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Background and Aims The efficacy and safety of early sacubitril/valsartan (Sac/Val) initiation after acute heart failure (AHF) has not been demonstrated outside North America. The present study aimed to evaluate the effect of in-hospital Sac/Val therapy initiation after an AHF episode on N-terminal pro-B-type natriuretic peptide (NT-proBNP) level in Japanese patients. Methods This was an investigator-initiated, multicentre, prospective, randomized, open-label, blinded-endpoint pragmatic trial. After haemodynamic stabilization within 7 days after hospitalization, eligible inpatients were allocated to switch from angiotensin-converting enzyme inhibitor or angiotensin receptor blocker to Sac/Val (Sac/Val group) or to continue angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (control group). The primary efficacy endpoint was the 8-week proportional change in geometric means of NT-proBNP levels. Results A total of 400 patients were equally randomized, and 376 (median age 75 years, 31.9% women, de novo heart failure rate 55.6%, and median left ventricular ejection fraction 37%) were analysed. The per cent changes in NT-proBNP level geometric means at Weeks 4/8 were −35%/−45% (Sac/Val group) and −18%/−32% (control group), and their group ratio (Sac/Val vs. control) was 0.80 (95% confidence interval 0.68–0.94; P =.008) at Week 4 and 0.81 (95% confidence interval 0.68–0.95; P =.012) at Week 8, respectively. In the pre-specified subgroup analyses, the effects of Sac/Val were confined to patients with a left ventricular ejection fraction < 40% and were more evident in those in sinus rhythm and taking mineralocorticoid receptor antagonists. No adverse safety signal was evident. Conclusions In-hospital Sac/Val therapy initiation in addition to contemporary recommended therapy triggered a greater NT-proBNP level reduction in Japanese patients hospitalized for AHF. These findings may expand the evidence on Sac/Val therapy in this clinical situation outside North America. Clinical Trial Registration ClinicalTrial.gov (NCT05164653) and Japan Registry of Clinical Trials (jRCTs021210046). [ABSTRACT FROM AUTHOR]

The article "Prevalence of high and low serum alkaline phosphatase levels and the associated factors in patients with rheumatoid arthritis: Results from the IORRA cohort study" published in Modern Rheumatology in 2024 discusses the prevalence of high and low serum alkaline phosphatase (ALP) levels in Japanese patients with rheumatoid arthritis (RA). The study found that 7.9% of patients had high ALP levels and 1.3% had low ALP levels. Factors associated with ALP levels included age, disease activity, serum AST levels, active vitamin D3 use, and antiresorptive agent use. The study highlights the importance of monitoring ALP levels in RA patients and the potential impact of medications on ALP levels. [Extracted from the article]

Objectives: To define groups and characterize differences in the prognosis of patients with adult-onset Still's disease (AOSD). Methods: We performed a retrospective cohort study. Patients with AOSD were grouped using hierarchical unsupervised cluster analysis according to age, sex, clinical features, and laboratory data. The primary endpoints were overall survival and drug-free remission rate. Results: A total of 153 patients with AOSD were placed into four clusters. Those in Cluster 1 had a young onset, tended to be female, and had fewer complications and moderate ferritin concentrations. Those in Cluster 2 had a young onset and had more complications and higher ferritin concentrations. Those in Cluster 3 had a young onset, tended to be male, and had no lymphadenopathy and fewer complications. Those in Cluster 4 had an older onset, tended to be female, and had more complications and higher ferritin concentrations. Overall survival tended to be lower (P = .0539) in Cluster 4, and drug-free remission was higher in Clusters 1, 2, and 3 [hazard ratios (HRs) 2.19, 3.37, and 3.62 vs. Cluster 4, respectively]. Conclusions: Four groups of AOSD that have distinct clinical manifestations, ferritin concentrations, severity, and drug-free remission rate were identified, which were lowest in Cluster 4. Graphical Abstract [ABSTRACT FROM AUTHOR]

Objectives: We characterised changes in absolute lymphocyte counts (ALCs) and lymphocyte subset counts (LSCs), and their relationship to incidence of serious infection events (SIEs) and herpes zoster (HZ) events in Japanese patients with moderate to severe rheumatoid arthritis enrolled in the tofacitinib clinical programme. Methods: Data included 765 patients receiving tofacitinib in Phase 2, Phase 3, and long-term extension studies. ALCs/LSCs and incidence rates (patients with events/100 patient-years) of SIEs and HZ were analysed over 75 months. Results: Median ALCs were generally stable over 75 months of treatment. Transient numerical increases from baseline in median LSCs were observed at Month 3; LSCs were generally lower than baseline for Months 36–75. SIE/HZ incidence rates were higher in patients with ALC <0.5 × 103 cells/mm3 versus those with ALC ≥0.5 × 103 cells/mm3 during tofacitinib treatment. Baseline LSCs were similar in patients with/without SIEs or HZ events. Conclusions: SIE/HZ risk was highest in patients with ALC <0.5 × 103 cells/mm3, supporting this threshold as clinically relevant for defining increased SIE/HZ risk in Japanese patients with rheumatoid arthritis receiving tofacitinib. However, SIEs and HZ events did not necessarily occur simultaneously with confirmed lymphopenia, preventing conclusions on possible causal relationships being drawn. [ABSTRACT FROM AUTHOR]

Objectives: To report up to 3-year safety and effectiveness of certolizumab pegol (CZP) in Japanese patients with rheumatoid arthritis from a postmarketing surveillance study. Methods: Patients enrolled previously completed 24 weeks of CZP in the 24-week postmarketing surveillance study. Adverse drug reactions (ADRs) were recorded for patients who received ≥1 CZP dose. Effectiveness outcomes were 28-joint Disease Activity Score with erythrocyte sedimentation rate and European Alliance of Associations for Rheumatology response. Week 24–156 safety and Week 0–52 effectiveness data are reported here. Results: A total of 781 patients were enrolled, with 735 and 376 patients evaluated for safety and effectiveness, respectively. Within the safety set, 17.8% (131/735) of patients reported ADRs; 9.4% (69/735) reported serious ADRs. Among patients with history of respiratory, thoracic, and mediastinal disorders, 38.4% (28/73) reported ADRs. The most frequent ADRs were infections and infestations (11.8%; 87/735); skin and subcutaneous tissue disorders (1.9%; 14/735); respiratory, thoracic, and mediastinal disorders (1.6%; 12/735). Mean 28-joint Disease Activity Score with erythrocyte sedimentation rate reduced from 4.6 (Week 0) to 2.8 (Week 52). At Week 52, 51.8% (161/311) of patients achieved European Alliance of Associations for Rheumatology Good response. Conclusions: The long-term safety and effectiveness of CZP in the real-world setting in Japan were consistent with previously reported data; no new safety signals were identified. [ABSTRACT FROM AUTHOR]

The lifetime attributable risk (LAR) of cancer caused by radiation exposure is crucial when deciding on radiological protection measures or protective actions for nuclear emergency preparedness and response. Although a model for estimating LAR among the Japanese population has been developed based on epidemiological data from A-bomb survivors, a flexible projection code implementing this model must be developed. This study investigated existing codes to contribute to the development of a projection code. Based on these investigations, we compared their LAR calculation results and explored the causes of their differences. [ABSTRACT FROM AUTHOR]

This retrospective matched cohort study investigated the protective effects of the 23-valent pneumococcal polysaccharide vaccine (PPSV23) against pneumonia mortality and all-cause mortality in Japanese adults aged ≥65 years. We analyzed claims data, vaccination records, and death certificate records between October 2016 and December 2019 from 55 509 PPSV23-vaccinated individuals and 55 509 unvaccinated individuals. Cox proportional hazards analyses were performed to calculate the adjusted hazard ratios (HRs) of PPSV23 vaccination for mortality. The results showed that PPSV23 vaccination was significantly associated with a reduction in all-cause mortality (adjusted HR, 0.52; P <.001) but not pneumonia mortality (adjusted HR, 0.70; P =.374). [ABSTRACT FROM AUTHOR]

