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Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a class of drugs used in the clinical management of patients with type 2 diabetes, and their prescriptions have been increasing in recent years. Herein, we performed a retrospective analysis of seasonal variation in SGLT2 inhibitor-associated adverse events recorded in the Japanese Adverse Drug Event Report (JADER) database, an adverse event reporting database which reflects real-world clinical practice. To this end, seasonal variations in SGLT2 inhibitor-related dehydration, cerebral infarction, urinary tract infection, and ketoacidosis were analyzed. Six SGLT2 inhibitors prescribed in Japan (ipragliflozin, empagliflozin, luseogliflozin, canagliflozin, dapagliflozin, and tofogliflozin) were included. The reporting ratio (RR) for SGLT2 inhibitor adverse events per month in the JADER database from April 2014 to December 2023 was determined. The RR for dehydration-related adverse events was highest in the summer months of July and August, as well as in the winter months of December, January, and February. The highest RR for cerebral infarction was in February. No association with seasonal variations in the occurrence of ketoacidosis related to dehydration was observed. Healthcare providers should take adequate precautions against dehydration caused by SGLT2 inhibitors, not only in summer but also in winter. These findings are instructive and informational for health care professionals involved in diabetes care., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval: Ethical approval was not sought for this study because the study was a database-related observational study which did not directly involve any research subjects. All results were obtained from data openly available online from the PMDA website ( www.pmda.go.jp ). All data from the JADER database were fully anonymized by the relevant regulatory authority before we accessed them. Our research does not fall within the purview of any of the following laws and guidelines: “Clinical Trials Act (Act No. 16 of April 14, 2017),” “Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices (Law number: Act No. 145 of 1960, Last Version: Amendment of Act No. 50 of 2015),” “Guideline for good clinical practice E6 (R1), https://www.pmda.go.jp/int-activities/int-harmony/ich/0076.html ,” “Ethical guidelines for human genome and gene analysis research, https://www.mhlw.go.jp/general/seido/kousei/i-kenkyu/genome/0504sisin.html ,” and “Ethical Guidelines for Medical and Health Research Involving Human Subjects, https://www.mhlw.go.jp/stf/seisakunitsuite/bunya/hokabunya/kenkyujigyou/i-kenkyu/index.html .” Therefore, it is not subject to ethical examination. The study was an observational study without any research subjects. No consent to participate was required due to the retrospective nature of this study., (© 2024. The Author(s).)

Objective: Tocilizumab (TCZ) is effective for giant cell arteritis (GCA). However, little is known regarding treatment modification and clinical outcomes after unfavorable events such as GCA relapses or TCZ discontinuation due to adverse events (AEs)., Methods: This multicenter retrospective study included patients with GCA who initiated TCZ from 2008 to 2021 at 5 Japanese hospitals. GCA relapses and TCZ-related AEs were monitored for 2 years after TCZ initiation. In patients with GCA relapses, subsequent clinical courses, including relapse symptoms and treatment modification, were followed for 90 days after the relapses. Similarly, patients who discontinued TCZ because of AEs were additionally followed until 1 year after the TCZ discontinuation to evaluate AEs, relapses, and treatment changes., Results: Of 62 eligible patients, 10 patients (16%) relapsed after initiating TCZ therapy. Most relapses (8 of 10) occurred after extending TCZ intervals or discontinuing TCZ. Combinations of adjusting TCZ intervals, adjusting glucocorticoid (GC) dose, and/or adding or increasing methotrexate (MTX) therapy could manage the relapses without serious complications. In the entire cohort, AEs occurred in 28 patients (45%), and 8 patients (13%) discontinued TCZ because of AEs. After AE-related TCZ discontinuation, 6 patients attempted to taper GCs without other immunosuppressive therapy (IST), and 4 subsequently relapsed. In contrast, 2 patients who used other IST or biologic therapy could decrease GCs without relapses., Conclusion: Although GCA relapses can occur after initiating TCZ therapy, most relapses can be safely managed by adjusting TCZ, GC, and/or MTX doses. Adding IST or biologic treatments may potentially be related to preventing relapses when patients discontinue TCZ because of AEs.

Natronomonas pharaonis halorhodopsin (NpHR) is a light-driven Cl - inward pump that is widely used as an optogenetic tool. Although NpHR is previously extensively studied, its Cl - uptake process is not well understood from the protein structure perspective, mainly because in crystalline lattice, it has been difficult to analyze the structural changes associated with the Cl - uptake process. In this study, we used solid-state NMR to analyze NpHR both in the Cl - -bound and -free states under near-physiological transmembrane condition. Chemical shift perturbation analysis suggested that while the structural change caused by the Cl - depletion is widespread over the NpHR molecule, residues in the extracellular (EC) part of helix D exhibited significant conformational changes that may be related to the Cl - uptake process. By combining photochemical analysis and dynamic nuclear polarization (DNP)-enhanced solid-state NMR measurement on NpHR point mutants for the suggested residues, we confirmed their importance in the Cl - uptake process. In particular, we found the mutation at Ala165 position, located at the trimer interface, to an amino acid with bulky sidechain (A165V) significantly perturbs the late photocycle and disrupts its trimeric assembly in the Cl - -free state as well as during the ion-pumping cycle under the photo-irradiated condition. This strongly suggested an outward movement of helix D at EC part, disrupting the trimer integrity. Together with the spectroscopic data and known NpHR crystal structures, we proposed a model that this helix movement is required for creating the Cl - entrance path on the extracellular surface of the protein and is crucial to the Cl - uptake process., 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. Published by Elsevier B.V.)

