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Summary: Our human observational study showed that elevated arginine vasopressin levels by heavy exercise, not catecholamines, were associated with elevated serum tartrate-resistant acid phosphatase 5b (TRACP-5b). The increase in serum calcium was positively associated with percent changes of TRACP-5b, implying the involvement of bone resorption in the pathogenesis of exercise-induced hypercalcemia. Introduction: It remains unclear whether enhanced bone resorption explains exercise-induced hypercalcemia. An experimental study demonstrated that arginine vasopressin (AVP) stimulated osteoclast activity. Methods: We conducted a prospective observational study, enrolling 65 trained healthy male officers of the Japan Self-Defense Forces (34 and 31 in waves 1 and 2, respectively). Before and after a 5-h heavy exercise, we collected laboratory data including bone markers, symptoms, and ionized calcium (iCa; wave 2 only). As blood calcium levels change after exercise, we estimated calcium (corrected calcium) levels immediately after the exercise using the correlation between blood calcium and time from the end of exercise in another cohort. Results: Body weight decreased by 6.9% after the exercise. Corrected post-exercise serum total calcium (tCa) and iCa levels were significantly higher than pre-exercise levels, and 18% of participants showed hypercalcemia defined as corrected tCa >10.4 mg/dL or iCa >1.30 mmol/L. Serum tartrate-resistant acid phosphatase 5b (TRACP-5b), plasma three fractions of catecholamines, and AVP elevated significantly (median 14.3 pg/mL), while procollagen type 1 N-terminal propeptide and whole parathyroid hormone showed significant decreases. Corrected tCa increase showed a non-linear positive association with percent changes of TRACP-5b (%ΔTRACP-5b) even after adjustment for confounders. In addition, %ΔTRACP-5b was not associated with catecholamines, but with post-exercise AVP levels after adjustment for pre-exercise TRACP-5b. Symptoms of nausea or vomiting (observed in 20%) were positively associated with corrected post-exercise iCa after adjustment for post-exercise blood pH. Conclusion: AVP elevation may explain bone resorption and the following hypercalcemia in the setting of heavy exercise. [ABSTRACT FROM AUTHOR]

Previous phylogeographic studies of arctic-alpine plants have partly elucidated that alpine areas at the southernmost edges of their distribution have been one of the most important areas for the survival of populations through Quaternary climatic oscillations. To reveal the genetic structure of arctic-alpine plants near the southern edge of their range in East Asia, 159 samples of Diapensia lapponica subsp. obovata (Diapensiaceae) were collected from 22 populations in Japan. Based on 1,134 bp of chloroplast DNA (cpDNA), we determined 10 haplotypes. Neighbor-joining (NJ) analysis, including D. lapponica from Sweden and Schizocodon soldanelloides, revealed that all haplotypes in Japan were monophyletic. Genetic differentiation between populations of central Honshu and northern Japan was strongly supported by the NJ tree (100%), analysis of molecular variance (AMOVA, 68%), and Monmonier’s algorithm (>95%). The most ancestral haplotype rarely occurred in Japan, which implied that the extant genetic structure was not caused by genetic divergence during colonization. Thus, these results suggest that the arctic-alpine plant D. lapponica subsp. obovata survived climatic oscillations in central Honshu. This finding supports the hypothesis that high mountains in temperate regions were important for survival of arctic-alpine plants during Quaternary climatic oscillations. [ABSTRACT FROM AUTHOR]

To describe the health information preferences in middle-aged Japanese workers based on health literacy (HL) levels and presence of medications. A cross-sectional study. We performed a web-based questionnaire survey with Japanese workers aged below 60 years. HL was assessed using the total score of communicative skills (five items) and critical skills (four items) from the 14-item Health Literacy Scale. Regarding their health information preferences, participants were asked about the health information they wanted (four items), could easily understand (six items), or easily use (two items) and answered on a 4-point scale (strongly agree/agree/disagree/strongly disagree). The percentages of the affirmative responses (strongly agree or agree) were compared among tertiles based on the HL score. We obtained data from a total of 3387 volunteers, of whom 510 participants were on either antihypertensive, lipid-lowering, or antidiabetic drugs. Compared with the high HL and middle HL groups, low HL had fewer affirmative responses to most health information items. Health information items received 70% of affirmative responses even in the low HL level. They were visually shown by figures or pictures, highlighted by colors for important points, could be read in 1–2 min, and were accessed on the Internet, regardless of the presence of medications. Additionally, the explanation for mechanisms of medications or lifestyle to prevent or improve diseases showed high affinity in all HL levels, only for those on medications. This result generates a hypothesis that low HL individuals have a low interest in health information. Our data showed several possible forms of health information with high affinity based on HL levels that would help plan future population approaches. • Health literacy (HL) relates to health behaviors via access to health information. • Preferences for information based on HL levels were examined in middle-aged people. • Quickly and visually understandable information was preferred across all groups. • Mechanisms about the effects of intervention may be available for patient education. • These data are expected to support the planning of population approaches. [ABSTRACT FROM AUTHOR]

Changes in hydration status occur throughout the day affecting physiological and behavioural functions. However, little is known about the hydration status of free-living Japanese children and the seasonality of this response. We evaluated hydration status estimated by urine osmolality (Uosm) in 349 children (189 boys and 160 girls, 9.5 ± 2.6 years, range: 6-15 years) upon waking at home and during a single school day in spring (April) and summer (July). Further, we assessed the efficacy of employing self-assessment of urine colour (UC; based on an 8-point scale) by children to monitor their hydration status. Early morning Uosm was greater in the spring (903 ± 220 mOsm L -1 ; n  = 326) as compared to summer (800 ± 244 mOsm L -1 ; n  = 125) ( P  = 0.003, paired t test, n  = 104). No differences, however, were observed in Uosm during the school day ( P  = 0.417, paired t test, n  = 32). While 66% and 50% of children were considered underhydrated (Uosm ≥ 800 mOsm L -1 ) upon waking in the spring and summer periods, respectively, more children were underhydrated (∼12%) during the school day. Self-reported UC was similar between seasons as assessed in the morning and school day ( P  ≥ 0.101, paired t test), which differed from the pattern of responses observed with Uosm. We showed that a significant number of Japanese children are likely underhydrated especially in the spring period. Children do not detect seasonal changes in hydration from self-assessed UC, limiting its utility to manage hydration status in children., Competing Interests: No conflicts of interest, financial or otherwise, are declared by the authors.

Background: Evaluating the selective pressure of antimicrobials on bacteria is important for promoting antimicrobial stewardship programs (ASPs). The aim of this study was to assess the selective pressure of antimicrobials by evaluating their use (carbapenem [CBP] and CBP-sparing therapy) over time and the detection status of CBP-resistant organisms using multicenter data., Methods: Among the facilities whose data were registered in the Japan Surveillance for Infection Prevention and Healthcare Epidemiology from 2017 to 2020, those that had data on the use of CBP and CBP-sparing therapy (fluoroquinolones [FQs], cefmetazole [CMZ], piperacillin-tazobactam [PIP/TAZ], ampicillin-sulbactam [ABPC/SBT], ceftriaxone/cefotaxime [CTRX/CTX], CAZ (ceftazidime), cefepime [CFPM], and aminoglycosides [AGs]) as well as on CBP-resistant Enterobacterales (CRE) and CBP-resistant Pseudomonas aeruginosa (CRPA) detection were included. Alcohol-based hand rubbing (ABHR) usage was also analyzed. Regression analyses, including multivariable regression analysis, were performed to evaluate trends. The association of antimicrobial use density (AUD) with CRE and CRPA detection rates was evaluated., Results: In 28 facilities nationwide, CBP, FQ, CAZ, AG, and PIP/TAZ use decreased over the 3-year period, whereas the use of CMZ, ABPC/SBT, CTRX/CTX, CFPM, and ABHR as well as the rates of CRE and CRPA detection increased. The average AUD did not significantly correlate with CRE and CRPA detection rates. The multivariable regression analysis did not reveal any significant correlation between each AUD or ABHR and CRE or CRPA detection., Conclusion: CBP and ABHR use showed a decreasing and an increasing trend, respectively, while CRPA and CRE detection rates exhibited a gradual increase. The considerably low CRE and CRPA detection rates suggest that slight differences in numbers may have been observed as excessive trend changes. Further investigation is warranted to evaluate selective pressure while considering the characteristics of ASP and the mechanisms underlying resistance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Japanese basic researchers, known for their dedication to the advancement of science without any expectation of economic benefit, are conventionally regarded as virtuous professionals. However, current social demand requires researchers to adopt a venture mindset, implement their research outcomes for societal benefit, and contribute to society through business. In this paper, I highlight the importance of overcoming the "valley of death" between society and researchers to create useful intersections between science and business, aimed at application of research outcomes to the society and encouraging a lifestyle and challenges as venture scientists who can contribute to the generation of new industries.