The use of halophilic bacteria in industrial chemical and food production has received great interest because of the unique properties of these bacteria; however, their safety remains under investigation. Halomonas sp. KM-1 intracellularly stores poly-D-β-hydroxybutyric acid under aerobic conditions and successively secretes D-β-hydroxybutyric acid (D-BHB) under microaerobic conditions. Therefore, we tested the safety of Halomonas sp. KM-1-derived D-BHB and the impurities generated during D-BHB manufacturing at a 100-fold increased concentration in acute tests using mice and daily intake of 16.0 g D-BHB in Japanese adults for 12 weeks. In the mice test, there were no abnormalities in the body weights or health of mice fed the purified D-BHB or its impurities. In the Japanese adult test, blood parameters and body condition showed no medically problematic fluctuations. These findings indicate that Halomonas sp. KM-1 is safe and can be used for commercial production of D-BHB and its derivatives. [ABSTRACT FROM AUTHOR]

Objectives This study aimed to investigate the association between falls and social frailty and its components among older Japanese adults. Methods This is a cross-sectional study. Participants were categorized into 3 groups based on the number of falls in the past year: no fall (none), a single fall (occasional), and more than one fall (recurrent). The participants who met 2 or more of the following criteria were defined as socially frail: living alone, going out less frequently compared with the previous year, rarely visiting friends, feeling unhelpful to friends or family, and not talking with someone daily. Results A total of 4,495 older Japanese adults living in a community analyzed in this study (51.0% women). Of the participants in this study, 3,851 (85.7%) were categorized as none, 443 (9.9%) as occasional, and 201 (4.5%) as recurrent. The proportion of participants considered socially frail was 11.5% in this study. Recurrent falls were associated with social frailty, even after adjusting for covariates (odds ratio [OR]: 1.49; 95% confidence interval [CI]: 1.01–2.19). The experience of recurrent falls was associated with the following components: "feeling unhelpful to friends and family" (OR: 1.62; 95% CI: 1.14–2.31) and "going outside less frequently compared with last year" (OR: 1.57; 95% CI: 1.06–2.31). Discussion Among older Japanese adults, recurrent falls were associated with social frailty and with 2 of its components in particular: social roles and social participation. Future longitudinal studies should be conducted to gain insight into any causal relationships between these variables. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the 2 year safety and effectiveness of denosumab 60 mg in patients with rheumatoid arthritis (RA) in clinical practice in Japan. Methods: This 2 year, prospective, observational cohort study included patients who initiated treatment with denosumab 60 mg for the progression of bone erosion associated with RA. Key endpoints were adverse drug reactions (ADRs), progression of bone erosion, and 28-joint Disease Activity Score based on C-reactive protein or erythrocyte sedimentation rate. Univariate and multivariate analyses were conducted to determine the risk factors for ADRs and the progression of bone erosion. Results: In the safety analysis set (n = 1239), the incidence of ADRs was 3.0%; the most common ADRs were hypocalcaemia (1.2%) and osteonecrosis of jaw-related events (0.6%). A history of any drug allergy was a statistically significant risk factor associated with the occurrence of ADRs. In the effectiveness analysis set (n = 815), the incidence of progression of bone erosion was 8.7%. Steinbrocker stage and initial steroid dose were statistically significant risk factors associated with the progression of bone erosion. Conclusion: Denosumab demonstrated safety and effectiveness over a 2 year period in RA patients without any new safety concerns. [ABSTRACT FROM AUTHOR]

Atypical femoral fracture (AFF) is generally a rare complication of long-term use of bisphosphonate (BP); glucocorticoid (GC) use and Asian race are also risk factors. Femoral localized periosteal thickening (LPT, also termed "beaking") of the lateral cortex often precedes AFF. This cohort study investigated the incidence of LPT and AFF and their clinical courses over 10 yr in patients with autoimmune inflammatory rheumatic diseases (AIRDs) treated with BP and GC. The study population consisted of 121 patients with AIRDs taking BP and GC. LPT was screened by X-ray, and the LPT shape was evaluated. Prednisolone (PSL) dose was 10 (8–12) mg/d at enrollment and 9 (6–10) mg/d at the last observation. LPT was evident in 10 patients at enrollment and increased linearly to 31 patients (26%) at the last observation. AFF occurred in 9 femurs of 5 patients with LPT. All patients with AFF had bilateral LPT, and the prevalence of pointed type and LPT height were higher in the AFF-positive group than in the AFF-negative group. AFF occurred before BP discontinuation in 2 patients, 1 yr after BP discontinuation in 1, after BP discontinuation followed by 7 yr of alfacalcidol use in 1, and after switching from alfacalcidol to denosumab in 1. The prevalence rates of AFF and LPT associated with long-term BP use with concomitant use of GC (mostly PSL ≥ 6 mg/d) in Japanese patients with AIRD increased over time. The selection of long-term osteoporosis treatment for LPT-positive patients is difficult in some cases. Lay Summary: Autoimmune inflammatory rheumatic diseases (AIRDs) are often treated with glucocorticoid (GC) and bisphosphonate (BP) is also often used to prevent and treat GC-induced osteoporosis. This study observed that femoral localized periosteal thickening of lateral cortex (LPT), which often precedes atypical femoral fracture (AFF), occurred in 10% of Japanese patients with AIRDs taking GC and BP. The prevalence increased to 26% over 10 yr. Furthermore, AFF occurred in 9 femurs of 5 patients with LPT. All patients with AFF had bilateral LPT. AFF occurred before BP discontinuation in 2, 1 yr after BP discontinuation in 1, after BP discontinuation followed by 7 yr of alfacalcidol use in 1, and after switching from alfacalcidol to denosumab in 1. Although AFF is generally a rare complication related to BP, the prevalence rates of AFF and LPT associated with long-term BP use with concomitant use of GC (mostly PSL ≥ 6 mg/d) in Japanese patients with AIRD increased over time. The selection of long-term osteoporosis treatment for LPT-positive patients is difficult in some cases. Graphical Abstract [ABSTRACT FROM AUTHOR]

Context Thyroglobulin (Tg), encoded by TG , is essential for thyroid hormone synthesis. TG defects result in congenital hypothyroidism (CH). Most reported patients were born before the introduction of newborn screening (NBS). Objective We aimed to clarify the phenotypic features of patients with TG defects diagnosed and treated since the neonatal period. Methods We screened 1061 patients with CH for 13 CH-related genes and identified 30 patients with TG defects. One patient was diagnosed due to hypothyroidism-related symptoms and the rest were diagnosed via NBS. Patients were divided into 2 groups according to their genotypes, and clinical characteristics were compared. We evaluated the functionality of the 7 missense variants using HEK293 cells. Results Twenty-seven rare TG variants were detected, including 15 nonsense, 3 frameshift, 2 splice-site, and 7 missense variants. Patients were divided into 2 groups: 13 patients with biallelic truncating variants and 17 patients with monoallelic/biallelic missense variants. Patients with missense variants were more likely to develop thyroid enlargement with thyrotropin stimulation than patients with biallelic truncating variants. Patients with biallelic truncating variants invariably required full hormone replacement, whereas patients with missense variants required variable doses of levothyroxine. Loss of function of the 7 missense variants was confirmed in vitro. Conclusion To our knowledge, this is the largest investigation on the clinical presentation of TG defects diagnosed in the neonatal period. Patients with missense variants showed relatively mild hypothyroidism with compensative goiter. Patients with only truncating variants showed minimal or no compensative goiter and required full hormone replacement. [ABSTRACT FROM AUTHOR]