Immune reconstitution after human leukocyte antigen (HLA)-mismatched (haploidentical) hematopoietic stem cell transplantation (haplo-HCT) can significantly influence long-term outcomes. The three possible HLA haplotypes after transplantation are: one carried by both the patient and the donor (shared HLA), one by donor only (donor-specific HLA), and one by patient only (host-specific HLA), and the donor T cells remain restricted to one of these three haplotypes. Understanding the presence of donor T cells restricted to each haplotype may provide more detailed insights into post-transplant immune response and potentially provide valuable information for the development of chimeric antigen receptor T cell or T cell receptor T cell constructs. In this study, patients or donors with HLA-A24 or HLA-A2 were tested with HLA-A*24:02- and A*02:01-restricted cytomegalovirus (CMV)-specific tetramers for detecting the respective HLA-restricted T cells. Sixty-four samples from 40 patients were assayed. More than half of the patients at day 90 and all patients by day 900 had shared HLA-restricted T cells. After day 90, half of the patients had donor-specific HLA-restricted T cells, but no host-specific HLA-restricted T cells were found. In the comparative analysis of the transplant types, shared HLA-restricted T cells were positive in all three categories: haplo-HCT (50%), 2-haplo-mis-HCT (75%), and spousal HCT (67%). Furthermore, donor-specific HLA-restricted T cells demonstrated positivity in haplo-HCT at 57% and in 2-haplo-mis-HCT at 60%, with a threshold of 0.01%. Donor-specific HLA-restricted T cells for spousal HCT were not examined due to the lack of an appropriate HLA combination for the tetramers. The presence of shared HLA-restricted T cells explains the host defense after HLA-haploidentical transplantation, while the presence of donor-specific HLA-restricted T cells may account for host defense against hematotropic viruses, such as CMV. However, this study failed to detect host-specific HLA-restricted T cells, leaving the host defense against epitheliotropic viruses unresolved, thus requiring further investigation., Competing Interests: Declaration of competing interest There are no conflicts of interest to report., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: We studied the current state and factors associated with the acceptance or hesitancy of booster doses of the coronavirus disease 2019 (COVID-19) vaccine among patients with autoimmune and rheumatic diseases (ARDs) in Japan., Methods: A single-center cross-sectional survey was conducted among outpatients with ARDs who visited the Immuno-Rheumatology Center at St. Luke's International Hospital from 1 October to 30 November in 2023. We investigated patient characteristics, COVID-19 vaccination-related status, decision-making preferences, health-related status and independent factors associated with the acceptance or hesitancy of booster doses of the COVID-19 vaccine., Results: A total of 241 patients were included in the analyses, and 198 patients (82.2%) received booster doses while 43 (17.8%) did not. Older age (adjusted odds ratio [aOR] = 0.43, 95% CI: 0.19, 0.95, P = 0.037), having rheumatoid arthritis (RA) (aOR = 0.41, 95% CI: 0.19, 0.92, P = 0.030) and having a physician recommend receiving the vaccine (aOR = 0.47, 95% CI: 0.23, 0.95, P = 0.035) were independently associated with receiving booster doses. The main reasons for hesitancy regarding booster doses were concerns about adverse reactions and long-term safety., Conclusion: Our findings could help physicians counsel patients with ARDs regarding their acceptance of COVID-19 vaccine booster doses to promote appropriate decision-making., (© Japan College of Rheumatology 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Background: Obesity indices reflect not only fat mass but also muscle mass and nutritional status in older people. Therefore, they may not accurately reflect prognosis. This study aimed to investigate associations between a body shape index (ABSI), body mass index (BMI), and mortality in the general older population., Methods: This nationwide observational longitudinal study included individuals aged between 65 and 74 years who underwent annual health checkups between 2008 and 2014. Exposures of interest were ABSI and BMI, and the primary outcome was all-cause mortality. Association between the ABSI and BMI quartile (Q1-4) and mortality was assessed using Cox regression analysis. A restricted cubic spline was also used to investigate nonlinear associations. The missing values were imputed using multiple imputation by chained equations., Results: Among 315,215 participants, 5074 died during a median follow-up period of 42.5 (interquartile range: 26.2-59.3) months. Compared with ABSI Q1, ABSI Q3 and Q4 were associated with increased risk of mortality, with the adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) of 1.13 (1.05-1.22) and 1.23 (1.13-1.35), respectively. Compared with BMI Q3, BMI Q1 and Q2 were associated with an increased risk of mortality, with aHRs and 95% CIs of 1.51 (1.39-1.65) and 1.12 (1.03-1.22), respectively. The impacts of these indices were greater in male than in female. The heatmap of the aHR for mortality by continuous ABSI and BMI showed that higher ABSI was consistently associated with higher mortality risk regardless of BMI, and that the combination of low BMI and high ABSI was strongly associated with increased mortality risk., Conclusions: High ABSI and low BMI are additively associated with the risk of all-cause mortality in the general older population in Japan. Combination of ABSI and BMI is useful for evaluating mortality risk in older people., (© 2024 The American Geriatrics Society.)

Diabetic patients as well as the elderly are known to have high pulse pressure (PP), but there are few studies on how microangiopathy and macroangiopathy are involved in its mechanism. In this study, we examined the association between PP and atherosclerotic lesions by vessel size in kidney biopsy tissue and examined how PP is associated with kidney prognosis. This retrospective observational study included 408 patients with biopsy-proven diabetic nephropathy at Nara Medical University Hospital. Exposure of interest was PP measured at kidney biopsy. Outcome variable was kidney failure with replacement therapy (KFRT). Cox proportional hazards and competing risk regression models with all-cause mortality as a competing event were used to examine these associations. A total of 408 patients were divided into tertiles based on PP (mmHg): Tertile 1 (reference), <51; Tertile 2, 51-64; and Tertile 3, >64. Among the 408 patients, 99 developed KFRT during a median follow-up period of 6.7 years. Higher PP was independently associated with higher incidences of KFRT (hazard ratio [95% confidence interval] for Tertile 3 vs. Tertile 1; 2.07 [1.05-4.09]. In histological lesions, PP was strongly associated with glomerular lesions, tubulointerstitial lesions, and arteriolar hyalinosis (all ps for trend <0.001), but not with intimal thickening (p for trend = 0.714). PP was significantly associated with diabetic glomerular/tubulointerstitial lesions and arteriolar hyalinosis but not with intimal thickening at the time of kidney biopsy and was also significantly associated with subsequent KFRT in patients with diabetic nephropathy., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Most elements of filamentous fungi seen in human tissue by pathologists are hyphae, and encountering other elements may interfere with diagnosis. Sporangia and chlamydospores are such elements that have been described in only a few case reports. We present an autopsy case with the extremely rare coexistence of Mucorales sporangia and chlamydospores in the lung. These fungal elements must be recognized and identified accurately because they can easily be mistaken for other fungi, microorganisms, or degenerated tissue structures., (© 2024 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Electrical stimulation-induced muscle contraction (ESMC) has demonstrated various physiological benefits, but its effects on the secretion of undercarboxylated osteocalcin (ucOC), a bone-derived cytokine, remain unclear. This study explored the relationship between ESMC, bone strain, and ucOC secretion through two experiments. In the first, young male Fischer 344 rats were divided into three groups: low-frequency ES (LF, 10 Hz), high-frequency ES (HF, 100 Hz), and control (CON). Acute 30-min transcutaneous ES was applied, and both bone strain and ucOC levels were measured. In the second experiment, rats underwent LF or HF long-term ES (two sessions per week for 4 weeks), with ucOC and insulin levels monitored. Results revealed a significant peak in ucOC at 6 h post-acute LF-ESMC. Despite HF-ESMC generating greater bone strain, LF-ESMC, with smaller but repetitive bone strain, proved more effective in stimulating ucOC secretion. In the long-term study, both ESMC groups exhibited early increases in ucOC, with a positive correlation to insulin levels. In conclusion, bone strain induced by ES-mediated muscle contraction promotes ucOC secretion, with both the magnitude and frequency of strain playing critical roles.