Several new studies have been conducted on cerebrospinal fluid (CSF) dynamics. Our educational guidelines, the Model Core Curriculum for Medical University, recommend access to the best current information. However, we do not know whether or when to introduce changes to this concept.We surveyed which theory of CSF dynamics taught to students by neurosurgeons. The old theory is the bulk flow theory, and the new theory explains that CSF is produced from the choroid plexus and capillaries; CSF then pulsates and drains into the venous and lymphatic systems through newly discovered pathways.Old and new theories were taught to 64.8% and 27.0% of students, respectively. The reason for teaching the old theory was to help them understand the pathogenesis of noncommunicating hydrocephalus (77.1%), whereas the reason for teaching the new theory was to teach the latest knowledge (40.0%). Physicians who wished to teach the new theory in the near future accounted for 47.3%, which was higher than those who would teach the new theory in 2022 (27.0%), and those who still wished to teach the old theory in the near future accounted for 43.2%.An education policy on CSF dynamics will be established when we interpret ventricular enlargement and its improvement by third ventriculostomy in noncommunicating hydrocephalus based on the new theory. The distributed answers in the survey shared that it is difficult to teach about CSF dynamics and provided an opportunity to discuss these issues.

Background: The cumulative antibiogram is essential to guide empirical therapy for infectious diseases and monitor the trend of antimicrobial resistance. However, the status of antibiogram generation at medical institutions in Japan is uncertain., Methods: A web-based questionnaire survey was conducted in February 2023 on the status of antibiogram preparation among facilities participating in the Japan Surveillance for Infection Prevention and Healthcare Epidemiology (J-SIPHE), an infection control surveillance system in Japan., Results: The questionnaire collection rate was 19.6% (379/1931). Of all facilities, 47% (178/379) performed microbiological tests mainly in-house, while 53% (201/379) performed microbiological tests mainly outsourced. Of all facilities, 78% (296/379) prepared antibiograms. Of those without antibiograms, 33% (27/83) were considering the development in the future. Some facilities cited staff shortage as a barrier to preparing antibiograms. Of the 214 facilities with antibiograms that could use the J-SIPHE system to prepare antibiograms, 19% (41/214) were using the J-SIPHE system to prepare their antibiograms., Conclusions: One-quarter of the facilities that responded to the survey had not prepared antibiograms. Technical support for surveillance and awareness activity for using cumulative antibiograms might promote antibiogram preparation in Japan, which may improve antimicrobial stewardship and antimicrobial resistance measures., Competing Interests: Declaration of competing interest None declared., (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.)

The distribution and clinical impact of cell-of-origin (COO) subtypes of diffuse large B-cell lymphoma (DLBCL) outside Western countries remain unknown. Recent literature also suggests that there is an additional COO subtype associated with the germinal center dark zone (DZ) that warrants wider validation to generalize clinical relevance. Here, we assembled a cohort of Japanese patients with untreated DLBCL and determined the refined COO subtypes, which include the DZ signature (DZsig), using the NanoString DLBCL90 assay. To compare the distribution and clinical characteristics of the molecular subtypes, we used a data set from the cohort of British Columbia Cancer (BCC) (n = 804). Through the 1050 patient samples on which DLBCL90 assay was successfully performed in our cohort, 35%, 45%, and 6% of patients were identified to have germinal center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, and DZsig-positive (DZsigpos) DLBCL, respectively, with the highest prevalence of ABC-DLBCL, differing significantly from the BCC result (P < .001). GCB-DLBCL, ABC-DLBCL, and DZsigpos-DLBCL were associated with 2-year overall survival rates of 88%, 75%, and 66%, respectively (P < .0001), with patients with DZsigpos-DLBCL having the poorest prognosis. In contrast, GCB-DLBCL without DZsig showed excellent outcomes after rituximab-containing immunochemotherapy. DZsigpos-DLBCL was associated with the significant enrichment of tumors with CD10 expression, concurrent MYC/BCL2 expression, and depletion of microenvironmental components (all, P < .05). These results provide evidence of the distinct distribution of clinically relevant molecular subtypes in Japanese DLBCL and that refined COO, as measured by the DLBCL90 assay, is a robust prognostic biomarker that is consistent across geographical areas., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Tisagenlecleucel, an autologous CD19-directed T-cell immunotherapy, can induce a durable response in adult patients with relapsed/refractory (r/r) B-cell lymphoma., Methods: To elucidate the outcome of chimeric antigen receptor (CAR) T-cell therapy in Japanese, we retrospectively analyzed the outcomes of 89 patients who received tisagenlecleucel for r/r diffuse large B-cell lymphoma (n = 71) or transformed follicular lymphoma (n = 18)., Results: With a median follow-up of 6.6-months, 65 (73.0%) patients achieved a clinical response. The overall survival (OS) and event-free survival (EFS) rates at 12 months were 67.0% and 46.3%, respectively. Overall, 80 patients (89.9%) had cytokine release syndrome (CRS), and 6 patients (6.7%) had a grade ≥ 3 event. ICANS occurred in 5 patients (5.6%); only 1 patient had grade 4 ICANS. Representative infectious events of any grade were cytomegalovirus viremia, bacteremia and sepsis. The most common other adverse events were ALT elevation, AST elevation, diarrhea, edema, and creatinine elevation. No treatment-related mortality was observed. A Sub-analysis showed that a high metabolic tumor volume (MTV; ≥ 80 ml) and stable disease /progressive disease before tisagenlecleucel infusion were both significantly associated with a poor EFS and OS in a multivariate analysis (P < 0.05). Notably, the combination of these 2 factors efficiently stratified the prognosis of these patients (HR 6.87 [95% CI 2.4-19.65; P < 0.05] into a high-risk group)., Conclusion: We report the first real-world data on tisagenlecleucel for r/r B-cell lymphoma in Japan. Tisagenlecleucel is feasible and effective, even in late line treatment. In addition, our results support a new algorithm for predicting the outcomes of tisagenlecleucel., (© 2023. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

While patients receiving dialysis therapy in the United States are more likely to develop cardiovascular disease (CVD) than those in Japan, direct comparisons of patients with predialysis chronic kidney disease (CKD) are rare. To study this, we compared various outcomes in patients with predialysis CKD using data from the Chronic Renal Insufficiency Cohort (CRIC) and CKD Japan Cohort (CKD-JAC) studies and determined mediators of any differences. Candidate mediators included left ventricular (LV) indices assessed by echocardiography. Among 3125 CRIC and 1097 CKD-JAC participants, the mean LV mass index (LVMI) and ejection fraction (EF) were 55.7 and 46.6 g/m 2 and 54% and 65%, respectively (both significant). The difference in body mass index (32 and 24 kg/m 2 , respectively) largely accounted for the differences in LVMI and C-reactive protein levels across cohorts. Low EF and high LVMI were significantly associated with subsequent CVD in both cohorts. During a median follow-up of five years, CRIC participants were at higher risk for CVD (adjusted hazard ratio [95% confidence interval]: 3.66 [2.74-4.89]) and death (4.69 [3.05-7.19]). A three-fold higher C-reactive protein concentration and higher phosphate levels in the United States cohort were moderately strong mediators of the differences in CVD. However, echocardiographic parameters were stronger mediators than these laboratory measures. LVMI, EF and their combination mediated the observed difference in CVD (27%, 50%, and 57%, respectively) and congestive heart failure (33%, 62%, and 70%, respectively). Thus, higher LV mass and lower EF, even in the normal range, were found to be predictive of CVD in CKD., (Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Axicabtagene ciloleucel (axi-cel) is an autologous, CD19-targeting chimeric antigen receptor T‑cell therapy. We recently reported the 3-month follow-up results of a phase 2, multicenter, open‑label, single-arm study of axi-cel in Japanese patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) (JapicCTI-183914). Here, we present 1-year efficacy and safety data and biomarker analysis data regarding mechanisms of resistance to axi-cel. Primary and secondary endpoints included investigator-assessed objective response rate (ORR), serious adverse events, and treatment-emergent adverse events. Axi-cel pharmacokinetics were also examined. Biomarker analysis was performed by cytokine measurement, immunohistochemistry, RNA sequencing, and whole-exome sequencing. At a median follow-up of 13.4 months, ORR was 86.7% (13/15 patients), and the complete response (CR) rate improved to 53.3% (8/15 patients) due to response conversion. Seven patients experienced disease progression, and one achieved CR after re-treatment with axi-cel. No new safety concerns were detected. Plausible resistance mechanisms to axi-cel varied among patients but included CD19 downregulation, programmed death-ligand 1 upregulation, and increased macrophage and angiogenesis signatures. The 1-year efficacy and safety of axi-cel were confirmed in Japanese patients with R/R LBCL. Resistance to treatment may involve multiple factors, including target antigen loss and an unfavorable tumor environment.Clinical trial registration: Japan Clinical Trials Information; JapicCTI-183914., (© 2022. Japanese Society of Hematology.)

