a member of the Data Review Committee for Asahi Kasei Pharma Corporation during the conduct of the study; K.K. has received grants from Asahi Kasei Pharma Corporation, Sumitomo Dainippon Pharma, and MSD, outside the submitted work. K.A. has received grants from Asahi Kasei Pharma Corporation, Sumitomo Dainippon Pharma, and Takeda Pharmaceutical, and honoraria from Pfizer and Janssen Pharmaceutical, outside the submitted work. H.M. has received consulting fees and honoraria from Asahi Kasei Pharma Corporation, outside the submitted work. F.O. was a member of the Data Review Committee for Asahi Kasei Pharma Corporation during the conduct of the study; F.O. has received consulting fees from Asahi Kasei Pharma Corporation, outside the submitted work. Y.K. has received grants from Asahi Kasei Pharma Corporation, Sumitomo Dainippon Pharma, and Pfizer, and honoraria from Asahi Kasei Pharma Corporation, Sumitomo Dainippon Pharma, Pfizer, MSD, Astellas Pharma, and Janssen Pharmaceutical, outside the submitted work. H.K. was a member of the Data Review Committee for Asahi Kasei Pharma Corporation during the conduct of the study; H.K. has received honoraria from MSD, Sumitomo Dainippon Pharma, Astellas Pharma, Pfizer, and Shionogi Pharma, outside the submitted work. S.K. was a member of the Data Review Committee for Asahi Kasei Pharma Corporation during the conduct of the study; S.K. has received consulting fees from Asahi Kasei Pharma Corporation, and honoraria from MSD, Sumitomo Dainippon Pharma, Pfizer, Bristol-Myers Squibb, Eisai, Takeda Pharmaceutical, Janssen Pharmaceutical, Meiji Seika Pharma, Astellas Pharma, Kyowa Kirin, Chugai Pharmaceutical, Ono Pharmaceutical, Nippon Kayaku, SymBio Pharmaceuticals, and Nippon Shinyaku, outside the submitted work. M.K. is an employee and stockholder of Asahi Kasei Pharma Corporation; M.K. also has patent 2021-157676 pending with Asahi Kasei Pharma Corporation. M.M. is an employee of Asahi Kasei Pharma Corporation; M.M. also has patent 2021-157676 pending with Asahi Kasei Pharma Corporation. Y.N. was a member of the Data Review Committee for Asahi Kasei Pharma Corporation during the conduct of the study; Y.N. has received consulting fees from Asahi Kasei Pharma Corporation, outside the submitted work. All other authors: none to declare., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objectives: To identify differences in patient characteristics, clinical practice and outcomes of cardiac implantable electronic device (CIED) therapy between Japan and the USA., Design: A cross-sectional study., Setting: Nationally representative administrative databases from Japan and the USA containing hospitalisations with first-time implantations of pacemakers, implantable cardioverter-defibrillators (ICD) and cardiac-resynchronisation therapy with or without defibrillators (CRTP/CRTD)., Participants: Patients hospitalised with first-time implantations of CIEDs., Outcome Measures: In-hospital mortality, in-hospital complication and 30-day readmission rates., Results: Overall, 107 339 (median age 78 (71-84), 48 415 women) and 295 584 (age 76 (67-83), 127 349 women) records with CIED implantations were included from Japan and the USA, respectively. Proportion of women in defibrillator recipients was lower in Japan than in the USA (ICD, 21% vs 28%, p<0.001; CRTD, 24% vs 29%, p<0.001). Length of stay after CIED implantation was longer in Japan than in the USA for all device types (conventional pacemaker, 8(7-11) vs 1 (1-3) days, p<0.001; leadless pacemaker, 5 (3-9) vs 2 (1-5) days, p<0.001; ICD, 8 (7-11) vs 1 (1-3) days, p<0.001, CRTP, 9 (7-13) vs 2 (1-4) days, p<0.001; CRTD, 9 (8-14) vs 2 (1-4) days, p<0.001). In-hospital mortality after CIED implantation was similar between Japan and the USA ((OR) (95% CI), conventional pacemaker 0.58 (0.83 to 1.004); ICD 0.77 (0.57 to 1.03); CRTP 0.85 (0.51 to 1.44); CRTD 1.11 (0.81 to 1.51)), except that after leadless pacemaker implantation in Japan was lower than that in the USA (0.32 (0.23 to 0.43)). 30-day readmission rates were lower in Japan than in the USA for all device types (conventional pacemaker 0.55 (0.53 to 0.57); leadless pacemaker 0.50 (0.43 to 0.58); ICD 0.54 (0.49 to 0.58); CRTP 0.51 (0.42 to 0.62); CRTD 0.57 (0.51 to 0.64))., Conclusions: International variations in patient characteristics, practice and outcomes were observed. In-hospital mortality after CIED implantation was similar between Japan and the USA, except in cases of leadless pacemaker recipients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Accelerated tumor growth during immunotherapy in pre-existing measurable lesions, hyperprogressive disease (HPD), has been reported. However, progression of non-measurable lesions and new lesions are frequently observed in patients with advanced gastric cancer (AGC)., Methods: This retrospective study involved AGC patients at 24 Japanese institutions who had measurable lesions