Background Cutavirus (CuV) is associated with mycosis fungoides; however, the CuV status in parapsoriasis en plaques (PP), a premalignant inflammatory condition of mycosis fungoides, has not been fully delineated. Methods Fifty-five Japanese patients with chronic inflammatory skin diseases, including 13 patients with PP, were studied. Results CuV DNA was detected significantly more frequently in biopsies of the lesional skin from patients with PP (38%; 4 of 13) than in those from patients with other inflammatory skin diseases (2%; 1 of 42; P =.009). All CuV-positive PP cases were of the large-plaque parapsoriasis (LPP) subtype. The viral loads ranged from 83 450 to 2 164 170 copies/103 cells. We recovered near–full-length CuV sequences from the CuV-positive LPP biopsies, all of which were of the Japanese/Asian genotype. The CuV genome appeared to be present within lymphoid cells infiltrating the epidermis and dermis. CuV NS1 and VP1 gene transcripts were also detected in the affected tissues. Conclusions The detection of high levels of CuV DNA with the expression of viral mRNA suggests a potential role for CuV in the pathogenesis of LPP, making it necessary to study further the impact of CuV, especially regarding the viral genotype, on the outcomes of patients with CuV-positive LPP. [ABSTRACT FROM AUTHOR]

Objectives: In clinical trials, tocilizumab (TCZ) is efficacious in patients with giant cell arteritis (GCA). This study evaluated the real-world tolerability and effectiveness of TCZ in Japanese patients with GCA. Methods: In this multicentre, prospective, Phase 4, large-scale, observational study, patients with GCA (with no TCZ treatment 6 months before the study) were recruited from 71 centres across Japan. Patients received subcutaneous TCZ 162 mg weekly (observation period, 52 weeks). Results: Of the 117 patients [female, 70.1%; mean age, 74.2 years; mean disease duration, 1.4 years; treated for new-onset GCA, 71.8%; presence of large-vessel lesions (LVLs), 61.5%; previous immunosuppressant use, 28.2%; glucocorticoids at baseline, 95.7% (mean: 22.4 mg/day)], 38.5% reported adverse events. The most common adverse events of special interest were neutropaenia and leukopaenia (7.7%), followed by serious infection (6.0%). The relapse-free proportion was 85.0%; relapse after remission, 6.0%; and no remission, 9.0%. At the last observation, 94.2% of relapse-free patients received a concomitant glucocorticoid dose of <10 mg/day. Fatigue, headache, neck pain, and absence of LVLs were positively associated with the relapse. Conclusions: TCZ was effective and well tolerated in Japanese patients with GCA and may be an effective treatment option combined with glucocorticoids. [ABSTRACT FROM AUTHOR]

Objectives: This article aims to examine the ability of the Rheumatoid Arthritis Observation of Biologic Therapy (RABBIT) risk score to predict the occurrence of serious infections in Japanese patients with rheumatoid arthritis (RA), after initiating their first biologic disease–modifying antirheumatic drug (bDMARD). Methods: We used data from the Institute of Rheumatology, Rheumatoid Arthritis cohort from 2008 to 2020. Patients with RA who were started on their first bDMARDs were included. Those with missing data required to calculate the score were excluded. A receiver operating characteristic curve was used to evaluate the discriminatory ability of the RABBIT score. Results: A total of 1081 patients were enrolled. During the 1-year observational period, 23 (1.7%) patients had serious infections; the most frequent one was bacterial pneumonia (n = 11, 44%). The median RABBIT score in the serious infection group was significantly higher than that in the non-serious infection group [2.3 (1.5–5.4) vs 1.6 (1.2–2.5), P < .001]. The area under the receiver operating characteristic curve for the occurrence of serious infections was 0.67 (95% confidence interval 0.52–0.79), suggesting that the score had low accuracy. Conclusions: Our present study revealed that the RABBIT risk score did not have sufficient discriminatory ability for predicting the development of severe infections in Japanese patients with RA after initiating their first bDMARD. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study is to investigate the effects of sarilumab on unacceptable pain [UP; visual analogue scale (VAS) >40 mm] and inflammation in patients with moderately-to-severely active rheumatoid arthritis. Methods: In this post hoc analysis of the KAKEHASI study, 243 patients received methotrexate with sarilumab 150 or 200 mg or placebo every other week, over 52 weeks. The proportion of patients with UP and correlations of changes in pain VAS from baseline with uncontrolled inflammation (C-reactive protein ≥1 mg/dl) and disease activity indices were assessed. Results: Almost 80% of patients (192/243) had UP at baseline, including ∼60% of patients with uncontrolled inflammation. Among patients receiving sarilumab, inflammation decreased rapidly, with 90% of patients achieving controlled inflammation by Week 2, while 63.1% continued to have UP. The proportion of patients with UP further decreased by Week 16 (28.5%, sarilumab vs. 64.0%, placebo). By Week 52, only ∼10% of patients had UP. Changes in pain VAS correlated with most disease activity indices and patient-reported outcomes. However, marked correlations between changes in pain VAS and C-reactive protein were observed only at Week 16. Conclusion: Sarilumab treatment reduced UP and inflammation in Japanese patients with rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Background This study aims to investigate the association and dose–response relationship between depression, dementia, and all-cause mortality based on a national cohort study of older adults in Japan. Methods We conducted a longitudinal study of 44,546 participants ≥65 years from 2010–2019 Japanese Gerontological Evaluation Study. The Geriatric Depression Scale-15 was used to assess depressive symptoms and the long-term care insurance was used to assess dementia. Fine–Gray models and Cox proportional hazard models were used to explore the effect of depression severity on the incidence of dementia and all-cause mortality, respectively. Causal mediation analysis were used to explore the extent of association between dementia-mediated depression and all-cause mortality. Results We found that both minor and major depressive symptoms were associated with the increased cumulative incidence of dementia and all-cause mortality, especially major depressive symptoms (p <.001). The multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for dementia were 1.25 (1.19–1.32) for minor depressive symptoms and 1.42 (1.30–1.54) for major depressive symptoms in comparison to non-depression; p for trend <.001. The multivariable-adjusted HRs and 95% CIs for all-cause mortality were 1.27 (1.21–1.33) for minor depressive symptoms and 1.51 (1.41–1.62) for major depressive symptoms in comparison to non-depression; p for trend <.001. Depression has a stronger impact on dementia and all-cause mortality among the younger group. In addition, dementia significantly mediated the association between depression and all-cause mortality. Discussion Interventions targeting major depression may be an effective strategy for preventing dementia and premature death. [ABSTRACT FROM AUTHOR]

John Lie's recent publication explores the economic, political, and social changes in Japan since the bursting of the economic bubble, focusing on the values and practices of earlier eras that have resurfaced in the age of limits. The author argues that these values, such as the artisanal ethos and ordinary pleasures of everyday life, may offer a more sustainable future in the face of rising inequality and environmental devastation. The book examines different historical regimes in Japan and their potential influence on the country's future. It also discusses the resurgence of ordinary virtues and the artisanal ethos in contemporary Japan, using examples such as sushi-making and traditional bathing practices. The author suggests that these practices can provide lessons for a more sustainable society. [Extracted from the article]

Existing studies found that entering the labor market during a recession has persistent negative effects—the scarring effects—on employment and earnings for Japanese men. The cohorts who entered the labor market during the prolonged recession between 1993 and 2004 are called "the ice-age cohorts," and the persistent gap between them and older cohorts who entered the labor market during the bubble economy is often interpreted as the scarring effect of business cycle conditions at entry. However, the existing studies in Japan use data covering cohorts who enter the labor market in the 1990s or earlier. Motivated by the lack of empirical evidence with updated data, this article revisits the scarring effects of a recession at labor market entry on employment and earnings using data covering graduation cohorts 1984–2013. Younger cohorts who enter the labor market during the recovery do not earn more or enjoy more stable employment than the cohorts who enter the bottom of the ice-age, and that the effects of unemployment rate at entry on employment and earnings are no longer statistically significant for cohorts who enter the labor market after the job market ice-age. I also discuss potential factors that may have weakened scarring effects. [ABSTRACT FROM AUTHOR]