Background: The Kidney Disease: Improving Global Outcomes guidelines advocate the cause-glomerular filtration rate (GFR)-albuminuria (CGA) classification for predicting outcomes. However, there is a dearth of data supporting the use of the cause of chronic kidney disease. This study aimed to address how to incorporate a prior biopsy-proven diagnosis in outcome prediction., Methods: We examined the association of biopsy-proven kidney disease diagnoses with kidney failure with replacement therapy (KFRT) and all-cause death before KFRT in patients with various biopsy-proven diagnoses (n = 778, analysis A) and patients with diabetes mellitus labeled with biopsy-proven diabetic nephropathy (DN), other biopsy-proven diseases and no biopsy (n = 1117, analysis B)., Results: In analysis A, adding biopsy-proven diagnoses to the GFR-albuminuria (GA) classification improved the prediction of 8-year incidence of KFRT and all-cause death significantly regarding integrated discrimination improvement and net reclassification index. Fine-Gray (FG) models with KFRT as a competing event showed significantly higher subdistribution hazard ratios (SHRs) for all-cause death in nephrosclerosis {4.12 [95% confidence interval (CI) 1.11-15.2)], focal segmental glomerulosclerosis [3.77 (95% CI 1.09-13.1)]} and membranous nephropathy (MN) [2.91 (95% CI 1.02-8.30)] than in immunoglobulin A nephropathy (IgAN), while the Cox model failed to show significant associations. Crescentic glomerulonephritis had the highest risk of all-cause death [SHR 5.90 (95% CI 2.05-17.0)]. MN had a significantly lower risk of KFRT than IgAN [SHR 0.45 (95% CI 0.24-0.84)]. In analysis B, other biopsy-proven diseases had a lower risk of KFRT than biopsy-proven DN in the FG model, with death as a competing event [SHR 0.62 (95% CI 0.39-0.97)]., Conclusions: The CGA classification is of greater value in predicting outcomes than the GA classification., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Introduction: Vascular access usage varies widely across countries. Previous studies have evaluated the association of clinical outcomes with the three types of vascular access, namely, arteriovenous fistula (AVF), arteriovenous graft (AVG), and tunneled and cuffed central venous catheter (TC-CVC). However, little is known regarding the association between arterial superficialization (AS) and the mortality of patients., Methods: A nationwide cohort study was conducted using data from the Japanese Society for Dialysis Therapy Renal Data Registry (2006-2007). We included patients aged ≥20 years undergoing hemodialysis with a dialysis vintage ≥6 months. The exposures of interest were the four types of vascular access: AVF, AVG, AS, and TC-CVC. Cox proportional hazard models were used to evaluate the associations of vascular access types with 1-year all-cause and cause-specific mortality., Results: A total of 183,490 maintenance hemodialysis patients were included: 90.7% with AVF, 6.9% with AVG, 2.0% with AS, and 0.4% with TC-CVC. During the 1-year follow-up period, 13,798 patients died. Compared to patients with AVF, those with AVG, AS, and TC-CVC had a significantly higher risk of all-cause mortality after adjustment for confounding factors: adjusted hazard ratios (95% confidence intervals) - 1.30 (1.20-1.41), 1.56 (1.39-1.76), and 2.15 (1.77-2.61), respectively. Similar results were obtained for infection-related and cardiovascular mortality., Conclusion: This nationwide cohort study conducted in Japan suggested that AVF usage may have the lowest risk of all-cause mortality. The study also suggested that the usage of AS may be associated with better survival rates compared to those of TC-CVC in patients who are not suitable for AVF or AVG., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

During the COVID-19 pandemic, donor grafts are frequently cryopreserved to ensure that a graft is available before starting a conditioning regimen. However, there have been conflicting reports on the effect of cryopreservation on transplantation outcomes. Also, the impact of cryopreservation may differ in bone marrow (BM) transplantation (BMT) and peripheral blood stem cell (PBSC) transplantation (PBSCT). In this retrospective study, we analyzed the clinical data of both cryopreserved unrelated BMTs (n = 235) and PBSCTs (n = 118) and compared these with data from a large control cohort without cryopreservation including 4133 BMTs and 720 PBSCTs. Among the patients with cryopreserved grafts, 10 BMT recipients (4.3%) and 3 PBSCT recipients (2.5%) did not achieve neutrophil engraftment after transplantation, including 4 of the former and all 3 of the latter who died early before engraftment. In a multivariate analysis, cryopreservation was not associated with neutrophil engraftment in BMT but significantly delayed neutrophil engraftment in PBSCT (hazard ratio [HR], .82; 95% confidence interval [CI], .69 to .97; P = .023). There was an interaction with borderline significance between cryopreservation and the stem cell source (P = .067). Platelet engraftment was delayed by cryopreservation after both BMT and PBSCT. Only 2 cryopreserved grafts (<1%) were unused during the study period. The cryopreservation of unrelated donor BM and PBSC grafts is associated with a slight delay in neutrophil and platelet engraftment but an acceptable rate of graft failure. PBSC grafts may be more sensitive to cryopreservation than BM grafts. Cryopreservation is a reasonable option during COVID-19 pandemic, provided that the apheresis and transplantation centers are adept at cryopreservation. © 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc., Competing Interests: Conflict of interest statement There are no conflicts of interest to report., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

In recent years, local governments in Japan have established a public financial support system for fertility preservation in pediatric, adolescent, and young adult cancer patients. Fertility preservation has become popular for patients with cancers included in the gonadal toxicity risk classification of the 2017 edition of the Guideline for Fertility Preservation in Children, Adolescents and Young Adult Cancer Patients from the Japan Society of Clinical Oncology. However, patients with cancer and non-cancer diseases that are not included in the Guideline's gonadal toxicity risk classification also often receive treatment that may affect fertility, but they are often denied the opportunity of fertility preservation because no public financial support is available for diseases not listed in the Guideline. The national research project proposes including these diseases in the indications and treatment for fertility preservation. Therefore, we cooperated with the Japan Society for Fertility Preservation and the Ministry of Health, Labour and Welfare research group to solicit opinions from experts in each therapeutic area and reviewed the literature and overseas guidelines. This paper summarizes the findings of the project. We believe that it will be an important source of information for clinicians treating patients who need fertility preservation but note that the appropriateness of fertility preservation for the disorders listed in this report needs to be continuously reviewed as medical care advances., (© 2021. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

The Japan Society of Clinical Oncology (JSCO) published the "JSCO Clinical Practice Guidelines 2017 for Fertility Preservation in Childhood, Adolescent, and Young Adult Cancer Patients" in 2017. This was the first guideline in cancer reproductive medicine in Japan. In the field of cancer reproductive medicine, close cooperation between an oncologist and a physician for reproductive medicine is important from before treatment initiation until long after treatment. The guideline takes into consideration disease specificity and provides opinions from the perspective of oncologists and specialists in reproductive medicine that are in line with the current state of the Japanese medical system. It is intended to serve as a reference for medical staff in both fields regarding the availability of fertility preservation therapy before the start of cancer treatment. Appropriate use of this guideline makes it easier to determine whether fertility preservation therapy is feasible and, ultimately, to improve survivorship in childhood, adolescent, and young adult cancer patients. In this article (Part 2), we describe details by organ/system and also for pediatric cancer., (© 2021. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

In 2017, the Japan Society of Clinical Oncology (JSCO) published the JSCO Clinical Practice Guidelines 2017 for Fertility Preservation in Childhood, Adolescent, and Young Adult Cancer Patients. These were the first Japanese guidelines to address issues of oncofertility. In this field of medicine, sustained close cooperation between oncologists and reproductive specialists is essential from the diagnosis of cancer until many years after completion of cancer treatment. These JSCO guidelines were intended to guide multidisciplinary medical staff in considering the availability of fertility preservation options and to help them decide whether to provide fertility preservation to childhood, adolescent, and young adult cancer patients before treatment starts, with the ultimate goal of improving patient survivorship. The guidelines are presented as Parts 1 and 2. This article (Part 1) summarizes the goals of the guidelines and the methods used to develop them and provides an overview of fertility preservation across all oncology areas. It includes general remarks on the basic concepts surrounding fertility preservation and explanations of the impacts of cancer treatment on gonadal function by sex and treatment modality and of the options for protecting/preserving gonadal function and makes recommendations based on 4 clinical questions. Part 2 of these guidelines provides specific recommendations on fertility preservation in 8 types of cancer (gynecologic, breast, urologic, pediatric, hematologic, bone and soft tissue, brain, and digestive)., (© 2021. The Author(s).)