and received nivolumab after ≥ 2 lines of chemotherapy. HPD was defined as a ≥ two-fold increase in the tumor growth rate of measurable lesions. The pattern of disease progression was classified according to new lesions in different organs and ascites appeared/increase of ascites., Results: Of 245 patients, 147 (60.0%) showed progressive disease (PD) as the best response and 41 (16.7%) showed HPD during nivolumab monotherapy. There was no significant difference in overall survival (OS) between patients with HPD and those with PD other than HPD (median OS 5.0 vs 4.8 months; hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.6-1.5; p = 1.0). Fifty-three patients developed new lesions in different organs and 58 had appearance/increase of ascites; these patients showed shorter OS than those without each of these features (median OS 3.3 vs 7.1 months, HR 1.8, 95% CI 1.2-2.7, p = 0.0031 for new lesions, and 3.0 vs 7.8 months, HR 2.6, 95% CI 1.8-3.8, p < 0.0001 for ascites). Thirty-one patients who had both features showed the worst prognosis (median OS 2.6 months)., Conclusions: New lesions in different organs and appearance/increase of ascites, rather than the original definition of HPD, are the patterns of disease progression associated with poor prognosis in AGC patients receiving nivolumab whose best response was PD., (© 2022. The Author(s).)

Background: Numerous studies investigated patients with IPF; however, only a few examined patients with idiopathic interstitial pneumonias (IIPs)., Methods: The Japanese Idiopathic Interstitial Pneumonias (JIPS) Registry, which was initiated in December 2016, is a multicenter prospective observational study of patients newly diagnosed with IIPs from 86 facilities treating ILDs. The plan is to enroll more than 600 new patients during the 2-year enrolment period and to follow their progress for 3 years after the last case enrolment. If additional consent is obtained, the study will continue for another 2 years. Research questions mainly focus on identifying the frequency by IIP classification, patient background, and diagnostic methods during enrolment, survival, acute exacerbation rate, changes in high-resolution CT imaging, forced vital capacity, and interstitial pneumonia markers over time. Other research questions, including those regarding disease behavior in patients with progressive fibrosing-ILD and new biomarkers associated with genetic predispositions, will be investigated., Discussion: The JIPS Registry will provide a comprehensive description of the disease progression, prognosis, treatment status, new biomarkers, and validity of guidelines and central multidisciplinary decisions for IPF and similar diseases that can be differentiated from IPF among IIPs., Ethics and Dissemination: Ethical approval was obtained from the institutional review board of Kanagawa Cardiovascular and Respiratory Center (KCRC-16-0005), and that of Jichi Medical University approved the biobank part (I18-005). Results will be published in peer-reviewed journals and will be presented at national and international conferences., Trial Registration: ClinTrials.gov Registry (NCT03041623, first posted on February 3, 2017)., Competing Interests: Conflict of Interest R. Okuda has received lecture fees from Nippon Boehringer Ingelheim Gmb. T. Ogura has received advisory board fees from Nippon Boehringer Ingelheim Gmb, Taiho Pharmaceutical Co. Ltd., Shionogi & Co. Ltd., and Bristol Myers Squibb Co. T. Ogura also has received lecture fees from Nippon Boehringer Ingelheim Gmb., Shionogi & Co. Ltd., Astellas Co., AstraZeneca K.K., and Eizai Inc. S. Hisata has received lecture fees from Nippon Boehringer Ingelheim Gmb. T. Baba has received lecture fees from Nippon Boehringer Ingelheim Gmb. Y. Kondoh has received advisory board fees and personal fees from Nippon Boehringer Ingelheim Gmb., Asahi Kasei Pharma Corp., and Shionogi & Co. Ltd., advisory board fees from Janssen Pharmaceutical K.K., Healios K.K., Chugai Pharmaceutical Co., Ltd., and Taiho Pharmaceutical Co., Ltd., and personal fees from Astellas, AstraZeneca K.K., Eisai inc., KYORIN Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma, and Novartis Pharma K.K., outside the presentation work. T. Suda has received grants or lecture fees from Nippon Boehringer Ingelheim Gmb. T. Johkoh has received lecture fees from Nippon Boehringer Ingelheim Gmb. T. Iwasawa has received grants from Canon Medical systems and received grants or lecture fees from Nippon Boehringer Ingelheim Gmb. H. Tomioka has received lecture fees from Nippon Boehringer Ingelheim Gmb. M. Bando has received lecture fees from Nippon Boehringer Ingelheim Gmb. A. Azuma has received a steering committee member fee, consultant fee, and lecture fee. Y. Inoue has received payments as lecture fees, participation on the steering committees, or advisor of Boehringer Ingelheim Gmb. T. Arai has received lecture fees from Boehringer