Amphotericin B deoxycholate (AMPH-B) is a polyene macrolide with antifungal activity. Liposomal AMPH-B (L-AMB) was developed to reduce side effects while maintaining antifungal activity. This study was aimed at evaluating and comparing the adverse event profiles of AMPH-B and L-AMB using a spontaneous reporting system. We analyzed the adverse event reports of AMPH-B and L-AMB from the United States Food and Drug Administration Adverse Event Reporting System (FAERS). Case report counts of adverse events were generated according to the preferred terms of the Medical Dictionary for Regulatory Activities (MedDRA). Standardized MedDRA queries (SMQs) and system organ classes (SOCs) were used to compare the organ-specific adverse event profiles of AMPH-B and L-AMB. The reporting odds ratio and proportional reporting rate were used to detect pharmacovigilance signals. The FAERS database contains 21,173,818 cases from January 2004 to March 2024. Adverse events were reported in 2438 cases receiving AMPH-B treatment and 3344 cases receiving L-AMB treatment, including 848 and 1591 cases receiving intravenous AMPH-B and L-AMB injections, respectively. The most frequently reported drug-related adverse event in the AMPH-B and L-AMB groups was hypokalemia. SOCs with statistically significant differences were "Inv" (laboratory tests), "Resp" (respiratory, thoracic, and mediastinal disorders), "Genrl" (general and systemic disorders and conditions at the site of administration), "Card" (cardiac disorders), and "Blood" (blood and lymphatic system disorders). No statistically significant difference was observed in the SMQ profile of adverse events in "Renal" (renal and urinary disorders) and "Hepat" (hepatobiliary disorders) between the L-AMB and AMPH-B formulations in this study. Based on real-world data from FAERS, adverse event profiles of AMPH-B and L-AMB were compared. No statistically significant difference was observed in the SMQ profile of adverse events in the renal and hepatic SOCs between the L-AMB and AMPH-B formulations. Our results suggest that L-AMB is more tolerated by the kidneys than AMPH-B., Competing Interests: Human subjects: All authors have confirmed that this study did not involve human participants or tissue. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: The authors disclose the receipt of the following financial support for the research, authorship, and/or publication of this article. This research was partially supported by JSPS KAKENHI,Grant Numbers 23H05264, 21K11100, and 21K06646. The funders played no role in the study design, data collection and analysis, decision to publish this article, or article preparation. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Nokura et al.)

Objective: Our objective was to evaluate associations of weight reduction with serum urate (SU) changes and achieving an SU level <6 mg/dL in the real-world setting, outside of specific weight reduction interventions., Methods: We analyzed systematically collected data of annual medical examination participants from October 2012 to October 2022. Exposure was weight change (increase or decrease) between two consecutive visits, categorized as minimal (≤0.9 kg, reference), small (1.0-4.9 kg), moderate (5.0-9.9 kg), and large (≥10 kg). Outcomes included SU changes between two consecutive visits and achieving an SU level <6 mg/dL in participants with hyperuricemia (SU level ≥7 mg/dL at the previous visit)., Results: We identified 58,630 eligible participants (median age 46 years, 51.3% female, 19.4% with overweight, median SU level 5.3 mg/dL, and 5.6% with a history of gout and/or hyperuricemia) with 336,814 visits over a median of 5.3 years. After adjustment for relevant covariates, linear general estimating equations estimated mean SU changes based on observed weight reductions (vs minimal changes) were as follows: small, -0.10 mg/dL (95% confidence interval [CI] -0.10 to -0.09 mg/dL); moderate, -0.34 mg/dL (95% CI -0.36 to -0.32 mg/dL); and large, -0.64 (95% CI -0.70 to -0.58 mg/dL). In participants with hyperuricemia, adjusted relative risks for achieving an SU level <6 mg/dL by modified Poisson regression were 1.25 (95% CI 1.15-1.37) in small weight reductions, 2.82 (95% CI 2.43-3.27) in moderate weight reductions, and 5.27 (95% CI 4.15-6.70) in large weight reductions, with corresponding numbers needed to treat of 61.1 for small weight reductions, 8.5 for moderate weight reductions, and 3.6 for large weight reductions., Conclusion: Small weight reductions were associated with only small SU changes. Some participants with hyperuricemia can achieve the target SU level with moderate to large weight reductions., (© 2024 American College of Rheumatology.)