Introduction: Recent studies have suggested a higher incidence of cardiovascular disease (CVD) among patients with chronic kidney disease (CKD) in the USA than in Japan. Hyperphosphatemia, a possible risk for CVD, may explain this difference; however, international differences in phosphate parameters in CKD have not been well elaborated., Methods: By using the baseline data from the USA and the Japanese nation-wide, multicenter, CKD cohort studies; the Chronic Renal Insufficiency Cohort Study (CRIC, N = 3,870) and the Chronic Kidney Disease-Japan Cohort Study (CKD-JAC, N = 2,632), we harmonized the measures and compared clinical parameters regarding phosphate metabolism or serum phosphate, fibroblast growth factor-23 (FGF23), and parathyroid hormone (PTH), in the cross-sectional model., Results: Multivariable linear regression analyses revealed that serum phosphate levels were significantly higher in CRIC across all levels of estimated glomerular filtration rate (eGFR) with the greatest difference being observed at lower levels of eGFR. Serum FGF23 and 25-hydroxy vitamin D (25OHD) levels were higher in CRIC, while PTH levels were higher in CKD-JAC at all levels of eGFR. Adjustments for demographics, 25OHD, medications, dietary intake or urinary excretion of phosphate, PTH, and FGF23 did not eliminate the difference in serum phosphate levels between the cohorts (0.43, 0.46, 0.54, 0.64, and 0.78 mg/dL higher in CRIC within eGFR strata of >50, 41-50, 31-40, 21-30, and ≤20 mL/min/1.73 m2, respectively). These findings were consistent when only Asian CRIC participants (N = 105) were included in the analysis., Conclusion: Serum phosphate levels in CRIC were significantly higher than those of CKD-JAC across all stages of CKD, which may shed light on the international variations in phosphate parameters and thus in cardiovascular risk among CKD patients. The key mechanisms for the substantial differences in phosphate parameters need to be elucidated., (© 2022 S. Karger AG, Basel.)

Background: Axicabtagene ciloleucel (axi-cel) is an autologous chimeric antigen receptor T-cell based anti-CD19 therapy. The ZUMA-1 study, multicenter, single-arm, registrational Phase 1/2 study of axi-cel demonstrated high objective response rate in patients with relapsed/refractory large B-cell lymphoma. Here, we present the results of the bridging study to evaluate the efficacy and safety of axi-cel in Japanese patients (JapicCTI-183914)., Methods: This study was the phase 2, multicenter, open-label, single-arm trial. Following leukapheresis, axi-cel manufacturing and lymphodepleting chemotherapy, patients received a single infusion of axi-cel (2.0 × 10 6 cells/kg). Bridging therapy between leukapheresis and conditioning chemotherapy was not allowed. The primary endpoint was objective response rate., Results: Among 17 enrolled patients, 16 received axi-cel infusion. In the 15 efficacy evaluable patients, objective response rate was 86.7% (95% confidence interval: 59.5-98.3%); complete response/partial response were observed in 4 (26.7%)/9 (60.0%) patients, respectively. No dose-limiting toxicities were observed. Grade ≥ 3 treatment-emergent adverse events occurred in 16 (100%) patients-most commonly neutropenia (81.3%), lymphopenia (81.3%) and thrombocytopenia (62.5%). Cytokine release syndrome occurred in 13 (81.3%) patients (12 cases of grade 1 or 2 and 1 case of grade 4). No neurologic events occurred. Two patients died due to disease progression, but no treatment-related death was observed by the data-cutoff date (October 23, 2019)., Conclusion: The efficacy and safety of axi-cel was confirmed in Japanese patients with relapsed/refractory large B-cell lymphoma who have otherwise limited treatment options., Trial Registration: JapicCTI-183914., (© 2021. The Author(s).)

Background: There is limited understanding of the characteristics of patients with coronavirus disease 2019 (COVID-19) requiring hospitalization in Japan., Methods: This study included 2638 cases enrolled from 227 healthcare facilities that participated in the COVID-19 Registry Japan (COVIREGI-JP). The inclusion criteria for enrollment of a case in COVIREGI-JP are both (1) a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test and (2) inpatient treatment at a healthcare facility., Results: The median age of hospitalized patients with COVID-19 was 56 years (interquartile range [IQR], 40-71 years). More than half of cases were male (58.9%, 1542/2619). Nearly 60% of the cases had close contact to confirmed or suspected cases of COVID-19. The median duration of symptoms before admission was 7 days (IQR, 4-10 days). The most common comorbidities were hypertension (15%, 396/2638) and diabetes without complications (14.2%, 374/2638). The number of nonsevere cases (68.2%, n = 1798) was twice the number of severe cases (31.8%, n = 840) at admission. The respiratory support during hospitalization includes those who received no oxygen support (61.6%, 1623/2636) followed by those who received supplemental oxygen (29.9%, 788/2636) and invasive mechanical ventilation/extracorporeal membrane oxygenation (8.5%, 225/2636). Overall, 66.9% (1762/2634) of patients were discharged home, while 7.5% (197/2634) died., Conclusions: We identified the clinical epidemiological features of COVID-19 in hospitalized patients in Japan. When compared with existing inpatient studies in other countries, these results demonstrated fewer comorbidities and a trend towards lower mortality., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

During the COVID-19 pandemic, donor hematopoietic stem cell grafts are frequently cryopreserved to ensure the availability of graft before starting a conditioning regimen. However, the safety of cryopreservation has been controversial in unrelated hematopoietic stem cell transplantation (HSCT), especially for bone marrow (BM) grafts. In addition, in unrelated HSCT, the effect of the time from harvest to cryopreservation of donor grafts required for the transportation of donor graft has not been fully clarified. In this study, we retrospectively analyzed the first 112 patients with available data who underwent cryopreserved unrelated blood and marrow transplantation through the Japan Marrow Donor Program during the COVID-19 pandemic. There were 112 patients, including 83 who received BM grafts and 29 who received peripheral blood stem cell (PBSC) grafts. The median time from stem cell harvest to cryopreservation was 9.9 hours (range, 2.6 to 44.0 hours), and the median time from cryopreservation to infusion was 231.2 hours. The incidence of neutrophil engraftment at day 28 after HSCT was 91.1%, and among 109 patients (excluding 3 patients with early death), all but 1 patient achieved neutrophil engraftment within 60 days after HSCT. The time to neutrophil engraftment and time to platelet engraftment were shorter in PBSC transplantation compared with BM transplantation (BMT), but the differences were not statistically significant (P = .064 and .18). Multivariate analysis among BM recipients revealed that a higher number of frozen nucleated cells and the absence of HLA mismatch were associated with faster neutrophil engraftment. The time to neutrophil engraftment after unrelated cryopreserved BMT was not different from that after unrelated BMT without cryopreservation. Our findings suggest that unrelated donor BM and PBSC grafts can be safely cryopreserved even after transit from the harvest center to the transplantation center. In the current COVID-19 pandemic, cryopreservation can be considered as an option while balancing the risks and benefits of the procedure., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Cardiovascular disease (CVD) is a major complication in individuals with chronic kidney disease (CKD). In Japan, the incidence of CVD among persons with CKD is lower than that in the United States. Although various classes of antihypertensive agents are prescribed to prevent CVD, the proportion varies between the United States and Japan. Until now, few studies have compared clinical practices and CVD prevalence among patients with CKD in the United States vs. Japan. In this study, we performed a cross-sectional comparison of the prevalence of CVD and the prescription of β-blockers at study entry to the Chronic Kidney Disease Japan Cohort (CKD-JAC) Study and the Chronic Renal Insufficiency Cohort (CRIC) Study. The mean patient age was 58.2 and 60.3 years, the mean estimated glomerular filtration rate (eGFR) was 42.8 and 28.9 (mL/min/1.73 m 2 ), and the median urinary albumin:creatinine ratio was 51.9 and 485.9 (mg/g) among 3939 participants in the CRIC Study and 2966 participants in the CKD-JAC Study, respectively. The prevalence of any CVD according to a self-report (CRIC Study) was 33%, while that according to a medical chart review (CKD-JAC Study) was 24%. These findings were consistent across eGFR levels. Prescriptions for β-blockers differed between the CRIC and CKD-JAC Studies (49% and 20%, respectively). The odds ratios for the association of any history of CVD and β-blocker prescription were 3.0 [2.6-3.5] in the CRIC Study and 2.0 [1.6-2.5] in the CKD-JAC Study (P < 0.001 for the interaction). In conclusion, the prevalence of CVD and treatment with β-blockers were higher in the CRIC Study across eGFR levels.