This article discusses the book "Eleven Winters of Discontent: The Siberian Internment and the Making of a New Japan" by Sherzod Muminov. The book examines the history of Japanese Siberian internment, where approximately 600,000 Japanese soldiers and civilian military personnel were interned by the Soviet Union after World War II. The author utilizes sources in Japanese, Russian, and English to provide a global history perspective on the topic. The book also explores the construction of a new national history in postwar Japan and the impact of the internment on Japanese sentiment towards the Soviet Union. While the book does not present new facts, it offers a theoretical framework that critiques postwar Japan's national history and analyzes the internees' position in the Cold War. The article highlights the challenges faced by Japanese studies in English-speaking countries and the difficulties of achieving academic recognition from both English-speaking and Japanese-speaking researchers. [Extracted from the article]

Whole blood transcriptome analysis is a valuable approachin medical research, primarily due to the ease of sample collection and the richness of the information obtained. Since the expression profile of individual genes in the analysis is influenced by medical traits and demographic attributes such as age and gender, there has been a growing demand for a comprehensive database for blood transcriptome analysis. Here, we performed whole blood RNA sequencing (RNA-seq) analysis on 576 participants stratified by age (20–30s and 60–70s) and gender from cohorts of the Tohoku Medical Megabank (TMM). A part of female segment included pregnant women. We did not exclude the globin gene family in our RNA-seq study, which enabled us to identify instances of hereditary persistence of fetal hemoglobin based on the HBG1 and HBG2 expression information. Comparing stratified populations allowed us to identify groups of genes associated with age-related changes and gender differences. We also found that the immune response status, particularly measured by neutrophil-to-lymphocyte ratio (NLR), strongly influences the diversity of individual gene expression profiles in whole blood transcriptome analysis. This stratification has resulted in a data set that will be highly beneficial for future whole blood transcriptome analysis in the Japanese population. [ABSTRACT FROM AUTHOR]

Background Disturbances in the cardiovascular system, bone and skeletal muscle are independent risk factors for death among patients receiving haemodialysis (HD). However, the combined impact of disorders of these three organs on morbidity and mortality is unclear in the HD population. Methods A total of 3031 Japanese patients on maintenance HD were prospectively followed. The outcomes were all-cause mortality, major adverse cardiovascular events (MACE) and bone fracture. Patients were divided into four groups (G1–G4) according to the baseline number of diseased organs represented as histories of cardiovascular disease and bone fractures and the presence of low skeletal muscle mass as follows: G1, no organ; G2, one organ; G3, two organs; G4, three organs. Multivariable-adjusted survival models were used to analyse associations between the number of diseased organs and outcomes. Results During a 4-year follow-up, 499 deaths, 540 MACE and 140 bone fractures occurred. In the Cox proportional hazards model, the risk for all-cause mortality was significantly higher in G2, G3 and G4 than in G1 as the reference {hazard ratio: G2, 2.16 [95% confidence interval (CI) 1.65–2.84], G3, 3.10 [95% CI 2.27–4.23] and G4, 3.11 [95% CI 1.89–5.14]}. Similarly, the risks for developing MACE and bone fractures were significantly elevated as the number of organ disorders increased. Conclusions Multiple disorders of the cardiovascular–bone–skeletal muscle axis are strong predictors of morbidity and mortality in patients undergoing HD. [ABSTRACT FROM AUTHOR]

Context HNF4A–maturity-onset diabetes of the young (MODY1) is a relatively rare subtype of monogenic diabetes caused by loss of function of the HNF4A gene, which encodes the transcription factor HNF4α. HNF4α is known to form heterodimers, and the various combinations of isoforms that make up these heterodimers have been reported to result in a diversity of targeted genes. However, the function of individual HNF4α variant isoforms and the heterodimers comprising both wild-type (WT) and variant HNF4α have not yet been assessed. Objective In this study, we analyzed the functional consequence of the HNF4A D248Y variant in vitro. Methods We investigated the case of a 12-year-old Japanese girl who developed diabetes at age 11 years. Genetic sequencing detected a novel heterozygous missense HNF4A variant (c.742G > T, p.Asp248Tyr; referred as "D248Y") in the patient and her relatives who presented with diabetes. Results Although the WT HNF4α isoforms (HNF4α2, HNF4α3, HNF4α8, HNF4α9) enhanced the INS gene promoter activity in HepG2 cells, the promoter activity of D248Y was consistently low across all isoforms. The presence of D248Y in homodimers and heterodimers, comprising either HNF4α8 or HNF4α3 or a combination of both isoforms, also reduced the INS promoter activity in Panc-1 cells. Conclusion We report the clinical course of a patient with HNF4A-MODY and the functional analysis of novel HNF4A variants, with a focus on the isoforms and heterodimers they form. Our results serve to improve the understanding of the dominant-negative effects of pathogenic HNF4A variants. [ABSTRACT FROM AUTHOR]

Objectives: An interim analysis of post-marketing surveillance data to assess the safety and effectiveness of sarilumab in Japanese patients with rheumatoid arthritis refractory to previous treatment. Methods: The interim analysis included patients who initiated sarilumab therapy between June 2018 and January 2021. The primary objective of this surveillance was safety. Results: In total, 1036 patients were enrolled and registered by 12 January 2021 (interim cut-off date). Of these, 678 were included in the safety analysis [75.4% female; mean age (± standard deviation) 65.8 ± 13.0 years]. Adverse drug reactions, defined as adverse events classified as possibly or probably related to sarilumab, were reported in 170 patients (incidence: 25.1%), with white blood cell count decreased (4.4%) and neutrophil count decreased (1.6%) most frequently reported. Serious haematologic disorders (3.4%) and serious infections (including tuberculosis) (2.5%) were the most frequently reported priority surveillance items. No malignant tumour was reported. An absolute neutrophil count (ANC) below the minimum standard value did not increase the incidence of serious infections. Conclusions: Sarilumab was well tolerated, and no new safety signals were noted in this analysis. There was no difference in the frequency of serious infections between patients with an ANC below or above normal. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this article is to investigate the efficacy and safety of tocilizumab in Japanese patients with systemic sclerosis. Methods: Post hoc subgroup analysis of a global, randomised, controlled trial in patients treated with weekly tocilizumab 162 mg or placebo subcutaneously in a 48-week double-blind period (tocilizumab and placebo groups) followed by tocilizumab for 48 weeks in an open-label extension (continuous-tocilizumab and placebo-tocilizumab groups). Results: Among 20 patients, 12 were randomised to tocilizumab (all had interstitial lung disease) and eight were randomised to placebo (six had interstitial lung disease). The modified Rodnan skin score improved in both treatment groups. The mean change in percent-predicted forced vital capacity was 3.3% [95% confidence interval (CI), −2.5 to 9.0] for tocilizumab and −3.8% (95% CI, −9.9 to 2.2) for placebo in the double-blind period and 2.0% (95% CI, −0.7 to 4.6) for continuous-tocilizumab and −1.4% (95% CI, −6.7 to 4.0) for placebo-tocilizumab in the open-label extension. Rates of serious adverse events per 100 patient-years were 19.3 for tocilizumab and 26.8 for placebo in the double-blind period and 0.0 for continuous-tocilizumab and 13.6 for placebo-tocilizumab in the open-label period. Conclusions: The efficacy and safety of tocilizumab in patients with systemic sclerosis were consistent between the Japanese subpopulation and the global trial population. [ABSTRACT FROM AUTHOR]