Ingelheim Gmb, and Shionogi & Co. Ltd. R. Nakamura has received grants or lecture fees from Nippon Boehringer Ingelheim Gmb. A. Miyamoto has received a lecture fee from Nippon Boehringer Ingelheim Gmb. Y. Miyazaki has received grants or lecture fees from Nippon Boehringer Ingelheim Gmb. H Chiba has received grants or lecture fees from Nippon Boehringer Ingelheim Gmb. H. Ishii has received grants or lecture fees from Nippon Boehringer Ingelheim Gmb. N. Hamada received grants from Nippon Boehringer Ingelheim Gmb. S. Sato has received grants and lecture fees from Nippon Boehringer Ingelheim Gmb. T. Suzuki has received a lecture fee from Nippon Boehringer Ingelheim Gmb. Y. Nishioka has received grants or lecture fees from Nippon Boehringer Ingelheim Gmb. N. Hattori has received grants and lecture fees from Nippon Boehringer Ingelheim Gmb. N. Hashimoto received research grants and lecture fees from Boehringer Ingelheim Gmb. K. Hagiwara has received lecture fees from Nippon Boehringer Ingelheim Gmb. K. Kobayashi has received lecture fees from AstraZeneca K.K. and Takeda Pharmaceutical Co. Y. Terasaki, I. Kuwahira, S. Kato, S. Sakamoto, N. Ichihara, H. Miyata and T. Nukiwa have no competing interests., (Copyright © 2022 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Therapeutic improvements are needed for patients with acute myeloid leukemia (AML), particularly those who have relapsed or who have treatment-refractory (R/R) AML or newly diagnosed patients with poor prognostic factors. Alvocidib (DSP-2033), a potent cyclin-dependent kinase 9 inhibitor, has previously demonstrated promising clinical activity for the treatment of AML. In this multicenter, open-label, uncontrolled, 3 + 3 phase I study, we investigated the safety and tolerability of alvocidib administered in combination with either cytarabine and mitoxantrone (ACM) for R/R AML or cytarabine/daunorubicin (A + 7 + 3) for newly diagnosed AML. Alvocidib was administered to all patients as a 30-min intravenous (i.v.) bolus (30 mg/m 2 /d), followed by a continuous i.v. infusion over 4 h on days 1-3 (60 mg/m 2 /d). A total of 10 patients were enrolled: six received ACM (at two dose levels of cytarabine and mitoxantrone) and four received A + 7 + 3. Alvocidib was tolerated and no dose-limiting toxicities were observed. All patients experienced adverse events, of which diarrhea was the most frequent (100%); hematologic events were also common. Alvocidib concentration peaked at the end of dosing (4.5 h after start of administration), plasma accumulation after repeated dosing was minimal and urinary excretion was negligible. The rate of complete remission/complete remission with incomplete hematologic recovery was 66.7% with the ACM regimen in R/R AML, including four complete remission (median duration 13.6 months), and 75% (three complete remission) with the A + 7 + 3 regimen. Further development of alvocidib in hematologic malignancies is warranted. The trial is registered with Clinicaltrials.gov, NCT03563560., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Different treatment strategies can have varying effects on disability and whole brain volume in patients with multiple sclerosis (MS). However, the association between regional brain volume and treatment efficacy is currently unclear. Our objective was to determine whether whole brain volume, as well as the regional volume of cortical and subcortical grey matter, differ with the administration of high-efficacy therapy (HET) versus low-efficacy therapy (LET)., Methods: We evaluated clinical data and change in regional brain volume in 44 patients with relapse-onset MS, who underwent HET (n = 19) or LET (n = 25). Regional brain volume was determined with three-dimensional T1-weighted magnetic resonance imaging using FreeSurfer. The association between volume change and treatment type was assessed via generalised linear mixed models (GLMMs)., Results: During the observation period (2.0 ± 0.16 years), the proportion of patients with a "no evidence of disease activity-3″ status was significantly greater in those who underwent HET versus LET (p = 0.012). HET was positively associated with volume changes in the cortex (β = 0.64, p = 0.0499), left (β = 0.98, p = 0.0033) and right (β = 0.77, p = 0.019) caudate and right putamen (β = 0.87, p = 0.0077), after adjusting for age, sex, and MS severity scores in the GLMMs. Further correction for multiple comparisons by false discovery rate revealed that HET was consistently associated with the volume changes of the left caudate (p = 0.049) and right putamen (p = 0.049)., Conclusion: HET can improve the mid-term prognosis of Japanese patients with relapse-onset MS by reducing disease activity and regional brain volume loss., Competing Interests: Declaration of Competing Interest Hiroaki Yokote has received honoraria for lectures from Biogen, Mitsubishi-Tanabe Pharma, Alexion Pharma Godo Kaisha, Chugai Pharma, and