Background: Quality of life can be influenced by oral mucositis (OM), and it is necessary to implement OM management strategies before the initiation of radiotherapy (RT) in patients with head and neck cancer (HNC)., Aims: To examine the association between the cumulative radiation dose and the incidence of severe OM in HNC patients receiving RT., Methods and Results: A retrospective observational cohort study was conducted in a Showa University Fujigaoka Hospital, in Japan. We retrospectively analyzed 94 patients with HNC who developed OM during RT. We defined OM as a more than grade 2 OM. The cumulative incidence of OM curves of the two categories was estimated using the Kaplan-Meier method and compared using the log-rank test. We estimated the hazard ratio (HR) for OM after the adjustment of factors for covariates using Cox's regression analysis. Patients with smoking history had a significantly later development of OM than those with no smoking history (20 Gy-incidence OM 68.7% vs 39.7%, P = .003). In contrast, patients undergoing concurrent chemotherapy had an earlier development of OM than those undergoing RT alone (20 Gy-incidence OM 24.2% vs 55.7%, P < .001). Multivariate analysis revealed that no smoking history and concurrent chemotherapy were independent predictive factors, with a HR of 0.526 (P = .025) and 2.690 (P < .001), respectively., Conclusion: We demonstrated that no smoking history and concurrent chemotherapy may be predictive of OM in HNC patients., (© 2020 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

To overcome the delayed or failed engraftment after unrelated cord blood transplantation (CBT), we conducted a multicenter phase II study of intrabone single-unit CBT without antithymocyte globulin (ATG) for adult patients with hematological malignancies (UMIN-CTR, UMIN000020997). Sixty-four patients received an intrabone injection of unwashed (n = 61) or washed (n = 3) cord blood after local anesthesia. All injection-related adverse events were mild and resolved spontaneously. Sixty-two patients were evaluable for the efficacy of intrabone CBT of serological HLA-A, -B, and -DR ≥ 4/6 matched cord blood with a median number of 2.57 × 10 7 /kg cryopreserved total nucleated cells. The probability of survival with neutrophil engraftment on day 28 was 77.4% (95% confidence interval, 67.0-85.8%), which exceeded the threshold value. The cumulative incidences of neutrophils ≥ 0.5 × 10 9 /L on day 60 was 80.6% (68.2-88.6%), with a median time to recovery of 21 days after transplantation. The cumulative incidences of platelets ≥ 20 × 10 9 /L and platelets ≥ 50 × 10 9 /L on day 100 were 75.8% (62.6-84.9%) and 72.6% (59.4-82.1%), respectively, with median time to platelets ≥ 20 × 10 9 /L and platelets ≥ 50 × 10 9 /L of 38 and 45 days after transplantation, respectively. The cumulative incidences of grade II-IV and III-IV acute graft-versus-host disease were 29.0% and 6.5%, respectively. All responded to steroid therapy, and secondary treatments were not required. The present study suggests the efficacy of intrabone single-unit CBT without ATG in terms of early engraftment and controllable acute graft-versus-host disease.

Background: Worldwide, there has been a growing interest in oncofertility issues. In 2017, the Japanese Society of Clinical Oncology published clinical practice guidelines for fertility preservation (FP) in cancer patients. We conducted a questionnaire survey to explore the FP practices among hematologists before the publication of this guideline., Methods: We sent 427 designated cancer hospitals in Japan a questionnaire about FP treatment for patients with hematological malignancies between January and December 2014., Results: Of these, 137 institutions responded, and 81 (19.0%) were included in the analysis. A total of 324 female and 441 male patients, aged < 40 years, were treated. The percentage of patients informed about FP was higher in patients treated with hematopoietic cell transplant than those without. Female patients were less likely to be informed about FP than male patients. FP was performed in a total of 27 female patients: 20 oocyte cryopreservation, 2 embryo cryopreservation, 3 ovarian tissue cryopreservation, and 2 ovarian shielding during total body irradiation. Sperm cryopreservation was performed in 115 male patients., Conclusions: Our findings indicate the reality of fertility preservation in 2014, before the guideline were issued. Further studies are warranted to investigate the improvement in fertility preservation since the guidelines were issued.

Breast involvement of Adult T-cell leukemia-lymphoma (ATLL) is extremely rare, and the data on the characteristics are limited. We herein describe a 49-year-old woman who presented with skin involvement of ATLL. Positron emission tomography/computed tomography showed bilateral breast lesions. Although the patient once achieved a complete metabolic response, a relapse of her ATLL occurred. The patient received subsequent allogeneic hematopoietic stem cell transplantation (HSCT). To our knowledge, only four cases of ATLL with breast involvement have previously been reported, and the prognoses have generally been poor. Breast lesions of ATLL have aggressive features, and intensive systemic chemotherapy and HSCT are required to improve survival.

The prognosis of systemic amyloid light chain (AL) amyloidosis is generally poor, hence requiring chemotherapy or hematopoietic stem cell transplantation, while the prognosis of localized AL amyloidosis without an abnormal monoclonal immunoglobulin light chain is good. Localized AL amyloidosis has been previously reported to be observed in pulmonary, urinary tract, gastrointestinal, oropharyngeal, and laryngeal sites. However, only a few cases of localized lymph node AL amyloidosis have so far been reported. We herein present a case of localized lymph node AL amyloidosis that could possibly be misdiagnosed as systematic AL amyloidosis.

Background: Although thrombocytopenia, anasarca, fever, reticulin fibrosis and organomegaly (TAFRO) syndrome was first described as a variant of idiopathic multicentric Castleman disease (CD), patients with TAFRO syndrome demonstrate more aggressive clinical features. Because these patients may present with fever of unknown origin, general physicians need to recognise its characteristic laboratory data and clinical features during hospitalisation., Aims: to describe the features, symptoms and characteristics of TAFRO syndrome and to compare them to those of idiopathic CD., Methods: This was a retrospective study of patients with histopathologically confirmed TAFRO syndrome and idiopathic multicentric CD who were diagnosed and managed between April 2012 and June 2018 in a Japanese university hospital's General Medicine Department., Results: We found that the hospitalisations were significantly longer among patients with TAFRO syndrome compared to those with idiopathic CD (median: 87 days; range: 34-236 days vs median: 30 days; range: 13-59 days; P < 0.01). Patients with TAFRO syndrome were more likely to present with fever, abdominal pain and elevated inflammatory markers and be misdiagnosed with an infectious disease during the first hospital visit. Approximately 40% of patients with TAFRO syndrome had no radiographically enlarged lymph nodes., Conclusions: TAFRO syndrome may present as an infectious disease with an aggressive clinical course. Our study highlights the importance of giving significance to chief complaints and laboratory data. Physicians need to recognise the clinical and laboratory features of this disease to avoid missing this potentially fatal disorder., (© 2019 Royal Australasian College of Physicians.)

High-dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) has been shown to improve the prognosis of patients with central nervous system (CNS) lymphoma. We queried the Japan Society for Hematopoietic Cell Transplantation Registry for 2006 to 2015 to analyze the outcomes of 102 patients with primary CNS lymphoma (PCNSL) who underwent first HDT/ASCT. The median patient age was 54 years (range, 20 to 74 years), and 65 patients were treated in an upfront setting. With a median duration of follow-up of 44 months, the 5-year overall survival (OS) and progession-free survival (PFS) were 54.9% and 38.4%, respectively. There were no significant differences in OS and PFS between upfront and salvage HDT/ASCT. Because thiotepa, a key agent in HDT/ASCT for PCNSL, has been unavailable since 2011 in Japan, the HDT regimens used were not uniform. Thiotepa-containing HDT was received by 16 out of 32 patients before 2010, but by only 2 of 70 patients after 2011. Thiotepa-containing HDT was associated with better PFS (P = .019), lower relapse (P = .042), and a trend toward a survival benefit. In multivariate analysis, noncomplete remission at HDT/ASCT was an independent predictor for OS (hazard ratio [HR], 2.40; 95% confidence interval [CI], 1.25 to 4.58; P = .008) and thiotepa-containing HDT remained significant for PFS (HR, .42; 95% CI, .19 to .95; P = .038). These results confirm the activity of thiotepa-containing regimens., (Copyright © 2019 American Society for Blood and Marrow Transplantation. All rights reserved.)