Background Primary membranous nephropathy (pMN) is one of the most common types of glomerulonephritis, with a third of patients progressing to renal insufficiency. Various prognostic factors have been reported, of which urinary protein and renal function are the most critical parameters. Fractional excretion of total protein (FETP) indicates protein leakage that accounts for creatinine kinetics and serum protein levels. In this study, we investigated the association between FETP and renal prognosis in pMN. Methods We retrospectively identified 150 patients with pMN. FETP was calculated as follows: (serum creatinine × urine protein)/(serum protein × urine creatinine) %. We divided the patients into three groups according to FETP values and compared the clinicopathological findings. The primary outcome was an estimated glomerular filtration rate (eGFR) decrease of ≥30% from the baseline level. Results FETP was associated with urinary protein and renal function, Ehrenreich and Churg stage, and global glomerulosclerosis. The primary outcome was observed in 38 patients (25.3%), and the frequency of the primary outcome was higher in the high FETP group (P  = .001). FETP is higher than protein–creatinine ratio (PCR) in the area under the curve. In the multivariate analysis adjusted for age, eGFR, PCR and treatment, FETP was significantly associated with primary outcome (adjusted hazard ratio, 8.19; P  = .019). Conclusions FETP is a valuable indicator that can reflect the pathophysiology and is more useful than PCR as a predictor of renal prognosis in patients with Japanese pMN. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Do copy-number variations (CNVs) in the azoospermia factor (AZF) regions and monogenic mutations play a major role in the development of isolated (non-syndromic) non-obstructive azoospermia (NOA) in Japanese men with a normal 46, XY karyotype? SUMMARY ANSWER Deleterious CNVs in the AZF regions and damaging sequence variants in eight genes likely constitute at least 8% and approximately 8% of the genetic causes, respectively, while variants in other genes play only a minor role. WHAT IS KNOWN ALREADY Sex chromosomal abnormalities, AZF-linked microdeletions, and monogenic mutations have been implicated in isolated NOA. More than 160 genes have been reported as causative/susceptibility/candidate genes for NOA. STUDY DESIGN, SIZE, DURATION Systematic molecular analyses were conducted for 115 patients with isolated NOA and a normal 46, XY karyotype, who visited our hospital between 2017 and 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS We studied 115 unrelated Japanese patients. AZF-linked CNVs were examined using sequence-tagged PCR and multiplex ligation-dependent probe amplification, and nucleotide variants were screened using whole exome sequencing (WES). An optimized sequence kernel association test (SKAT-O), a gene-based association study using WES data, was performed to identify novel disease-associated genes in the genome. The results were compared to those of previous studies and our in-house control data. MAIN RESULTS AND THE ROLE OF CHANCE Thirteen types of AZF-linked CNVs, including the hitherto unreported gr/gr triplication and partial AZFb deletion, were identified in 63 (54.8%) cases. When the gr/gr deletion, a common polymorphism in Japan, was excluded from data analyses, the total frequency of CNVs was 23/75 (30.7%). This frequency is higher than that of the reference data in Japan and China (11.1% and 14.7%, respectively). Known NOA-causative AZF-linked CNVs were found in nine (7.8%) cases. Rare damaging variants in known causative genes (DMRT1 , PLK4 , SYCP2, TEX11 , and USP26) and hemizygous/multiple-heterozygous damaging variants in known spermatogenesis-associated genes (TAF7L , DNAH2 , and DNAH17) were identified in nine cases (7.8% in total). Some patients carried rare damaging variants in multiple genes. SKAT-O detected no genes whose rare damaging variants were significantly accumulated in the patient group. LIMITATIONS, REASONS FOR CAUTION The number of participants was relatively small, and the clinical information of each patient was fragmentary. Moreover, the pathogenicity of identified variants was assessed only by in silico analyses. WIDER IMPLICATIONS OF THE FINDINGS This study showed that various AZF-linked CNVs are present in more than half of Japanese NOA patients. These results broadened the structural variations of AZF-linked CNVs, which should be considered for the molecular diagnosis of spermatogenic failure. Furthermore, the results of this study highlight the etiological heterogeneity and possible oligogenicity of isolated NOA. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by Grants from the Japan Society for the Promotion of Science (21K19283 and 21H0246), the Japan Agency for Medical Research and Development (22ek0109464h0003), the National Center for Child Health and Development, the Canon Foundation, the Japan Endocrine Society, and the Takeda Science Foundation. The results of this study were based on samples and patient data obtained from the International Center for Reproductive Medicine, Dokkyo Medical University Saitama Medical Center, Koshigaya, Japan. The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Several population-based studies have reported that higher serum N-terminal pro-brain natriuretic peptide (NT-proBNP) levels are associated with brain morphological changes. However, no population-based studies have examined the relationship between serum NT-proBNP and various regional brain volumes in detail. We here analyzed the brain MRI data of 1 201 community-dwelling Japanese aged ≥65 years. Regional gray matter volumes (GMV) and intracranial volume (ICV) were estimated by applying voxel-based morphometry (VBM) methods. The associations of serum NT-proBNP with regional GMV/ICV were examined by analysis of covariance. The regional gray matter atrophy patterns associated with elevated serum NT-proBNP levels were investigated using VBM without a priori regions of interest. The multivariable-adjusted means of the frontal, temporal, hippocampal, parahippocampal, and entorhinal GMV/ICV decreased significantly with elevated serum NT-proBNP levels (all p for trend and q values of false discovery rate correction < .05). In VBM, elevated serum NT-proBNP levels were correlated with atrophy of the bilateral hippocampi, bilateral amygdalas, bilateral parahippocampal gyri, bilateral entorhinal areas, bilateral fusiform gyri, left middle temporal gyrus, left inferior temporal gyrus, right central operculum, right posterior orbital gyrus, bilateral middle frontal gyri, anterior cingulate gyrus and bilateral medial frontal cortices. In a sensitivity analysis excluding 254 participants with mild cognitive impairment or dementia, serum NT-proBNP levels were correlated with atrophy of the bilateral hippocampi, bilateral amygdalas, bilateral parahippocampal gyri, bilateral fusiform gyri, and left middle frontal gyrus. Our data suggest that elevated serum NT-proBNP levels are associated with gray matter atrophy in brain regions that play an important role in cognitive function. [ABSTRACT FROM AUTHOR]

Postoperative radiotherapy for breast cancer reportedly increases the risk of thoracic soft tissue sarcomas, particularly angiosarcomas; however, the risk in the Japanese population remains unknown. Therefore, this study aimed to investigate the incidence of thoracic soft tissue sarcoma among patients with breast cancer in Japan and determine its association with radiotherapy. This retrospective cohort study used data from the population-based cancer registry of the Osaka Prefecture. The inclusion criteria were female sex, age 20–84 years, diagnosis of breast cancer between 1990 and 2010, no supraclavicular lymph node or distant metastasis, underwent surgery and survived for at least 1 year. The primary outcome was the occurrence of thoracic soft tissue sarcomas 1 year or later after breast cancer diagnosis. Among the 13 762 patients who received radiotherapy, 15 developed thoracic soft tissue sarcomas (nine angiosarcomas and six other sarcomas), with a median time of 7.7 years (interquartile range, 4.0–8.6 years) after breast cancer diagnosis. Among the 27 658 patients who did not receive radiotherapy, four developed thoracic soft tissue sarcomas (three angiosarcomas and one other sarcoma), with a median time of 11.6 years after diagnosis. The 10-year cumulative incidence was higher in the radiotherapy cohort than in the non-radiotherapy cohort (0.087 vs. 0.0036%, P  < 0.001). Poisson regression analysis revealed that radiotherapy increased the risk of thoracic soft tissue sarcoma (relative risk, 6.8; 95% confidence interval, 2.4–24.4). Thus, although rare, breast cancer radiotherapy is associated with an increased risk of thoracic soft tissue sarcoma in the Japanese population. [ABSTRACT FROM AUTHOR]

Vitamin D deficiency during infancy has been associated with increased bone turnover rate and bone mineral loss. However, few studies have examined bone turnover markers (BTMs) for both bone formation and resorption in infants with vitamin D deficiency. Here, we analyzed serum concentrations of 25OHD, intact parathormone (iPTH), and BTMs including total alkaline phosphatase (ALP), tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), and serum type I collagen N-telopeptide (NTx) as well as basic clinical characteristics of 456 infants (626 samples) aged less than 12 mo born at Saitama City Hospital, Japan (latitude 35.9° North) between January 2021 and December 2022. One hundred sixteen infants (147 samples) were classified as having vitamin D deficiency (25OHD < 12.0 ng/mL), and 340 infants (479 samples) had sufficient vitamin D levels (25OHD ≥ 12.0 ng/mL). In addition to 25OHD and ALP, both TRACP-5b and sNTx were measured in 331 infants (418 samples), while 90 infants (105 samples) had only TRACP-5b measured and 101 infants (103 samples) had only sNTx measured. Statistical comparison of 104 subjects each in the vitamin D deficiency and sufficiency groups after matching for the background characteristics revealed that the vitamin D deficiency group had significantly higher levels of ALP and iPTH compared with the sufficiency group (P  = <.0001,.0012, respectively). However, no significant differences were found in TRACP-5b and NTx levels between the 2 groups (P  = .19,.08, respectively). Our findings suggest discordant responses between bone formation and resorption markers in subclinical vitamin D deficiency during infancy. [ABSTRACT FROM AUTHOR]