Novartis. Yusei Miyazaki has received honoraria for lectures from Biogen, Alexion Pharma Godo Kaisha, Chugai Pharma and Novartis. Yoichiro Nishida has received honoraria for lectures from Alexion Pharma Godo Kaisha. Masaaki Niino has received speaker honoraria from Novartis Pharma, Biogen Japan, Mitsubishi Tanabe Pharma, Takeda Pharmaceutical Company, and Alexion Pharma Godo Kaisha. Nobuo Sanjo received honoraria for lectures from Takeda, Biogen, and Novartis. Takanori Yokota has received personal fees from Mitsubishi Tanabe Pharma and Takeda, outside the submitted work; Takanori Yokota has a patent Takeda with royalties paid. The other authors declare that they have no competing interests., (Copyright © 2022. Published by Elsevier B.V.)

Background: Transcatheter aortic valve implantation (TAVI) is increasingly being performed in very elderly patients, although its efficacy and validity remain unclear. This study evaluated real-world TAVI outcomes in Japanese nonagenarians with severe aortic stenosis.Methods and Results: This single-center study retrospectively assessed the early and long-term clinical outcomes of TAVI in nonagenarians (n=35) and in patients aged <90 years (group Y; n=171). There were no in-hospital deaths in either group. The device success rate and early safety were comparable between the 2 groups. The 5-year rates of freedom from cardiac events and deaths were equivalent in both groups. The cumulative survival rate at 5 years was non-significantly lower in nonagenarians (32.6% in nonagenarians vs. 57.5% in patients aged <90 years, P=0.49). There were no differences in the 5-year survival between nonagenarians after TAVI and the sex- and age-matched populations (P=0.18). The Cox regression model revealed that lower hemoglobin levels were associated with all-cause mortality (P=0.02), and age ≥90 years was not associated with all-cause mortality., Conclusions: The early and long-term clinical outcomes of TAVI for selected Japanese nonagenarians were comparable to those in patients aged <90 years. Nonagenarians who underwent TAVI achieved an acceptable prognosis compared to the sex- and age-matched population; thus, TAVI appears to be effective for treating aortic stenosis in Japanese nonagenarians.

Objectives: To clarify the effectiveness and safety of induction therapy with mycophenolate mofetil (MMF) in patients with lupus nephritis (LN)., Methods: Patients with LN administered MMF (n = 35) or intravenous cyclophosphamide pulse therapy (IVCY) (n = 25) plus high-dose corticosteroids between July 2015 and June 2020 were included. MMF was increased from 2 to 3 g/day, with no adverse events (AEs). The primary endpoint was the 6 month renal remission rate. Secondary endpoints were retention rate and AEs., Results: There were no significant differences in age, sex, disease duration, renal histological type, SLE disease activity index, and urine protein creatinine ratio between the two groups. Twenty-six patients (74%) continued with MMF therapy, whereas 12 (48%) completed six IVCY courses. The retention rate was significantly higher in the MMF than in the IVCY group (p = 0.048). Twenty-four and 14 patients in MMF and IVCY groups, respectively, achieved renal remission with insignificant differences. Grade 3 or higher AEs were observed in 8 and 14 patients in the MMF and IVCY groups, respectively (p = 0.014)., Conclusions: The efficacy of high-dose MMF was comparable to that of IVCY in Japanese patients with proliferative LN, with fewer AEs and a higher retention rate than IVCY, suggesting the high tolerability of MMF., (© Japan College of Rheumatology 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In 2020, COVID-19 spread throughout the world, and international measures such as travel bans, quarantines, and increased social distancing were implemented. In Japan, the number of infected people increased, and a state of emergency was declared from 16 April to 25 May 2020. Such a change in physical activity could lead to a decline in physical function in people with disabilities. A retrospective study was conducted to determine the impact of the pandemic on the physical function of disabled persons living in the community. Data were collected at four points in time: two points before the declaration of the state of emergency was issued and two points after the declaration period had ended. Time series data of physical function at four points in time were compared for 241 people with disabilities. The mean age was 72.39 years; 157 had stroke, 59 musculoskeletal disease, and 26 other diseases. Overall, there was a long-term decrease in walking speed ( p < 0.001) and a worsening of the Timed Up-and-Go (TUG) score ( p < 0.001) after the period of the state of emergency. The TUG score worsened only in the group with a walking speed of 1.0 m/s or less before the state of emergency ( p = 0.064), suggesting that this group was more susceptible.