Due to the population aging and improved prognosis of hemodialysis patients, fracture has become one of important clinical outcomes that often degrade patients' quality of life and indirectly increase mortality. As Japanese hemodialysis patients have five to six-fold higher incidence of hip fracture than general population, risk factors and prophylactic interventions for fracture should be investigated. Being one of the eldest countries in the world, Japan should conduct more researches and publish more evidences in this field. The Japanese Renal Data Registry has been playing an important role in generating new evidences on non-classical risk factors of hip fracture that are specific to hemodialysis patients. Yet, the preventative intervention has not been established even in the newly-updated KDIGO CKD-MBD guideline. Notable finding is that the incidence rate of hip fracture has been decreased in Japanese females despite aging. The investigation of the reason may shed light on undetermined therapeutic approaches to hip fracture in hemodialysis patients.

Randomized controlled trials (RCTs) are essential for evidence-based medicine; however, cohort studies and registries provide an important information about risk factors and, hence, shed light on the target of laboratory parameters. The uniqueness of the current Japanese CKD-MBD guidelines lies in the lower target range of intact parathyroid hormone levels than those used in other countries, which is based on analyses of the nationwide Japan Renal Data Registry. Cohort studies were also useful in exploring risk factors of renal outcome in predialysis patients. It was revealed that low vitamin D status (very prevalent in Japan) and high fibroblast growth factor 23 (FGF23) levels predict poor renal outcome. The reported association of FGF23 levels with left ventricular hypertrophy (LVH) and heart failure observed in cohort studies may support the idea of adding the 4th component of CKD-MBD, namely, "LVH" to the three original components. When it is not feasible to conduct RCTs regarding intervention, we have no choice but to rely on observational studies with sophisticated analysis methods, such as facility-level analysis and marginal structural model minimizing indication bias. Observational studies conducted in Japan revealed that the side effects of medications for CKD-MBD, resultant compliance, and effective doses in terms of hard outcome in Japanese patients were found to be different from those in other countries. For example, the MBD-5D study confirmed the benefit of cinacalcet in terms of mortality despite its median dose of only 25 mg/day. These data are very helpful for future guidelines specific to Japanese patients with CKD.

A nationwide statistical survey of 4279 dialysis facilities was conducted at the end of 2012, among which 4238 responded (99.0%). The number of new dialysis patients was 38055 in 2012. Since 2008, the number of new dialysis patients has remained almost the same without any marked increase or decrease. The number of dialysis patients who died in 2012 was 30710; a slight decrease from 2011 (30743). The dialysis patient population has been growing every year in Japan; it was 310007 at the end of 2012, which exceeded 310000 for the first time. The number of dialysis patients per million at the end of 2012 was 2431.2. The crude death rate of dialysis patients in 2012 was 10.0%, a slight decrease from that in 2011 (10.2%). The mean age of new dialysis patients was 68.5 years and the mean age of the entire dialysis patient population was 66.9 years. The most common primary cause of renal failure among new dialysis patients was diabetic nephropathy (44.2%). The actual number of new dialysis patients with diabetic nephropathy has been approximately 16000 for the last few years. Diabetic nephropathy was also the most common primary disease among the entire dialysis patient population (37.1%), followed by chronic glomerulonephritis (33.6%). The percentage of dialysis patients with diabetic nephropathy has been continuously increasing, whereas not only the percentage but also the actual number of dialysis patients with chronic glomerulonephritis has decreased. The number of patients who underwent hemodiafiltration (HDF) at the end of 2012 was 21725, a marked increase from that in 2011 (14115). In particular, the number of patients who underwent on-line HDF increased threefold from 4890 in 2011 to 14069 in 2012. From the results of the facility survey, the number of patients who underwent peritoneal dialysis (PD) was 9514 and that of patients who did not undergo PD despite having a PD catheter in the abdominal cavity was 347. From the results of the patient survey, among the PD patients, 1932 also underwent another dialysis method using extracorporeal circulation, such as hemodialysis (HD) and HDF. The number of patients who underwent HD at home in 2012 was 393, a marked increase from that in 2011 (327)., (© 2014 Japanese Society for Dialysis Therapy. Reproduced with permission.)

Purpose: Although many studies have described various features of neuroimaging tests associated with intracranial hypotension, few have examined their validity and reliability. We evaluated the association between CSF leaks detected by radionuclide cisternography and abnormal MRI findings in the accurate diagnosis of intracranial hypotension., Patients/methods: We retrospectively assessed 250 patients who were suspected of intracranial hypotension and underwent subsequent radionuclide cisternography. We obtained 159 sagittal and 153 coronal T2-weighted MRI images and 101 gadolinium-enhanced T1-weighted MRI images. We assessed the CSF leaks in relation to a sagging brain, the maximum subdural space in sagittal and coronal images, and dural enhancement., Results: Overall, 186 (74%) patients showed CSF leaks on radionuclide cisternography. A sagging brain was observed in 21 (13%) of the 159 patients with sagittal MRIs. A sagging brain was not associated with CSF leaks (14% vs. 10%; p=0.49). Compared to patients without CSF leaks, those with CSF leaks tended to have a larger maximum subdural space in both the sagittal (3.7 vs. 4.1mm) and coronal (2.5 vs. 2.8mm) images; however, the differences were not significant (p=0.18 and p=0.53, respectively). Dural enhancement was observed only in one patient, who presented with CSF leaks on radionuclide cisternography., Conclusions: Our study, which included a relatively large population, did not find any association between the findings of radionuclide cisternography and MRI. Future research should focus on identifying more valid neuroimaging findings to diagnose intracranial hypotension accurately., (Copyright © 2014 Medical University of Bialystok. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)

Background: Sense of coherence (SOC) is associated with a reduced risk of various health problems and is thought to be a major factor related to the ability to cope with stress. In the present study, we examined the association between caregiver burden and SOC among caregivers to persons with dementia., Methods: Participants included 274 caregivers or family members of community-dwelling elderly dementia patients. To assess the cognitive function of patients, neuropsychological tests (e.g. Mini-Mental State Examination, Clinical Dementia Rating) were conducted by a clinical psychologist who was well trained in interviewing participants; the tests used a semi-structured interview protocol. Senior neurologists and psychiatrists also independently evaluated the dementia status of patients. To assess the SOC and caregiver burden, a social welfare counsellor asked questions from a 13-item version of the SOC scale and the short, eight-item Japanese version of the Zarit Caregiver Burden Interview (ZBI)., Results: Among 78 caregivers of elderly subjects with cognitive impairment due to dementia, the ZBI score was significantly associated with SOC (r = -0.38, P = 0.001). Multiple regression analyses revealed that SOC scores (β = -0.42, P < 0.001) and Mini-Mental State Examination scores (β = -0.28, P = 0.009) were significantly associated with ZBI scores (F(2, 76)  = 10.51, P < 0.001). SOC was closely associated with personal strain in the ZBI (β = -0.41, P < 0.001; F(3, 75)  = 8.53, P < 0.001)., Conclusion: Caregivers with a strong SOC may be less prone to experiencing personal strain from their burden. These results suggest that reinforcement of SOC would contribute to reducing the personal strain., (© 2014 The Authors. Psychogeriatrics © 2014 Japanese Psychogeriatric Society.)