Background The objective was to report critical respiratory syncytial virus (RSV)–related epidemiological and healthcare resource utilization measures among Japanese children stratified by gestational and chronological age groups. Methods The JMDC (formerly the Japan Medical Data Center) was used to retrospectively identify infants with or without RSV infection (beginning between 1 February 2011 and 31 January 2016, with follow-up through 31 December 2017). The incidence of RSV medically attended lower respiratory tract infection (MALRI) was captured by flagging hospitalizations, outpatient, and emergency department/urgent care visits with an RSV diagnosis code during the season. Results Of 113 529 infants and children identified, 17 022 (15%) had an RSV MALRI (14 590 during the season). The RSV MALRI and hospitalization rates in the first 5 months were 14.3/100 child-years (CY) and 6.0/100 CY, respectively (13.4/100 and 5.8/100 CY for full-term infants and 20/100 and 6.8/100 CY for late preterm infants, respectively). Among those with ≥1 type of MALRI event during the RSV season, >80% of children had it by 24 months of chronological age, although this observation differed by prematurity status. Sixty percent of healthcare resource utilization measures started in the outpatient setting. Conclusions This study emphasizes the RSV burden in young children and critically highlights the data needed to make decisions about new preventive strategies. [ABSTRACT FROM AUTHOR]

Background: Fish are rich in omega-3 polyunsaturated fatty acids and vitamin D, which can promote testosterone synthesis and secretion. However, some contaminants present in fish may disrupt testosterone production. Objective: This study aimed to investigate the association between fish intake (total, fatty, and lean fish) and serum testosterone levels in older males. Methods: This cross-sectional study included 1545 Japanese males aged 60-69 y who participated in the baseline survey of the Hitachi Health Study II. Fish intake was estimated using a validated brief-type self-administered diet history questionnaire. Total testosterone levels were measured by chemiluminescence immunoassay. Multivariable linear regression analysis was used to analyze the association between fish intake and serum testosterone levels. Results: Higher total fish intake was associated with higher levels of serum testosterone, with an adjusted mean [95% confidence interval (CI) of 5.63 (5.43, 5.83) and 5.99 (5.78, 6.20)] ng/mL for the 1st and 4th quartiles of total fish intake, respectively (P for trend = 0.06). When analyzing fatty and lean fish separately, higher intake of lean fish, but not fatty fish, was associated with higher levels of serum testosterone: adjusted mean (95% CI): 5.63 (5.43, 5.82) and 6.00 (5.79, 6.20) ng/mL for the 1st and 4th quartiles of lean fish intake, respectively (P for trend = 0.01). Conclusions: Among older males, higher intake of total fish, particularly lean fish, was associated with higher serum testosterone levels. Curr Dev Nutr 20xx;x:xx. [ABSTRACT FROM AUTHOR]

The article discusses the concept of settler colonialism and its application to events in Israel and Palestine, as well as the Hawaiian Islands. It explores the historical processes by which European and U.S. empires brought nonwhite societies under their control during the eighteenth and nineteenth centuries. The author focuses on the 1893 haole revolution in Hawaii and the subsequent efforts to secure U.S. annexation, highlighting the ways in which marginalized empires like Portugal and Japan contested the situation. The article also examines the Hawaiian Republic's policies and debates regarding nonwhite citizenship and voting rights, ultimately condemning the nineteenth-century U.S. nation state and the local white residents who participated in overthrowing the Hawaiian monarchy. The author suggests the need for serious solutions to address past wrongs, but also acknowledges the complexity of replacing the nation state with a nonstate entity that values equality under the law for all residents. [Extracted from the article]

Insulin antibody syndrome (IAS), also known as Hirata disease, is a rare condition characterized by spontaneous hypoglycemic episodes unrelated to exogenous insulin exposure. It is caused by elevated serum levels of insulin autoantibodies (IAA). IAS typically occurs when a triggering factor, such as medication or viral infection, interacts with a predisposing genetic background. Diagnosing IAS is challenging due to its rarity and the presence of multiple potential causes for hyperinsulinemic hypoglycemia. The presence of Whipple triad--symptoms of hypoglycemia, low plasma glucose concentration, and relief of symptoms after raising plasma glucose--strongly supports the diagnosis of IAS. However, the detection of IAA is considered the most reliable test. Timely diagnosis can facilitate appropriate treatment and prevent unnecessary imaging studies and invasive procedures, thereby reducing costs. Currently, no definitive guidelines exist for managing IAS. Most management strategies involve supportive measures due to the high rate of spontaneous remission, with hypoglycemia often managed through dietary interventions. However, a few medications have shown benefit. Although predominantly observed in the Japanese population, IAS cases have been reported in other ethnicities, including Caucasians. This report presents a unique case of IAS in an African American male. [ABSTRACT FROM AUTHOR]

Objectives: This study elucidated the prognosis and risk factors associated with damage accrual during long-term remission maintenance therapy for patients with antineutrophil cytoplasmic antibody–associated vasculitis (AAV). Methods: We obtained data from 120 patients registered in a nationwide prospective cohort study on remission induction therapy in Japanese patients with AAV and rapidly progressive glomerulonephritis (RemIT-JAV-RPGN), who achieved remission at 24 months after treatment initiation and were followed up for additional 24 months. The primary outcome was the vasculitis damage index (VDI) score at Month 48, and the secondary outcome included risk factors associated with increased total VDI at Month 48. Results: The understudied patients comprised 52 men and 68 women aged 68 ± 13 years. Between Months 25 and 48, the patients' survival rate was 95% (114/120). End-stage renal disease developed in seven patients by Month 48, and 64 cases had increased VDI. The multivariable analysis results revealed that oral prednisolone (PSL) doses at Month 24 were associated with damage accrual between Months 24 and 48. Conclusions: VDI accrual was observed in more than half of patients with AAV during maintenance therapy, and increased VDI scores were associated with oral PSL doses 24 months after initiating remission induction therapy in Japan. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this article is to investigate the mortality rate of patients with early rheumatoid arthritis (RA) over the past 17 years. Methods: Japanese patients with early RA enrolled in the Institute of Rheumatology, Rheumatoid Arthritis cohort from 2001 to 2012 were classified into Groups A (2001–06) and B (2007–12). The standardized mortality ratio (SMR) and 5-year survival rate were calculated. Results: Groups A and B had 1609 and 1608 patients, of which 167 and 178 patients were lost during follow-up and 47 and 45 deaths were confirmed, respectively. The SMR (95% confidence intervals) for Groups A and B were 0.81 (0.59–1.08) and 0.78 (0.57–1.04), respectively, with the condition that all untraceable patients were alive. Assuming that the mortality rate of untraceable patients was twice as high as that of the general population, the SMR was 0.90 (0.68–1.19) for Group A and 0.92 (0.68–1.23) for Group B. The 5-year survival rates were 96.9% and 97.0% for Groups A and B, respectively. Conclusions: The 5-year mortality of patients with early RA has been comparable to that of the general Japanese population. The 5-year survival rate has been stable over the past 17 years. [ABSTRACT FROM AUTHOR]