Purpose: General surgeons are at high risk for work-related musculoskeletal disorders (WRMSDs), especially in their neck and back. The prevalence and risk factors for surgeons' WRMSDs in Japan have not been well surveyed., Methods: A cross-sectional questionnaire survey on WRMSDs was conducted among general surgeons in Japan. Surgeons were asked about the presence and degree of neck, shoulder, and back disability in relation to open and laparoscopic surgery., Results: The questionnaire was sent to 174 general surgeons in 21 hospitals and 106 (60.9%) responded. The prevalence of WRMSDs in the last month was 65.1%, and the prevalence at least once in a lifetime was 79.2%. The rate of WRMSDs of the neck and back was higher after open surgery (44.3%, 42.5%) than after laparoscopic surgery (28.2%, 31.1%), but there was no marked difference in shoulder pain. Age was the strongest risk factor for WRMSDs, and the pain scores, prevalence of chronic pain, and rate of WRMSD-related absence from work tended to increase with age., Conclusion: A questionnaire survey of surgeons in Japan showed that about 80% of surgeons suffer from WRMSDs. Countermeasures for WRMSDs among surgeons are urgently desired to ensure that limited numbers of surgeons work in the operating theatre throughout their career., Clinical Trial Registration: Registry name: a survey of surgeons' musculoskeletal pain associated with performing surgery. University of Tsukuba Institutional Review Board registration number: 1519., (© 2022. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

The increasing incidence of candidemia and the emergence of drug-resistant Candida species are major concerns worldwide. Therefore, long-term surveillance studies are required. Here, we provide one of the largest longitudinal overviews of the trends in the prevalence of Candida species using national data of 57 001 candidemia isolates obtained from > 2000 hospitals for the 2010-2019 period in the Japan Nosocomial Infections Surveillance database. The proportion of Candida species, except Candida krusei and Candida guilliermondii, was almost the same during the study period. The proportion of C. guilliermondii surpassed that of C. krusei in 2014. The incidence of candidemia due to C. albicans (P < 0.0001), C. parapsilosis (P = 0.0002), and C. tropicalis (P < 0.0001) have decreased significantly over this period. Azole susceptibility of C. tropicalis was low, with 17.8% of isolates resistant to fluconazole and 13.5% resistant to voriconazole. The micafungin susceptibility of C. glabrata was low, with 8.0% of isolates showing resistance. The resistance rate of C. krusei toward amphotericin B fluctuated considerably (between 3.2% and 35.7%) over this period. The incidence rate of candidemia caused by C. parapsilosis and C. guilliermondii in hospitals responsible for bone marrow transplantation was significantly higher than that in other hospitals. Overall, our study suggests that in Japan, the species distribution of Candida was almost the same in this period and similar to that reported in North America and Europe. A relatively high resistance to azoles and micafungin was observed in C. glabrata, C. tropicalis, and C. krusei isolates, which require continued surveillance., (© The Author(s) 2022. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge 1-5 . Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target., (© 2022. The Author(s).)

Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection., (© 2022. The Author(s).)