This study aimed to investigate the genetic association between fluoroquinolone (FQ) and/or cephalosporin (CEP) resistance in Escherichia coli isolates from dogs, and the risk to human health. We characterized E. coli clinical isolates, derived from faecal samples of dogs attending veterinary hospitals, using phylogenetic grouping, determination of virulence factor (VF) prevalence, multilocus sequence typing (MLST) and O serotyping. The D group was the dominant phylogenetic group among strains resistant to FQ and/or CEP. In contrast, the dominant group among susceptible strains was group B2. Group D strains showed a significantly higher prevalence of VFs than strains belonging to groups A and B1, and were resistant to significantly more antimicrobials than group B2 strains. The phylogenetic distribution of FQ-CEP-resistant E. coli groups (FQ-CEPRECs) and FQ-resistant groups was significantly correlated (r = 0.98), but FQ-CEPRECs and CEP-resistant E. coli groups were not correlated (r = 0.58). Data from PFGE, O serotype and MLST analyses indicated that the majority of FQ-resistant strains derived from a particular lineage of phylogenetic group D: serotype O1 and sequence type (ST) 648. Some D-O1-ST648 strains carried blaCMY-2, showed multidrug resistance and possessed a higher prevalence of the VFs kspMT, ompT and PAI compared with other group D strains. Our data indicate that the emergence of FQ-CEP-resistant E. coli is based primarily on FQ-resistant E. coli. Moreover, as strains of the D-O1-ST648 lineage have been found in clinical isolates derived from humans at a relatively high frequency, our findings indicate that the spreading of D-O1-ST648 strains may cause serious difficulties in both veterinary and human clinical fields in the future.

Although previous studies in the general population showed that hypomagnesemia is a risk for cardiovascular diseases (CVD), the impact of magnesium on the prognosis of patients on hemodialysis has been poorly investigated. To gain information on this we conducted a nationwide registry-based cohort study of 142,555 hemodialysis patients to determine whether hypomagnesemia is an independent risk for increased mortality in this population. Study outcomes were 1-year all-cause and cause-specific mortality with baseline serum magnesium levels categorized into sextiles. During follow-up, a total of 11,454 deaths occurred, of which 4774 had a CVD cause. In a fully adjusted model, there was a J-shaped association between serum magnesium and the odds ratio of all-cause mortality from the lowest to highest sextile, with significantly higher mortality in sextiles 1-3 and 6. Similar associations were found between magnesium and both CVD and non-CVD mortality. The proportion of patients with a baseline intact parathyroid hormone level under 50 pg/ml was significantly higher in the highest sextile; however, after excluding these patients, the CVD mortality risk in the highest sextile was attenuated. Thus, hypomagnesemia was significantly associated with an increased risk of mortality in hemodialysis patients. Interventional studies are needed to clarify whether magnesium supplementation is beneficial for improving patient prognosis.

A nationwide statistical survey of 4255 dialysis facilities was conducted at the end of 2011. Responses were submitted by 4213 facilities (99.0%). The number of new patients started on dialysis was 38,613 in 2011. Although the number of new patients decreased in 2009 and 2010, it increased in 2011. The number of patients who died each year has been increasing; it was 30,743 in 2011, which exceeded 30,000 for the first time. The number of patients undergoing dialysis has also been increasing every year; it was 304,856 at the end of 2011, which exceeded 300,000 for the first time. The number of dialysis patients per million at the end of 2011 was 2385.4. The crude death rate of dialysis patients in 2011 was 10.2%, which exceeded 10% for the first time in the last 20 years. The mean age of new dialysis patients was 67.84 years and the mean age of the entire dialysis patient population was 66.55 years. The most common primary cause of renal failure among new dialysis patients was diabetic nephropathy (44.3%). Diabetic nephropathy was also the most common primary disease among the entire dialysis patient population (36.7%), exceeding chronic glomerulonephritis (34.8%) which had been the highest until last year. The survey included questions related to the Great East Japan Earthquake, which occurred on 11 March 2011. The results on items associated with the Great East Japan Earthquake were reported separately from this report. The mean uric acid levels of the male and female patients were 7.30 and 7.19 mg/dL, respectively. Certain drugs for hyperuricemia were prescribed for approximately 17% of patients. From the results of the facility survey, the number of patients who underwent peritoneal dialysis (PD) was 9642 and the number of patients who did not undergo PD despite having a peritoneal dialysis catheter was 369. A basic summary of the results on the survey items associated with PD is included in this report and the details were reported separately., (© 2013 The Authors. Therapeutic Apheresis and Dialysis © 2013 International Society for Apheresis.)

Mineral metabolism affects mortality in hemodialysis patients and is identified by imbalances in serum phosphate (P), calcium (Ca), and parathyroid hormone (PTH). We examined associations between annual mineral values (P, Ca, PTH) and mortality in a 3-year cohort (Dec 2006-2009) of 128,125 hemodialysis patients using three models, that is, baseline, time-dependent and time-average Cox models. We also examined associations between achieved Japanese guideline targets (P: 3.5-6.0 mg/dL, corrected Ca 8.4-10.0 mg/dL, intact PTH 60-180 mg/dL) and all-cause survival to elucidate which parameter should be controlled as a priority. High and low serum P (>6.0 or ≤ 3.5 mg/dL), high Ca (>9.5 mg/dL), higher PTH (>300 pg/mL) and lower PTH (≤ 60 pg/mL) were significantly associated with high mortality in all three models (P < 0.01). When we examined the association between combination of mineral targets and mortality, patients who achieved all targets simultaneously (20% of subjects, reference) showed lowest mortality. Those who achieved both P and Ca targets showed the same mortality as the reference group. Those who only met P target had a lower risk of death (hazard ratio = 1.17) compared to those that achieved Ca or PTH target (1.41, 1.47, respectively). As time of achieving P and Ca targets increased, all-cause mortalities diminished incrementally, significantly. Mineral metabolism disorder would lead to high mortality in prevalent hemodialysis patients. Among mineral values, P would be the strongest predictor for high mortality. Consistent achievement of P and Ca targets would lead to good survival., (© 2013 The Authors. Therapeutic Apheresis and Dialysis © 2013 International Society for Apheresis.)

Background: Multidrug-resistant Escherichia coli, especially a lineage of O25b:H4-ST131, has increased and spread worldwide. The surveillance of cross-resistance of E. coli is necessary., Methods: Cross-resistance to fluoroquinolones (FQs) and aminoglycosides (AGs) was examined in E. coli isolated in Hokkaido Prefecture, Japan, between 2008 and 2009., Results: Gentamicin (GEN) resistance was more common in FQ-resistant isolates (30/112 strains; 26.8%) than in FQ-susceptible isolates (2/100 strains; 2%). The frequency of GEN resistance was similar in two groups of FQ-resistant strains, O25b:H4-ST131 genotype (22/87 strains; 25.3%) and a group of other FQ-resistant genotypes (8/25 strains; 32.0%). The main AG resistance gene was aac(3)-II (87.5% of GEN-resistant strains). The only amikacin-resistant strain which was FQ resistant carried the aac(6')-Ib-cr gene. CTX-M type extended-spectrum β-lactamase (ESBL) genes were also found in FQ-resistant strains at a high frequency. However, the number of strains with both ESBL and AG-modifying enzyme genes was relatively low (8 strains)., Conclusion: All FQ-resistant strains, not only O25b:H4-ST131, appeared to preferentially acquire ESBL genes and/or genes encoding AG-modifying enzymes; however, the acquisitions of these genes seemed to occur independently.

A nationwide statistical survey of 4226 dialysis facilities was conducted at the end of 2010, and 4166 facilities (98.6%) responded. The number of new patients introduced into dialysis was 37,512 in 2010. This number has decreased for two consecutive years since it peaked in 2008. The number of patients who died in 2010 was 28,882, which has been increasing every year. The number of patients undergoing dialysis at the end of 2010 was 298,252, which is an increase of 7591 (2.6%) compared with that at the end of 2009. The number of dialysis patients per million at the end of 2010 was 2329.1. The crude death rate of dialysis patients in 2010 was 9.8%, and has been gradually increasing. The mean age of the new patients introduced into dialysis was 67.8 years and the mean age of the entire dialysis patient population was 66.2 years. Regarding the primary disease of the new patients introduced into dialysis, the percentage of patients with diabetic nephropathy was 43.6%, which is a slight decrease from that in the previous year (44.5%). Patients with diabetic nephropathy as the primary disease accounted for 35.9% of the entire dialysis patient population, which approaches the percentage of patients with chronic glomerulonephritis as the primary disease (36.2%). The percentage of patients who had undergone carpal tunnel release surgery (CTx) was 4.3%, which is a slight decrease from that at the end of 1999 (5.5%). The decrease in the percentage of patients who had undergone CTx was significant among the patients with dialysis durations of 20-24 years (1999, 48.0%; 2010, 23.2%). A total weekly Kt/V attributable to peritoneal dialysis and their residual functional kidney was 1.7 or higher for 59.4% of patients who underwent peritoneal dialysis., (© 2012 The Authors. Therapeutic Apheresis and Dialysis © 2012 International Society for Apheresis.)