Context Older adults with sarcopenic obesity are at high risk for type 2 diabetes mellitus (T2DM). However, few East Asians have sarcopenic obesity. Since many East Asians have insulin resistance (IR) without obesity, it is possible that older East Asians with sarcopenia and IR might be at high risk for T2DM. However, this relationship has not been studied. Methods This cross-sectional study included 1629 older adults aged 65 to 84 years registered in the Bunkyo Health Study. All underwent a 75-g oral glucose tolerance test and handgrip strength measurement. Participants were classified into 4 groups by possible sarcopenia (handgrip strength <28 kg in men and <18 kg in women) and IR status (triglyceride glucose [TyG] index ≥8.79 for men and ≥8.62 for women [third quartile]). Modified Poisson regression was used to estimate relative risk (RR) and 95% CIs for T2DM with adjustment for confounding factors. Results The mean age was 73.1 ± 5.4 years. T2DM was diagnosed in 212 (13.0%) participants. After adjusting for age, sex, body mass index, use of lipid-lowering medications, hypertension, and cardiovascular disease, possible sarcopenia and IR were associated with T2DM, with their coexistence showing a notably stronger association (control: RR, 1.00 [Reference]; possible sarcopenia: RR, 1.55 [95% CI, 1.04-2.30]; IR: RR, 2.69 [95% CI, 1.99-3.65]; and IR possible sarcopenia: RR, 4.76 [95% CI, 3.34-6.79]). Conclusion Possible sarcopenia based on low handgrip strength and IR based on the TyG index are independently associated with T2DM in older Japanese individuals. Their coexistence shows a particularly strong association with T2DM. [ABSTRACT FROM AUTHOR]

Background Recent studies have found that long-term changes in weight during adulthood are associated with a high risk of mortality. The objective of this study was to characterize body mass index (BMI) trajectories during adulthood and to examine the association between BMI trajectories and risk of death in the Japanese population. Methods The data were extracted from Japan Public Health Center-based Prospective Study—a population-based prospective cohort study in Japan with participants aged 40–69 years followed over 20 years. The participants were categorized into multiple BMI trajectory groups using the latent class growth model. The Cox proportional-hazards model was conducted using all-cause mortality and cause-specific mortality as outcomes and the identified BMI trajectory groups as a predictor. In total, 65 520 participants were included in the analysis. Results Six BMI trajectory groups were identified: underweight stable (Group 1), low-to-high normal (Group 2), high-to-low normal (Group 3), normal to overweight (Group 4), overweight to normal (Group 5) and normal to obese (Group 6). Our Cox models showed a higher hazard (risk) of all-cause mortality among participants in the BMI-declining groups [Group 3, adjusted hazard ratio (aHR): 1.10, 95% CI: 1.05–1.16; Group 5, aHR: 1.16, 95% CI: 1.08–1.26], underweight stable group (Group 1, aHR: 1.27, 95% CI: 1.21–1.33) and normal to obese group (Group 6, aHR: 1.22, 95% CI: 1.13–1.33) than Group 2 (low-to-high normal BMI trajectory). Conclusions Stable underweight and weight loss were associated with a high risk of mortality, both of which were uniquely observed in a Japanese population. [ABSTRACT FROM AUTHOR]

The appendicular extracellular-to-intracellular water ratio (A-E/I) is a potential marker of skeletal muscle quality, reflecting the balance of water distribution between the extracellular and intracellular compartments of the appendicular limb regions. A-E/I has been increasingly used in recent studies; however, its association with adverse outcomes remains unclear. This study investigated the potential association between A-E/I and all-cause mortality. A prospective cohort study of 8 015 middle-aged and older adults (comprised of 4 755 women, aged 45–74 years) residing in a Japanese community was conducted. The baseline assessment was performed between 2010 and 2012, and the follow-up period lasted until July 2022. A-E/I and skeletal muscle mass were measured using segmental bioelectrical impedance spectroscopy. Handgrip strength (HGS) was measured using a Smedley-type dynamometer. Lifestyle, medical history, and physical activity were assessed by questionnaire and accelerometer. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for each quartile (Q) of A-E/I were estimated using the multivariable Cox regression model. During a 10.5-year median follow-up, the mortality rates were 8.9 and 3.6 per 1 000 person-years for men (292 deaths) and women (174 deaths), respectively. A-E/I quartiles were positively associated with all-cause mortality in both sexes (men: Q1, HR: 1.0 [95% CI: reference], Q4, HR: 1.8 [1.1–2.9], p trend < .05; women, Q4, HR: 2.2 [1.3–3.8], p trend < .01). This association remained significant after further adjustment for skeletal muscle mass and HGS (p trend < .05). Our findings suggest that A-E/I serves as an early predictive marker for mortality in middle-aged and older Japanese adults. [ABSTRACT FROM AUTHOR]

Objectives: We evaluate the socioeconomic impact of treatment with biological and targeted synthetic disease–modifying antirheumatic drugs in Japanese patients with rheumatoid arthritis. Methods: We analysed data retrospectively from the prospective observational CorEvitas RA Japan Registry (March 2016–February 2020). Patients were categorised into paid workers (PWs) and home workers (HWs) and further based on drug classes. We assessed medication persistence, treatment outcomes, health care resource utilisation, and socioeconomic impact over 12 months, including direct (drugs and health care resource utilisation) and indirect (loss of productivity) costs. Results: Overall, 187 PWs and 114 HWs were identified. Over 12 months, medication persistence was high, treatment outcomes improved, and outpatient visits reduced in both groups. Following treatment initiation, direct costs increased, whereas indirect (loss of productivity) costs decreased in both groups. The unadjusted socioeconomic impact [Japanese yen (JPY)] increased across all drug classes in PWs (range: 29,700–151,700) and HWs (range: −28,700 to 83,000). Adjusted change in monthly socioeconomic impact was JPY 29,700–138,900 for PWs and JPY −28,000 to 92,800 for HWs. Conclusions: In this study of Japanese patients with rheumatoid arthritis, the socioeconomic burden increased across patient groups and drug classes. The decrease in indirect (loss of productivity) costs partially offset the increase in direct costs. [ABSTRACT FROM AUTHOR]

Methotrexate (MTX), the anchor drug in the current treatment strategy for rheumatoid arthritis (RA), was first approved for the treatment of RA in Japan in 1999 at a recommended dose of 6–8 mg/week. The approved maximum dose of MTX has been 16 mg/week since February 2011 when MTX was approved as a first-line drug in the treatment of RA. Recent evidence of MTX-polyglutamate concentration in the red blood cells of Japanese patients with RA justifies the current daily use of MTX in Japan. Additionally, after a nationwide clinical trial, a subcutaneous MTX injection formula (7.5–15 mg/week) was approved for RA treatment in September 2022. Therefore, in March 2023, a subcommittee of the Japan College of Rheumatology updated the guidance (formerly 'guidelines') for the use of MTX in Japanese patients with RA. This article, an abridged English translation summarizing the 2023 update of the Japan College of Rheumatology guidance for the use of MTX and management of patients with RA, will be helpful to both Japanese and global rheumatology communities. [ABSTRACT FROM AUTHOR]

"Ryokan: Mobilizing Hospitality in Rural Japan" is a well-researched book that explores the nature of work in Japanese culture, particularly in the context of traditional Japanese inns called ryokans. The book examines the gendered nature of work, with women typically working in the "inside" roles associated with nurturing and caregiving, while men work outside. It also highlights how working in a ryokan can serve as a last resort for Japanese women who are divorced or fleeing abusive marriages, providing them with employment and housing but also keeping them in an oppressed position. The book touches on the importance of smiling in Japanese hospitality work, although it notes that the expectation of smiling has only emerged in recent decades. Overall, "Ryokan: Mobilizing Hospitality in Rural Japan" offers valuable insights into the rhythms, constraints, and possibilities of work in Japanese culture. [Extracted from the article]