Hyperuricemia causes gout and has also been associated with metabolic syndrome and cardiovascular disease. Uric acid-lowering drugs (ULDs) are used to reduce uric acid levels for the treatment of hyperuricemia and gout. However, there is a lack of robust and real-world data on the history and treatment of patients with newly diagnosed hyperuricemia or gout in Japan. This retrospective, longitudinal, historical cohort study determined the characteristics of patients with hyperuricemia and/or gout, and prescription of, and adherence to, ULDs using data from the JMDC Claims Database. The primary evaluation population included 64 677 patients with newly diagnosed hyperuricemia and/or gout. Of these, only 26 501 (41.0%) had a prescription for ULDs at diagnosis. Even when ULDs were prescribed, the persistence rate of prescriptions declined over time, with a 54.4% persistence rate for ULDs at 12 months after the index diagnosis. In subgroups of patients with or without hypertension and diabetes, the rate of ULD prescription continuation was significantly higher in those with comorbidities than in those without (76.8% vs. 42.6% in those with vs. without hypertension, and 78.7% vs. 52.2% in those with vs. without diabetes). These finding suggest that therapeutic interventions to lower serum uric acid levels are under-utilized for patients with newly diagnosed hyperuricemia and/or gout in Japan., (© 2022 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

BACKGROUND: Risk stratification and therapeutic decision-making for myelodysplastic syndromes (MDS) are based on the International Prognostic Scoring System–Revised (IPSS-R), which considers hematologic parameters and cytogenetic abnormalities. Somatic gene mutations are not yet used in the risk stratification of patients with MDS. METHODS: To develop a clinical-molecular prognostic model (IPSS-Molecular [IPSS-M]), pretreatment diagnostic or peridiagnostic samples from 2957 patients with MDS were profiled for mutations in 152 genes. Clinical and molecular variables were evaluated for associations with leukemia-free survival, leukemic transformation, and overall survival. Feature selection was applied to determine the set of independent IPSS-M prognostic variables. The relative weights of the selected variables were estimated using a robust Cox multivariable model adjusted for confounders. The IPSS-M was validated in an external cohort of 754 Japanese patients with MDS. RESULTS: We mapped at least one oncogenic genomic alteration in 94% of patients with MDS. Multivariable analysis identified TP53multihit, FLT3 mutations, and MLLPTD as top genetic predictors of adverse outcomes. Conversely, SF3B1 mutations were associated with favorable outcomes, but this was modulated by patterns of comutation. Using hematologic parameters, cytogenetic abnormalities, and somatic mutations of 31 genes, the IPSS-M resulted in a unique risk score for individual patients. We further derived six IPSS-M risk categories with prognostic differences. Compared with the IPSS-R, the IPSS-M improved prognostic discrimination across all clinical end points and restratified 46% of patients. The IPSS-M was applicable in primary and secondary/therapy-related MDS. To simplify clinical use of the IPSS-M, we developed an open-access Web calculator that accounts for missing values. CONCLUSIONS: Combining genomic profiling with hematologic and cytogenetic parameters, the IPSS-M improves the risk stratification of patients with MDS and represents a valuable tool for clinical decision-making. (Funded by Celgene Corporation through the MDS Foundation, the Josie Robertson Investigators Program, the Edward P. Evans Foundation, the Projects of National Relevance of the Italian Ministry of University and Research, Associazione Italiana per la Ricerca sul Cancro, the Japan Agency for Medical Research and Development, Cancer Research UK, the Austrian Science Fund, the MEXT [Japanese Ministry of Education, Culture, Sports, Science and Technology] Program for Promoting Research on the Supercomputer Fugaku, the Japan Society for the Promotion of Science, the Taiwan Department of Health, and Celgene Corporation through the MDS Foundation.)

Introduction: Influenza remains a clinically heavy burden worldwide. It is well known that some populations are at high risk of complications from influenza, whereas, even previously healthy people might suffer from severe influenza. The objective of this study was to clarify clinical manifestations of hospitalized patients without risk factors infected with influenza., Methods: The clinical data for patients who were severely ill with influenza, and required hospitalization were gathered and analyzed between November 2014 and August 2020 (6 influenza seasons) using an internet-surveillance system. Among them, the patients who had no risk factors of complications from influenza were extracted., Results: Finally, a total of 91 patients (9.0% of all influenza-related hospitalizations) without risk factors were analyzed. The no risk group was younger than the risk group, though other significant differences of clinical characteristics were not recognized between the groups. Pneumonia was the most common cause of hospitalization in the no risk group, and primary influenza viral pneumonia was the most common pneumonia. Antiviral drugs were administered in 96.7% of the no-risk group, and artificial ventilation was performed in 18.7%. In-hospital death was recorded