Purpose: Low 25-hydroxyvitamin D (25D), increased levels of fibroblast growth factor 23 (FGF23), parathyroid hormone (PTH), and alkaline phosphatase (ALP) were reported to be risk factors for mortality in chronic kidney disease (CKD). However, the independent associations of these factors with cardiovascular disease (CVD), the leading cause of death among CKD patients, remain unclear. Our purpose was to identify which of these factors predict incident CVD in CKD., Methods: In this prospective cohort study, we enrolled 738 predialysis outpatients in the two nephrology departments. We employed Cox proportional hazards analyses to elucidate predictors of the endpoint, defined as fatal or non-fatal cardiovascular event requiring hospitalization. Multiple imputation was performed for missing values., Results: Mean estimated glomerular filtration rate (eGFR) was 35 mL/min/1.73 m(2). During a median duration of 4.4 years, 86 patients developed the endpoint, of whom 62 patients achieved it before the initiation of dialysis. Multivariable analyses revealed that high serum intact FGF23 levels predicted the outcome preceding dialysis initiation (hazard ratio (HR) per lnFGF23 (SD), 1.64 (1.27-2.30)), while 25D, PTH, and bone-specific ALP did not. Adding FGF23 to the conventional model of age, sex, diabetes, prior CVD, pulse pressure, and eGFR, led to a net reclassification improvement of 6.87% (P=0.04). Not censoring the patients at the start of dialysis and continuing follow-up even after dialysis, FGF23 levels did not predict the outcome (HR, 1.16 (0.91-1.48)). Complete case analyses yielded similar results., Conclusions: Intact FGF23 levels in predialysis CKD predicted incident cardiovascular events requiring hospitalization before starting dialysis, but did not predict events during the entire follow-up period, including post dialysis initiation., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Malnutrition in the early stage has been reported as an independent predictor of survival in amyotrophic lateral sclerosis (ALS). We analyzed retrospectively the effect of variation of body mass index (BMI) on survival in ALS patients. In total, 77 consecutive ALS patients were enrolled from nine hospitals in Japan. Reduction rate of BMI was calculated from BMI before the disease onset and at the time of the first visit to each hospital. We analyzed the correlation between BMI reduction rate and total disease duration. Results showed that the median BMI reduction rate was 2.5 per year (interquartile range 1.3-3.8). The BMI reduction rate was significantly correlated with survival length (p <0.0001). There was also a significant difference in survival between ALS patients with a BMI reduction rate ≥ and < 2.5 (Kaplan-Meier survival analysis and the log-rank test, p < 0.0001; hazard ratio by the Cox model, 2.9816). In conclusion, faster reduction of BMI at the initial stage before the first visit to hospital predicts shorter survival length also in Japanese ALS patients.

Even in cases in which geographic isolation appears to have driven the speciation of regional endemics, range shifts during the Pleistocene climatic oscillations may also have influenced their evolutionary history. Elucidating speciation history can provide novel insights into evolutionary dynamics following climatic oscillations. We demonstrated a sister relationship between the Japanese alpine endemic Cardamine nipponica and the currently allopatric, widespread arctic-alpine Cardamine bellidifolia (Brassicaceae) based on internal transcribed spacer (ITS) sequences and 10 other nuclear genes. Speciation history was inferred using demographic parameters under the isolation with migration model. The estimated demographic parameters showed that the population size of C. nipponica was similar to that of C. bellidifolia and that gene flow occurred exclusively from C. nipponica to C. bellidifolia after speciation. The inferred speciation history, which included gene flow, suggests that geographic barriers between the peripheral C. nipponica and the widespread C. bellidifolia were reduced during the Pleistocene. The asymmetric introgression implies that genetic isolation may have been involved in the speciation of C. nipponica. Our results suggest that even currently allopatric species may not have diverged solely under geographic isolation, and that their evolutionary history may have been influenced by Pleistocene range dynamics., (© 2012 The Authors. New Phytologist © 2012 New Phytologist Trust.)

A nationwide statistical survey of 4196 dialysis facilities was conducted at the end of 2009, and 4133 facilities (98.5%) responded. The number of patients undergoing dialysis at the end of 2009 was determined to be 290 661, an increase of 7240 patients (2.6%) compared with that of 2008. The number of dialysis patients per million at the end of 2009 was 2279.5. The crude death rate of dialysis patients from the end of 2008 to the end of 2009 was 9.6%. The mean age of the new patients introduced into dialysis was 67.3 years old and the mean age of the entire dialysis patient population was 65.8 years old. Primary diseases such as diabetic nephropathy and chronic glomerulonephritis for new dialysis patients, showed a percentage of 44.5% and 21.9%, respectively. Based on the facilities surveyed, 84.2% of the facilities that responded to the questionnaire satisfied the microbiological quality standard for dialysis fluids for the Japanese Society for Dialysis Therapy (JSDT), with an endotoxin concentration of less than 0.05 EU/mL in the dialysis fluid. Similarly, 98.2% of the facilities surveyed satisfied another standard of the society of a bacterial count of less than 100 cfu/mL in the dialysis fluid. The facility survey indicated that the number of patients who were treated by blood purification by both peritoneal dialysis and extracorporeal circulation, such as hemodialysis, was 1720. Among the total number of patients, 24.8% were satisfied with the management target recommended in the treatment guidelines for secondary hyperparathyroidism. These standards are set by the JSDT, based on the three parameters, i.e. serum calcium concentration, serum phosphorus concentration, and serum intact parathyroid hormone concentration. According to the questionnaire, 9.8% of the patients were considered to have a complication of dementia., (© 2012 The Authors. Therapeutic Apheresis and Dialysis © 2012 International Society for Apheresis.)

Background: Fluoroquinolone-resistant and extended-spectrum β-lactamase (ESBL)-carrying multidrug-resistant Escherichia coli have become severely problematic. In particular, a lineage of multilocus sequence-type ST131 which belongs to O25:H4 and carries ESBL CTX-M-15 has spread worldwide., Methods: Fluoroquinolone-resistant E. coli strains were isolated from various clinical specimens in a commercial clinical laboratory in 2008 and 2009 in Hokkaido Prefecture, Japan., Results: Among 478 clinical isolates, 112 strains (23.4%) showed levofloxacin (LVX) resistance. About 80% of the fluoroquinolone-resistant strains (88 strains) showed common features, namely O25:H4-ST131, phylogenetic group B and the same mutation pattern in quinolone resistance-determining regions. Pulsed field gel electrophoresis patterns suggested numerous lineages of O25:H4-ST131. The fluoroquinolone-resistant strains, including strains of O25:H4-ST131 and other types, more frequently shared CTX-type ESBL genes than did fluoroquinolone-susceptible strains. The ESBL genes fell into the CTX-M-9 and CTX-M-2 groups. CTX-M-15 (CTX-M-1 group) was not found among any of the strains isolated in this study. Sitafloxacin showed markedly potent activity against E. coli isolates compared with LVX, ciprofloxacin and ulifloxacin., Conclusion: The most prevalent fluoroquinolone-resistant strains of E. coli isolated in Hokkaido Prefecture, Japan, are O25:H4-ST131. However, similar to other areas of Japan, the ST131 clones represent distinct lineages from the general worldwide dispersal of multidrug-resistant clones which carry CTX-M-15., (Copyright © 2012 S. Karger AG, Basel.)

In the developed countries, especially Japan, elderly population is rapidly increasing, but outcomes of elderly patients with the age of 80 years and older suffering from subarachnoid hemorrhage (SAH) remain still unclear. We retrospectively reviewed the medical records of nontraumatic SAH patients aged 80 years and older, who were hospitalized in a single center between 1998 and 2009. There were 28 patients (80-90 years old and 75% female), representing 5.9% of all non-traumatic SAHs (n = 474). Of those, 16 patients received an intervention (ten clipping and six endovascular coiling) and the remaining 12 patients were managed conservatively. The median survival time of intervention group was 110 days and that of conservative group 49 days (p = 0.12, log rank analysis). Cox's proportional hazards model yielded two variables, the Japan Coma Scale (JCS) grade on admission ( hazard ratio: 2.93 [p = 0.009]) and conservative treatment (hazard ratio: 2.14 [p = 0.054]). In the outcome of the modified Rankin Scale between these two groups, logistic regression analysis had significant variable; the JCS grade on admission (odds ratio: 280, [p = 0.020]). In the elderly patients with good initial clinical condition, an acute intervention may have good outcome.