Objective: The aim of this multicenter retrospective study was to analyze the impact of prophylactic neck dissection and adjuvant therapy in transoral surgery for hypopharyngeal cancer., Methods: We compared the impact of surgical margin assessment, neck dissection, and adjuvant treatment on oncologic outcomes in patients who underwent transoral surgery for hypopharyngeal squamous cell carcinoma between 2015 and 2021., Results: Two hundred and twenty-one patients were included. The 3-year local recurrence-free survival was 89.1 %, and local recurrence did not significantly impact overall survival. Positive vertical margins resulted in 60 % of patients receiving additional treatment, with no increase in local recurrence and a significant increase in regional recurrence (p = 0.007) and distant metastasis (p < 0.001). Half of the patients with regional recurrence after neck dissection also had distant metastases and worse survival (p = 0.069), while those with regional recurrence without prophylactic neck dissection did not have worse survival., Conclusion: In cases of positive vertical margin, careful surveillance for regional recurrence and distant metastasis is also warranted. Prophylactic neck dissection may not be necessary., Competing Interests: Declaration of competing interest The authors have no funding, financial relationship, or conflicts of interest to disclose., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: Providing medical, nursing, and welfare services in each community is becoming increasingly important as population ages in Japan, and the demand for aseptic preparation in community pharmacies is expected to increase. In this study, the disparity in the distribution of community pharmacies providing aseptic preparation services were examined to explore how the unequal distribution of the pharmacies can be improved in the future., Methods: The regional inequality of community pharmacies providing aseptic preparation services was evaluated using Gini coefficients. The regional distribution was evaluated using a geographic information system application., Results: Only 8.0% of all insurance community pharmacies in Japan provided aseptic preparation services. The Gini coefficient of pharmacies providing aseptic preparation services for the total population of each municipality was 0.410. The population coverage, within 16 km of pharmacies providing aseptic preparation services, was 96.5% of the total population. The residential grid coverage, within 16 km of the pharmacies, was 75.2% of the total network, approximately one quarter not covered. It is estimated that the coverage ratios will improve by some percentage by 2050, although the projected population in 2050 is expected to decrease by approximately 20%., Conclusion: The current number and distribution of pharmacies providing aseptic preparation services are inadequate, and measures need to be taken to avoid future problems., Competing Interests: The authors declare no conflicts of interest regarding this research., (© 2024 Nonomura et al.)

A Gram-negative, obligatory anaerobic, chemoheterotrophic bacterium, designated strain IA91 T , was isolated from sediments and formation water from deep aquifers in Japan. IA91 T derives its peptidoglycan, energy and carbon from exogenous cell wall fragments, namely muropeptides, released from actively reproducing bacteria, and is dependent on other bacteria for cell wall formation, growth and even cell shape: IA91 T is irregular rod-shaped but coccoids when muropeptide is absent. IA91 T grew in a temperature range of 25-45 °C with optimum growth at 40 °C. IA91 T utilized limited substrates, yeast extract, muropeptides and d-lactate. The major end products from yeast extract degradation were acetate, hydrogen and carbon dioxide. Co-cultivation with a hydrogen-scavenging methanogenic archaeon promoted IA91 T growth. No anaerobic respiration with nitrate, nitrite, sulphate or Fe(III) was observed. The major cellular fatty acids are C16 : 0, C18 : 1 trans 9, C18 : 0 and C17 : 0. The G+C content of the genomic DNA was 45.6 mol%. Phylogenetic analysis based on 16S rRNA gene and conserved protein sequences involved in replication, transcription and translation indicated that IA91 T belonged to the candidate phylum Marine Group A (MG-A, SAR406 or Ca . Marinimicrobia) with no cultivated representatives. Based on the phenotypic and phylogenomic characteristics, a new genus and species, Fidelibacter multiformis gen. nov., sp. nov., is proposed for IA91 T (= JCM 39387 T = KCTC 25736 T ). In addition, a new bacterial phylum named Fidelibacterota phyl. nov. is proposed for the candidate phylum MG-A represented by F. multiformis and Fidelibacteraceae fam. nov., Fidelibacterales ord. nov. and Fidelibacteria classis nov.

Aims: Both low and high serum levels of high-density lipoprotein cholesterol (HDL-C) were reported to be associated with adverse kidney outcomes. However, this association has not been well investigated in the general Japanese population., Methods: This nationwide longitudinal study used data from the Japan Specific Health Checkups Study conducted between 2008-2014. The association between serum HDL-C levels and 40% decline in estimated glomerular filtration rate (eGFR) was analyzed using Cox regression analysis. Trajectories of eGFR were compared using mixed-effects model., Results: Among 768,495 participants, 6,249 developed 40% decline in eGFR during the median follow-up period of 34.6 (interquartile range: 14.8-48.4) months. Using serum HDL-C levels of 40-59 mg/dL as a reference, the adjusted hazard ratios (95% confidence intervals) for the kidney outcome of serum HDL-C levels of ＜40, 60-79 and ≥ 80 mg/dL were 1.26 (1.14-1.39), 0.91 (0.86-0.96), and 0.86 (0.78-0.93), respectively. Restricted cubic spline analysis showed that HDL-C levels of less than approximately 60 mg/dL were associated with an increased risk of kidney outcomes. Subgroup analysis showed that baseline eGFR and proteinuria modified the effects of serum HDL-C levels on kidney outcomes. The mixed-effects model showed that the lower category of HDL-C level was associated with a higher eGFR decline rate (p for interaction ＜0.001)., Conclusions: Low HDL-C levels were associated with kidney function decline; however, high HDL-C levels were not associated with adverse kidney outcomes in the general Japanese population.

Introduction In neuropsychiatric pharmacotherapy, neuroleptic malignant syndrome (NMS) is a potentially serious side effect of antipsychotics characterized primarily by fever, disorientation, extrapyramidal disorders, and autonomic nervous system imbalance, which can lead to death if left untreated. We visualized the NMS profile of antipsychotics using a self-organizing map (SOM). We combined it with decision tree analysis to discriminate between 31 antipsychotics in more detail than typical antipsychotic (TAP) and atypical antipsychotic (AAP) classifications. Method A total of 20 TAPs and 11 AAPs were analyzed. We analyzed NMS reports extracted from the Japanese Adverse Drug Event Report (JADER) database based on standardized Medical Dictionary for Regulatory Activities (MedDRA) queries (Standardized MedDRA Queries (SMQ) code: 20000044, including 68 preferred terms). The SOM was applied using the SOM package in R version 4.1.2 (R Foundation for Statistical Computing, Vienna, Austria). Results The Japanese Adverse Drug Event Report (JADER) database contained 887,704 reports published between April 2004 and March 2024. The numbers of cases of NMS (SMQ code: 20000044) reported for risperidone, aripiprazole, haloperidol, olanzapine, and quetiapine were 1691, 1294, 1132, 1056, and 986, respectively. After the antipsychotics were classified into six units using SOM, they were adapted for decision tree analysis. First, 31 antipsychotics branched off into groups with loss of consciousness, with one group (10 TAPs) consisting entirely of TAPs, and the other consisting of antipsychotics that were further separated into two groups with coma induced by TAPs and AAPs. Conclusion The results of this study provide a reference for healthcare providers when predicting the NMS characteristics induced by each drug in patients, thereby facilitating the effective treatment of schizophrenia., Competing Interests: Human subjects: All authors have confirmed that this study did not involve human participants or tissue. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: This research was partially supported by JSPS KAKENHI Grant Number, 21K06646 and 21K11100. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Miyasaka et al.)