To manage the COVID-19 pandemic, the Japanese government has cooperated with multiple actors, such as experts, prefectural governments, and medical professionals, who generally attract limited attention in non-crisis times. While cooperation with such actors allows the central government to mobilize knowledge and utilize resources it does not have, such collaboration could diffuse the responsibility of COVID-19-related measures onto other actors. To empirically test this conjecture, we conducted an online survey experiment prior to the 2021 Japanese general election. It investigated whether the government's cooperation with experts, prefectural governors, medical professionals, and the International Olympic Committee obscured its responsibility in the declaration of stay-at-home advisories, securing of beds, and conducting of the 2020 Summer Olympic Games. The results deliver no evidence that informing people of the influence of any actor diffused the government's responsibility for the implementation of COVID-19-related measures. The findings of this study imply that the Japanese people held the national government accountable even during the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Background Exercise-induced vasospastic angina (VSA) is a relatively uncommon clinical scenario and is difficult to diagnose in the catheterization laboratory. Case summary A 61-year-old Japanese man presented to our hospital with complaints of angina upon exertion in the morning. Neither a 12-lead electrocardiogram nor an echocardiogram showed any abnormal findings. Invasive coronary angiogram revealed moderate stenosis in the left anterior descending coronary artery. A hand grip test was performed, during which the patient experienced chest pain, and coronary angiogram showed coronary spasm at the site of organic stenosis with delayed coronary flow. Intracoronary nitrates (300 ug) were administered, resulting in the release of coronary spasm. Conclusion The hand grip test may serve as a useful method for diagnosing exercise-induced VSA in the catheterization laboratory. [ABSTRACT FROM AUTHOR]

Objectives Life enjoyment, linked to the ability to engage pleasurably with one's environment, may be related to the risk of developing dementia. This prospective cohort study examined the association between level of life enjoyment and disabling dementia incidence among Japanese community residents. Methods The participants were Japanese, aged 45–74 years old at 5-years follow-up, in the Japan Public Health Center–based Study (N = 38,660). Psychological conditions and other confounding variables were identified through self-administered questionnaires. Incident disabling dementia registered based on the Japan's Long-Term Care Insurance system from 2006 to 2016. Hazard ratios [95% confidence intervals] were assessed using Cox proportional hazards models. Results Over a median follow-up period of 9.4 years, a total of 4,642 cases of disabling dementia developed. Level of life enjoyment was inversely associated with the risk of disabling dementia: the multivariable hazard ratios were 0.75 [0.67–0.84] (p <.001) and 0.68 [0.59–0.78] (p <.001) with medium and high life enjoyment, respectively, compared to low life enjoyment. Furthermore, the association between greater life enjoyment and low risk for disabling dementia was strongest in the subgroup with low–medium mental stress. In the high mental stress group, this association was evident for poststroke disabling dementia, but not for disabling dementia without a history of stroke. Discussion A higher level of life enjoyment was associated with a lower risk of disabling dementia, particularly in the low–medium mental stress group. This finding suggests the importance of having life enjoyment by managing mental stress for reducing risk of disabling dementia. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this article is to evaluate the effectiveness and safety of rituximab (RTX) for microscopic polyangiitis and granulomatosis with polyangiitis in Japan. Methods: In this prospective observational study, all patients with microscopic polyangiitis and granulomatosis with polyangiitis administered RTX were enrolled at each institution. During the observation period of 2 years, data up to 6 months were analysed. Cox proportional hazards analysis was used to assess the factors associated with an outcome. Results: Of the 75 patients who received RTX for remission induction therapy, 53 achieved remission by the sixth month and 50 were in remission at the sixth month. During therapy, 38 serious adverse events were observed in 24 patients, 21 serious infections in 16 patients, and 9 patients died. No factors were associated with remission; however, there was a significant difference between patients with and without remission in serious adverse events (22.6% vs. 54.5%), serious infections (11.3% vs. 45.4%), and death (1.9% vs. 36.4%). The hazard ratio (95% confidence interval) for serious infection was 3.49 (1.29-9.74) for patients aged ≥75 years and 3.53 (1.31-9.53) for pulmonary complications. Four patients maintained remission for 6 months. Conclusions: The effectiveness and safety of RTX for microscopic polyangiitis and granulomatosis with polyangiitis for up to 6 months was demonstrated. [ABSTRACT FROM AUTHOR]

Objectives: The objective of the study was to report the efficacy and safety of canakinumab treatment in Japanese patients with systemic juvenile idiopathic arthritis (sJIA) over a 48-week study period. Methods: Patients were administered canakinumab 4 mg/kg (maximum dose 300 mg) every 4 weeks, with no dose adjustments. The key outcome measures included adapted American College of Rheumatology paediatric (aACR pedi) 30/50/70/90/100 response, proportion of patients with inactive disease, and corticosteroid (CS) tapering. Results: In total, 16/19 (84.2%) patients received canakinumab for ≥96 weeks reaching end-of-study (EOS) visit without premature discontinuation. Regardless of the level of joint involvement at baseline, high aACR pedi responses were observed throughout the study; at the EOS, aACR pedi 90/100 response rates were 84.2%/63.2%, respectively. The proportion of patients who successfully tapered CSs at EOS was 66.7% (12/18), of which 10 patients were steroid-free. The most common adverse events were infections (238.3 events/100 patient-years). Serious adverse events were observed in 52.6%. The event (n=1) adjudicated as possible macrophage activation syndrome was preceded by sJIA flare. No deaths were reported. Conclusions: Canakinumab treatment resulted in a sustained treatment response in sJIA patients over 48 weeks and was associated with CS tapering in majority of patients. No new safety findings were reported. [ABSTRACT FROM AUTHOR]

Objectives: This study investigated the current practice of prophylactic treatment against Pneumocystis jirovecii pneumonia (PCP) and its effectiveness in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). Methods: This study included 319 patients registered from 53 institutions in Japan and newly diagnosed with AAV. During the 2-year observation period, we examined the frequency of usage, effectiveness and safety of prophylactic drugs against PCP. Results: Most patients received prophylactic drugs against PCP with the initiation of immunosuppressive agents, and >50% of them remained on chemoprophylaxis against PCP at 2 years after. The initial daily dose of oral prednisolone and the proportion of cyclophosphamide administration were higher in patients who received chemoprophylaxis against PCP than in those who did not. PCP occurred in nine patients (3%) and resulted in the death of four. The incidence rate of PCP in patients who received chemoprophylaxis was 1.13/100 patient-years (95% confidence interval, 0.38-2.68) and that in those who did not was 2.74 (1.04-6.02). The incidence rate ratio was 0.41 (0.11-1.53). Conclusions: The markedly low incidence of PCP may be attributed to the continuous chemoprophylaxis against PCP received by >50% of Japanese patients with AAV, although the effectiveness of chemoprophylaxis against PCP was not statistically confirmed. [ABSTRACT FROM AUTHOR]

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.5 became prevalent in July 2022 in Japan. Bivalent messenger RNA (mRNA) vaccines were approved as booster doses for individuals who received the primary series or booster dose by monovalent vaccines. We aimed to assess the effectiveness of bivalent vaccines in Japanese adults aged ≥65 years. Methods We conducted a population-based cohort study using data collected from January 2019 to February 2023 in Japan. We included individuals aged ≥65 years in a municipality who received the first or second booster dose of monovalent mRNA vaccines. We estimated the effectiveness of the second or third booster dose of bivalent mRNA vaccines during the Omicron BA.5–predominant period (July–December 2022), compared with ≥90 days after the booster dose of monovalent vaccines. We used a Cox proportional hazard regression model with vaccination status as a time-dependent covariate. Results A total of 81 977 individuals aged ≥65 years (mean [standard deviation] age, 78.3 [7.4] years; 33 487 male [40.8%]) were included in the study cohort. Among them, 57 396 were vaccinated with the second or third dose of bivalent vaccines (BA.1 or BA.4/5). The effectiveness against coronavirus disease 2019 (COVID-19) was estimated to be 57.9% (95% confidence interval, 52.7%–62.5%) for ≥14 days after the second or third bivalent booster dose, compared with 90 days after the first or second monovalent booster dose. Conclusions The study showed that the bivalent mRNA vaccines as the second and third doses would provide protection against COVID-19 among adults ≥65 years in Japan. [ABSTRACT FROM AUTHOR]