for 3 patients without risk factors., Conclusions: Severe complications of influenza which required hospitalization may occur in a certain degree of patients with no risk factors. Efforts are needed to diagnose and treat influenza appropriately even in previously healthy younger patients. Continuous nationwide surveillance will be required to clarify risk factors for severe influenza even in previously healthy younger patients. (UMIN000015989)., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Real-world evidence on the preference for and effectiveness of third- or later-line (3L +) monotherapy for HER2-positive gastric cancer is limited in Japan. This study evaluated the utility of nivolumab, irinotecan, and trifluridine/tipiracil (FTD/TPI) monotherapy as 3L + treatment in Japanese patients with HER2-positive gastric/gastroesophageal junction (G/GEJ) cancer who were previously treated with trastuzumab., Methods: In this multicenter, retrospective, observational study (20 centers), data of eligible patients were extracted from medical records (September 22, 2017-March 31, 2020), with follow-up until June 30, 2020. Outcomes included overall survival (OS), real-world progression-free survival (rwPFS), time to treatment failure (TTF), objective response rate (ORR; complete response [CR] + partial response [PR]), and disease control rate (DCR)., Results: Of 127 enrolled patients, the overall analysis population comprised 117 patients (median [range] age, 71 [38-89] years). The most commonly prescribed 3L + monotherapy was nivolumab (n = 100), followed by irinotecan (n = 12) and FTD/TPI (n = 5). The median (95% confidence interval [CI]) OS, rwPFS, and TTF were 6.2 (4.5-8.0), 1.9 (1.5-2.3), and 1.8 (1.5-2.2) months, respectively, at median (range) 150 (25-1007) days of follow-up. The ORR (CR + PR) and DCR were 9.0% (1% + 8%) and 32.0%, respectively. Factors such as higher neutrophil-lymphocyte ratio (≥ 2.54), Glasgow prognostic score (≥ 1), Eastern Cooperative Oncology Group performance status (ECOG PS; ≥ 2), and hepatic metastasis significantly impacted OS., Conclusions: The observed OS in this study for HER2-positive G/GEJ cancer was shorter than that reported previously, suggesting that the effectiveness of nivolumab, irinotecan, or FTD/TPI as 3L + therapy may be limited., (© 2022. The Author(s).)

A multicenter phase II study was conducted in 44 elderly (≥ 65 years) Japanese patients with newly diagnosed acute myeloid leukemia (AML) to evaluate whether azacitidine is also effective and feasible in Japanese AML patients. The 28 patients with AML with poor-risk cytogenetics and/or myelodysplasia-related changes (unfavorable AML) were randomly assigned to receive either azacitidine or conventional care regimens (CCR), and the other 16 patients without unfavorable AML received azacitidine alone. The primary endpoint was overall survival. At the median follow-up of 29 months, among the 26 evaluable patients with unfavorable AML, the median survival time (MST) of patients who received azacitidine (N = 14) was 9.6 months and that of patients who received CCR (N = 12) was 5.3 months (HR 0.73; 95% CI 0.31-1.69; log-rank P = 0.459). The MST of all 29 patients who received azacytidine, including the 15 evaluable patients without unfavorable AML, was 12.4 months. Adverse events of azacitidine were manageable and consistent with its established safety profile. Azacitidine tended to prolong survival in newly diagnosed elderly Japanese patients with AML, and was feasible as a front-line therapy for elderly AML patients., (© 2022. Japanese Society of Hematology.)

Background: Tubulointerstitial nephritis (TIN) is an important cause of acute kidney injury (AKI) and advanced CKD. Only a limited number of studies have reported etiology-based differences in the clinical and/or histopathological properties and kidney outcomes of the biopsy-proven TIN., Methods: Patients with biopsy-proven TIN identified from 2005 to 2016 in five hospitals were categorized based on the etiologies and were retrospectively analyzed in relation to the clinicopathological findings and kidney outcomes., Results: Among 4815 biopsy cases screened, 153 Japanese TIN patients were identified, of whom 139 patients with ≥ 6 months of follow-up data (median 58 years old, 45.3% female, median 31.5 months follow-up) were further analyzed. TIN was drug-induced in 32.4%, autoimmune-related in 24.5%, of unknown etiology in 27.3% and other disease-related in 15.8%. Non-steroidal anti-inflammatory drugs and antibiotics were major causative drugs in drug-induced TIN, and IgG4-related disease, Sjögren's syndrome and sarcoidosis were common in autoimmune-related TIN. Among etiology groups, drug-induced TIN showed advanced AKI with elevated serum creatinine (sCr) and increased C-reactive protein levels at the diagnosis. TIN patients with autoimmune diseases showed less-severe AKI, but were more frequently treated with corticosteroids than others. Tubulointerstitial injury expansion in biopsy specimens was comparable among the groups. Complete or partial kidney function recovery at 6 months was more frequent in drug-induced and autoimmune-related TIN than in others. sCr levels at 6 months were similar among the groups., Conclusions: This largest case series study of the biopsy-proven TIN in Japan provides detailed information regarding both etiology-based clinicopathological properties and kidney outcomes., (© 2022. Japanese Society of Nephrology.)