Objectives: This study aimed to review and describe isolated sixth cranial nerve or abducens nerve palsy that may present with subtle ophthalmoplegia in patients with giant cell arteritis (GCA)., Materials and Methods: In this systematic review following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) Extension for Scoping Reviews, MEDLINE and EMBASE were searched for all peer-reviewed articles using the keywords "cranial nerve six," "abducens nerve," and "giant cell arteritis" from their inception to December 22, 2022., Results: Twenty-five articles, including seven observational studies and 18 cases, were included. While the incidence and prevalence of sixth nerve palsy in GCA were variable, up to 48% of diplopia in GCA were attributed to the sixth cranial nerve palsy, according to the observational studies included. While 88.2% had a resolution of symptoms with 40-50 mg/day of prednisone-equivalent corticosteroids, it took a median of 24.5 days until the resolution of symptoms from the initiation of treatment., Conclusion: This review summarizes the current understanding of the characteristics of sixth nerve palsy in GCA. While most patients may have reversible clinical courses, a few can suffer from persistent ophthalmoplegia, which is a potentially missed yet crucial clinical finding in GCA. Increased awareness of the sixth nerve palsy in GCA is crucial., Competing Interests: Conflict of Interest: The authors declared no conflicts of interest with respect to the authorship and/or publication of this article., (Copyright © 2024, Turkish League Against Rheumatism.)

This study aimed to develop a prostatic pharmacokinetic model of ceftazidime and suggest more effective dosing strategy for the bacterial prostatitis, based on a site-specific pharmacokinetic and pharmacodynamic perspective. Subjects were prostatic hyperplasia patients prophylactically receiving a 0.5-h infusion of 1.0 g or 2.0 g ceftazidime before transurethral resection of the prostate. Plasma and prostate samples were premeditatedly collected after the administration and the concentrations were measured by high-performance liquid chromatography. The prostate tissue/plasma ratio in area under the drug concentration-time curve was approximately 0.476. The prostatic population pharmacokinetic model incorporated creatinine clearance (CL cr ) into ceftazidime clearance was developed, and adequately predicted prostate tissue concentrations by diagnostic scatter plots and visual predictive checks. Aiming for a bactericidal target of 70% of time above minimum inhibitory concentration (T > MIC) in prostate tissue, 2.0 g twice daily achieved ≥90% expected probability against main pathogens like Escherichia coli and Proteus species in patients regardless of renal function (CL cr = 60 and 90 mL/min). However, since the expected probability of attaining the bactericidal target of 0.5-h infusion dosing regimen did not achieve 90% against Pseudomonas aeruginosa in patients with CL cr = 60 and 90 mL/min, 4-h infusion dosing regimen of 2.0 g three times daily (6 g/day) might be required for empirical treatment. Based on site-specific simulations, the present study provides more effective dosing strategy for bacterial prostatitis., (© 2024, The American College of Clinical Pharmacology.)

Eccentric training induces greater hypertrophy while causing more muscle damage than concentric training. This study examined the effects of small-range eccentric contractions (SR-ECCs) and large-range eccentric contractions (LR-ECCs) on muscle morphology, contractility, and damage in rats. Thirty male Fischer 344 rats were divided into five groups: small-range ECC single-bout (SR-ECC SB , n = 4), large-range ECC single-bout (LR-ECC SB , n = 4), SR-ECC intervention (SR-ECC Intv , n = 7), LR-ECC intervention (LR-ECC Intv , n = 8), and control (Cont, n = 7). These groups underwent transcutaneous electrical stimulation involving 80 ECCs twice a week for four weeks. The results indicated that the LR-ECC SB group had more Evans blue dye-positive fibers than other groups. The SR-ECC Intv group showed no increase in the mean myofiber cross-sectional area. However, Pax7+ and Ki67+ cells significantly increased in both ECC Intv groups compared to the Cont group, and the connective tissue area was significantly greater in the LR-ECC Intv than in others. Muscle force was lower in both ECC Intv groups compared to the Cont group. These findings suggest that SR-ECC intervention may induce a smaller increase in the number of fibers with a large myofiber cross-sectional area and satellite cell proliferation with less muscle damage and myofibrosis compared to LR-ECCs.

Background: Hypopharyngeal carcinoma is likely to spread to the lymph nodes, but there is no established strategy for management in transoral surgery., Methods: We compared oncologic and functional outcomes in a retrospective multicenter study of patients who underwent transoral surgery for hypopharyngeal carcinoma between 2015 and 2021., Results: Two-hundred and thirty-two patients were included. Comparing patients with and without adjuvant radiotherapy, 3-year regional recurrence-free survival (RRFS) was not significantly different in pN2b and pN2c, but was significantly worse in pN3b without adjuvant radiotherapy. In patients without neck dissection, the 3-year RRFS was 85.6%, 76.8%, and 70.0% for T1, T2, and T3 primary lesions, respectively, and was significantly worse for T2 or higher (p = 0.035)., Conclusions: In the absence of extracapsular invasion, regional control did not deteriorate without adjuvant therapy. If prophylactic neck dissection is not performed, careful follow-up is necessary if the primary lesion is T2 or greater., (© 2024 Wiley Periodicals LLC.)

Most of Earth's prokaryotes live under energy limitation, yet the full breadth of strategies that enable survival under such conditions remain poorly understood. Here we report the isolation of a bacterial strain, IA91, belonging to the candidate phylum Marine Group A (SAR406 or 'Candidatus Marinimicrobia') that is unable to synthesize the central cell wall compound peptidoglycan itself. Using cultivation experiments and microscopy, we show that IA91 growth and cell shape depend on other bacteria, deriving peptidoglycan, energy and carbon from exogenous muropeptide cell wall fragments released from growing bacteria. Reliance on exogenous muropeptides is traceable to the phylum's ancestor, with evidence of vertical inheritance across several classes. This dependency may be widespread across bacteria (16 phyla) based on the absence of key peptidoglycan synthesis genes. These results suggest that uptake of exogenous cell wall components could be a relevant and potentially common survival strategy in energy-limited habitats like the deep biosphere., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

A new configuration for near-field ptychography using a full-field illumination with a structured electron beam is proposed. A structured electron beam illuminating the entire field of view is scanned over the specimen, and a series of in-line holograms formed in the near-field region below the specimen are collected. The structured beam is generated by a conductive film with random openings, which ensures high stability and coherence of the beam. Observation in the near-field region reduces the beam concentration that occurs in the far-field region, which contributes to accurate recording of the beam intensity with a finite dynamic range of the detectors. The use of full-field illumination prevents the accumulation of errors caused by concatenating the local structures, which is the method used in conventional reconstruction. Since all holograms are obtained from the entire field of view, they have uniform multiplicity in terms of specimen information within the field of view. This contributes to robust and efficient reconstruction for a large field of view. The proposed method was tested using both simulated and experimental holograms. For the simulated holograms, the reconstruction of the specimen transmission function was achieved with an error less than 1/3485 of the wavelength. The method was further validated using experimental holograms obtained from MgO particles. The reconstructed phase transmission function of the specimen was consistent with the specimen structure and was equivalent to a mean inner potential of V on the MgO particle, which is in close agreement with previously reported values., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Society of Microscopy.)

Introduction: Despite the established cross-sectional association between alcohol intake and serum urate (SU), its longitudinal association remains unknown. This study aimed to determine whether changes in alcohol intake have a clinically relevant association with SU change., Method: We conducted retrospective analyses using systematically collected annual medical examination data from October 2012 to October 2022 in a Japanese preventive medicine centre. The exposure was changes in alcohol intake between two consecutive visits. The association of SU changes with alcohol intake changes was estimated by mixed-effect linear regression with adjustment for relevant covariates., Results: We analysed 63 486 participants (median age, 47.0 years; 55% women; 58.6% regular alcohol drinkers with a median of 1.4 drinks/day) with 370 572 visits. The median SU level was 5.3 mg/dL, and 506 (0.8%) participants had diagnoses of gout or hyperuricemia without medication use during the study period. Decreasing one daily alcohol intake had a clinically small association with SU changes (-0.019 (95% CI: -0.021 to -0.017) mg/dL). Beer had the largest association with SU (-0.036 (95% CI: -0.039 to -0.032) mg/dL for one beer decrease). Complete discontinuation of any alcohol from a mean of 0.8 drinks/day was associated with -0.056 mg/dL (95% CI: -0.068 to -0.043) decrease in SU; the association became larger in hyperuricemic participants (-0.110 mg/dL (95% CI: -0.154 to -0.066) for alcohol discontinuation from a mean of 1.0 drinks/day)., Conclusions: This study revealed changes in alcohol intake had small associations with SU change at the general Japanese population level. Complete discontinuation of alcohol in hyperuricemic participants had only modest improvement in SU., Competing Interests: Competing interests: HT reports personal fees from Chugai Pharmaceutical, AbbVie, Ono Pharmaceutical, Kyowa-Kirin, Takeda Pharmaceutical, Astellas Pharma, Tanabe-Mitsubishi, GSK, Pfizer, Dai-ichi-Sankyo, Eisai, Illy-lily and Ayumi, outside the submitted work. MK reports consulting fees and honoraria from AbbVie, Amgen, Asahi-Kasei Pharma, Astellas, Ayumi Pharma, BMS, Celgene, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Kyowa Kirin, Novartis, Ono Pharma, Pfizer, Tanabe-Mitsubishi, Teijin Pharma, and UCB Pharma, outside the submitted work. SKT reports consulting fees from Novartis.DS reports research grants from CorEvitas, Janssen, Moderna, and Novartis, and royalties from UpToDate. All other authors have no conflict of interest., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

A novel anaerobic, thermophilic bacterium of the class Atribacteria, strain M15 T , was isolated from a high-temperature gas reservoir, Japan. Cells of strain M15 T were gram-negative, short oval-shaped, and lacked flagella. Growth occurred at 45-75 °C (optimum 70-75 °C) and pH 6.5-8.5 (optimum pH 7.5-8.0) and was fast under optimal conditions (doubling time 11.4 h). Yeast extract was required for growth. Fermentative growth with glucose, arabinose, xylose, and cellobiose was observed. The major fermentative end products of glucose were acetate and hydrogen. The major cellular fatty acids were C 16:0 , iso-C 15:0 , and C 18:0 . The genomic G + C content was 46.0 mol%. Fluorescence and electron microscopy observations revealed the intracellular localization of genomic DNA surrounded by a membrane in the cells of strain M15 T as reported in a sole validly described species of the class Atribacteria in the phylum Atribacterota, Atribacter laminatus strain RT761 T , suggesting that the unique morphological traits are widely shared in this class. Phylogenetic analyses indicated that strain M15 T belongs to a distinct family-level lineage in the class Atribacteria and shows low similarities to Atribacter laminatus strain RT761 T (16S rRNA gene sequence identity of 90.1 %, average nucleotide identity [ANI] of 66.1 %, average amino acid identity [AAI] of 55.8 %). Phenotypic traits of strain M15 T (thermophilic, fast-growing, relatively high G + C content, etc.) were clearly distinct from A. laminatus. Based on these phenotypic and genomic properties, we propose a novel genus and species, Atrimonas thermophila gen. nov., sp. nov. for strain M15 T (=JCM39389 T , =KCTC25731 T ) representing a novel family Atrimonadaceae fam., nov. in the class Atribacteria., 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 Authors. Published by Elsevier GmbH.. All rights reserved.)