Nationwide surveys of adult T-cell leukemia/lymphoma (ATL) have played an important role in helping us to understand the pathophysiology of this disease and analyze its prognosis in Japan. Classifications of clinical subtypes have been proposed based on the results of nationwide surveys of patients with ATL diagnosed in the 1980s. This article highlighted the classification and prognosis of ATL based on different surveys and focused on the comparison of data derived from the available surveys. The 11th nationwide hospital-based survey was conducted in patients with ATL diagnosed in 2010-2011 using the same method as that used in the 1980s survey. The median age of disease onset was 68 years, which was increased compared with previous surveys. While median survival of patients with the acute and lymphoma types had not improved much since the 1980s, the 4-year survival rate was higher. Little improvement in the prognosis was observed for the chronic and smoldering types. The 12th nationwide survey of patients with ATL diagnosed in 2012-2013 also showed an increase in age at onset. Further epidemiological research that includes more cases is needed to deepen our understanding of the actual state of treatment and prognosis of this disease.

Background: Chronic hypersensitivity pneumonitis (CHP) is a heterogeneous fibrotic interstitial pneumonia resulting from the immune response of susceptible individuals to inhaled antigens. Genetic predispositions have been suggested in CHP; however, the link between susceptibility genes and fibrotic progression has not been elucidated fully. Recent data suggest that variants in Toll-interacting protein gene (TOLLIP) are associated with lung diseases., Research Question: Can TOLLIP variants be associated with any clinical features in patients with CHP?, Study Design and Methods: We genotyped rs5743899 and rs3750920 in TOLLIP and analyzed the association with clinical parameters in 101 patients with CHP (67 for the retrospective cohort and 34 for the prospective cohort). We evaluated the expression of TOLLIP and fibrogenic signals in affected lung tissues and periostin in sera. Furthermore, we performed immunologic analysis in the lungs and sera., Results: The rs5743899 GG genotype was associated with rapid deterioration in FVC over time, which demonstrated significant annual decline in the retrospective cohort (vs AA, P = .0006; vs AG, P < .0001), prospective cohort (vs AA, P < .0001; vs AG, P = .003), and combined cohort (both P < .0001). The patients with the GG genotype demonstrated lower transcription-translation levels of TOLLIP as well as increased phosphorylation of Smad2 and inhibitor of kappa B in the lung tissues and exhibited higher serum levels of periostin, IL-1α, IL-1β, IL-6, IL-8, tumor necrosis factor α, and IFN-γ., Interpretation: The functional changes by TOLLIP variant were associated with rapid FVC decline through dysregulated Smad/transforming growth factor β and NF-κB signaling in CHP., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: The phase 3 VIALE-A trial (NCT02993523) reported that venetoclax-azacitidine significantly prolonged overall survival compared with placebo-azacitidine in patients with newly diagnosed acute myeloid leukemia ineligible for intensive chemotherapy. Herein, efficacy and safety of venetoclax-azacitidine are analyzed in the Japanese subgroup of VIALE-A patients., Methods: Eligible Japanese patients were randomized 2:1 to venetoclax-azacitidine (N = 24) or placebo-azacitidine (N = 13). Primary endpoints for Japan were overall survival and complete response (CR) + CR with incomplete hematologic recovery (CRi). Venetoclax (target dose 400 mg) was given orally once daily. Azacitidine (75 mg/m2) was administered subcutaneously or intravenously on Days 1-7 of each 28-day cycle., Results: Median follow-up was 16.3 months (range, 1.0-20.3). Median overall survival was not reached with venetoclax-azacitidine (hazard ratio 0.409 and 95% confidence interval: 0.151, 1.109); overall survival estimate was higher with venetoclax-azacitidine than placebo-azacitidine at 12 (67 and 46%) and 18 months (57 and 31%), respectively. CR and CRi rates were 67% with venetoclax-azacitidine and 15% with placebo-azacitidine. Most common any-grade adverse events were febrile neutropenia (79 and 39%), thrombocytopenia (54 and 77%), constipation (54 and 54%) and decreased appetite (54 and 38%) in the venetoclax-azacitidine and placebo-azacitidine arms, respectively. Only 1 patient in the venetoclax-azacitidine arm, and no patients in the placebo-azacitidine arm, had grade 4 febrile neutropenia that led to treatment discontinuation., Conclusions: This Japanese subgroup analysis of VIALE-A demonstrates comparable safety and efficacy outcomes compared with the global study and supports venetoclax-azacitidine as first-line standard-of-care for Japanese treatment-naive patients with acute myeloid leukemia who are ineligible for intensive chemotherapy., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)