In this study, we investigated a deleterious mutation in the β-xylosidase gene, xylA (AkxylA), in Aspergillus luchuensis mut. kawachii IFO 4308 by constructing an AkxylA disruptant and complementation strains of AkxylA and xylA derived from A. luchuensis RIB2604 (AlxylA), which does not harbor the mutation in xylA. Only the AlxylA complementation strain exhibited significantly higher growth and substantial β-xylosidase activity in medium containing xylan, accompanied by an increase in XylA expression. This resulted in lower xylobiose and higher xylose concentrations in the mash of barley shochu. These findings suggest that the mutation in xylA affects xylose levels during the fermentation process. Because the mutation in xylA was identified not only in the genome of strain IFO 4308 but also the genomes of other industrial strains of A. luchuensis and A. luchuensis mut. kawachii, these findings enhance our understanding of the genetic factors that affect the fermentation characteristics., (© The Author(s) 2024. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Our previous studies indicate the abundant and diverse presence of yet-to-be-cultured microorganisms in the micropore-filtered fractions of various environmental samples. Here, we isolated a novel bacterium (designated as strain TMPK1T) from a 0.45-μm-filtered soil suspension by using a gel-filled microwell array device comprising 900 microwells and characterized its phylogenetic and physiological features. This strain showed low 16S rRNA gene sequence identities (<91%) and low average nucleotide identity values (<70%) to the closest validly described species, and belonged to a novel-family-level lineage within the order Rhodospirillales of Alphaproteobacteria. Strain TMPK1T exhibited small cell sizes (0.08-0.23 μm3) and had a high cyclopropane fatty acid content (>13%), and these characteristics were differentiated from other Rhodospirillales bacteria. A comprehensive habitability search using amplicon datasets suggested that TMPK1T and its close relatives are mainly distributed in soil and plant-associated environments. Based on these results, we propose that strain TMPK1T represents a novel genus and species named Roseiterribacter gracilis gen. nov., sp. nov. (JCM 34627T = KCTC 82790T). We also propose Roseiterribacteraceae fam. nov. to accommodate the genus Roseiterribacter., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Nakai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Transoral surgery is a minimally invasive treatment but may cause severe dysphagia at a lower rate than chemoradiotherapy., Methods: We compared clinical information, surgical complications, and swallowing function in patients who underwent transoral nonrobotic surgery for laryngo-pharyngeal squamous cell carcinoma between 2015 and 2021 in a multicenter retrospective study., Results: Six hundred and forty patients were included. Postoperative bleeding was observed in 20 cases (3.1%), and the risk factor was advanced T category. Postoperative laryngeal edema was observed in 13 cases (2.0%), and the risk factors were prior radiotherapy, advanced T stage, and concurrent neck dissection in patients with resected HPC. Dysphagia requiring nutritional support was observed in 29 cases (4.5%) at 1 month postoperatively and in 19 cases (3.0%) at 1 year postoperatively, respectively. The risk factors for long-term dysphagia were prior radiotherapy and advanced T category. Short-term risk factors for dysphagia were prior radiotherapy, advanced T category, and concurrent neck dissection, while long-term risk factors for dysphagia were only prior radiotherapy and advanced T category., Conclusion: Prior radiotherapy, advanced T stage, and concurrent neck dissection increased the incidence of postoperative laryngeal edema and short-term dysphagia, but concurrent neck dissection did not affect long-term dysphagia. Such features should be considered when considering the indication for transoral surgery and postoperative management., Competing Interests: Declaration of competing interest The authors have no funding, financial relationship, or conflicts of interest to disclose., (Copyright © 2024. Published by Elsevier B.V.)

Background: Unlike systolic blood pressure (SBP), the prognostic value of diastolic blood pressure (DBP) in kidney function has not been established. We hypothesized that pulse pressure (PP), which is associated with arteriosclerosis, would affect the prognostic value of DBP., Methods: This longitudinal study used data from the Japan Specific Health Checkups Study was conducted between 2008 and 2014. The participants were stratified into three PP subgroups (low PP ≤39, normal PP 40-59 and high PP ≥60 mmHg). The exposures of interest were SBP and DBP, and the association between SBP/DBP and kidney outcomes (30% decline in the estimated glomerular filtration rate from baseline) was examined in each PP subgroup using a Cox proportional hazards model., Results: Among 725 022 participants, 20 414 (2.8%) developed kidney outcomes during a median follow-up period of 34.6 months. Higher SBP was consistently associated with a higher incidence of kidney outcome in all PP subgroups. Although DBP had a positive linear association with the incidence of kidney outcome in low- and normal-PP subgroups, both lower (≤60 mmHg) and higher (≥101 mmHg) DBP were associated with a higher incidence of kidney outcome in the high-PP subgroup, with a U-shaped curve. Hazard ratios (95% confidence intervals) of ≤60 mmHg (reference: 61-80 mmHg in normal-PP subgroup) and ≥101 mmHg were 1.26 (1.15-1.38) and 1.86 (1.62-2.14), respectively., Conclusions: In this large population-based cohort, DBP was differently associated with kidney outcome by PP level; lower DBP was significantly associated with a higher incidence of kidney outcome in the high-PP subgroup but not in the low- and normal-PP subgroups., Competing Interests: Nothing to disclose., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Studies on kidney function and histological findings in diabetic nephropathy (DN) with low urinary protein (UP) are few. We examined the differential impact of histological changes on kidney outcomes between non-proteinuric and proteinuric DN., Methods: Patients diagnosed with DN by renal biopsy during 1981-2014 were divided into non-proteinuric (UP ≤ 0.5 g/day) and proteinuric (UP > 0.5 g/day) DN. The Cox proportional hazard model was used to examine the association of glomerular lesions (GLs) and interstitial fibrosis and tubular atrophy (IFTA) with end-stage kidney disease (ESKD) development after adjusting for relevant confounders., Results: The non-proteinuric and proteinuric DN groups included 197 and 199 patients, respectively. During the 10.7-year median follow-up period, 16 and 83 patients developed ESKD in the non-proteinuric and proteinuric DN groups, respectively. In the multivariable Cox hazard model, hazard ratios (HRs) [95% confidence intervals (CIs)] of GL and IFTA for ESKD in proteinuric DN were 2.94 [1.67-5.36] and 3.82 [2.06-7.53], respectively. Meanwhile, HRs [95% CIs] of GL and IFTA in non-proteinuric DN were < 0.01 [0-2.48] and 4.98 [1.33-18.0], respectively. IFTA was consistently associated with higher incidences of ESKD regardless of proteinuria levels (P for interaction = 0.49). The prognostic impact of GLs on ESKD was significantly decreased as proteinuria levels decreased (P for interaction < 0.01)., Conclusions: IFTA is consistently a useful predictor of kidney prognosis in both non-proteinuric and proteinuric DN, while GLs are a significant predictor of kidney prognosis only in proteinuric DN., (© 2023. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Haploidentical hematopoietic cell transplantation (HCT) using glucocorticoids for acute graft-versus-host disease prophylaxis (GC-haplo) may become a curative treatment option for nonremission acute myeloid leukemia (AML). This retrospective study aimed to identify pre-HCT predictors of survival in a cohort of 97 nonremission AML treated with GC-haplo in Hyogo Medical University Hospital between 2010 and 2020. Relapse and primary induction failure included in 70 (72%) and 27 (28%) patients, respectively. Sixty-one patients (63%) had undergone previous HCT. Multivariate analysis revealed that ≤ 6 months' duration between first complete remission (CR1) and first relapse (Rel1) (CR1-Rel1 interval) (hazard ratio 2.11, 95% confidence interval [CI] 1.15-3.89, P = 0.016) and serum albumin before starting the conditioning treatment of ≤ 3.5 g/dL (hazard ratio 1.80, 95%CI 1.09-2.96, P = 0.022) as risk factors for overall survival. Among three groups categorized according to serum albumin and CR1-Rel1 interval, the best 3-year overall survival was observed in patients with albumin > 3.5 g/dL and CR1-Rel1 interval > 6 months or primary induction failure (50.2%, 95%CI 28.9%-68.3%, P < 0.001), revealing that survival could be predicted using albumin and past CR duration in patients with very high-risk AML not in remission before GC-haplo., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The white koji fungus Aspergillus luchuensis mut. kawachii secretes substantial amounts of citric acid through the expression of the citric acid exporter CexA, a member of the DHA1 family. In this study, we aimed to characterize 11 CexA homologs (Chl proteins) encoded in the genome of A. luchuensis mut. kawachii to identify novel transporters useful for organic acid production. We constructed overexpression strains of chl genes using a cexA disruptant of the A. luchuensis mut. kawachii as the host strain, which prevented excessive secretion of citric acid into the culture supernatant. Subsequently, we evaluated the effects of overexpression of chl on producing organic acids by analyzing the culture supernatant. All overexpression strains did not exhibit significant citric acid accumulation in the culture supernatant, indicating that Chl proteins are not responsible for citric acid export. Furthermore, the ChlH overexpression strain displayed an accumulation of 2-oxoglutaric and fumaric acids in the culture supernatant, while the ChlK overexpression strain exhibited the accumulation of 2-oxoglutaric, malic and succinic acids. Notably, the ChlH and ChlK overexpression led to a substantial increase in the production of 2-oxoglutaric acid, reaching approximately 25 mM and 50 mM, respectively. Furthermore, ChlH and ChlK overexpression also significantly increased the secretory production of dicarboxylic acids, including 2-oxoglutaric acid, in the yellow koji fungus, Aspergillus oryzae. Our study demonstrates that overexpression of DHA1 family gene results in enhanced secretion of organic acids in koji fungi of the genus Aspergillus., (Copyright © 2024 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

A novel method for background signal suppression is introduced to improve the selectivity of dynamic nuclear polarization (DNP) NMR spectroscopy in the study of target molecules within complex mixtures. The method uses subtraction between positively and negatively enhanced DNP spectra, leading to an improved contrast factor, which is the ratio between the target and background signal intensities. The proposed approach was experimentally validated using a reverse-micelle system that confines the target molecules together with the polarizing agent, OX063 trityl. A substantial increase in the contrast factor was observed, and the contrast factor was optimized through careful selection of the DNP build-up time. A simulation study based on the experimental results provides insights into a strategy for choosing the appropriate DNP build-up time and the corresponding selectivity of the method. Further analysis revealed a broad applicability of the technique, encompassing studies from large biomolecules to surface-modified polymers, depending on the nuclear spin diffusion rate with a range of gyromagnetic ratios.

Hematopoietic cell transplantation (HCT) for hematologic malignancies with non-remission disease and/or prior post-transplant relapse have poor relapse-free survival. We previously demonstrated the efficacy of haploidentical reduced-intensity HCT regimen with glucocorticoid-based graft-versus-host disease (GVHD) prophylaxis. We recently showed a possible association between rabbit antithymocyte globulin (rATG) exposure and acute GVHD (aGVHD) risk, leading to hypothesize that optimization of rATG exposure may further improve this regimen. We retrospectively examined the exposure-response association of rATG and key clinical outcomes post haploidentical HCT. We subsequently developed an individualized rATG dosing that optimizes rATG exposure using a previously developed population pharmacokinetic model. Of the 103 patients analyzed, the median age was 47 years (range: 17-70) and majority had a non-remission disease prior to HCT (88%). rATG concentration on day 0 of HCT (C day&#95;0 ) was the strongest predictor of Grade 2-4 aGVHD through day +100. Patients with C day&#95;0  ≥ 20 μg/mL had an approximately 3-fold lower risk of Grade 2-4 aGVHD (hazard ratio [HR]: 0.32, 95% confidence interval [CI]: 0.16, 0.62) and Grade 3-4 aGVHD (HR: 0.33, 95% CI: 0.16, 0.68) as well as an approximately 2-fold lower risk of overall mortality (HR: 0.47, 95% CI: 0.28, 0.77) and relapse (HR: 0.50, 95% CI: 0.26, 0.94). In conclusion, this reduced-intensity haploidentical HCT regimen with exposure-optimized rATG may provide a promising option to patients undergoing high-risk HCT for hematologic malignancy. The developed rATG dosing warrant prospective validation., (© 2024 Wiley Periodicals LLC.)

Isoamyl alcohol is a precursor of isoamyl acetate, an aromatic compound that imparts the ginjo aroma to sake. The isoamyl alcohol biosynthesis pathway in yeasts involves the genes PDC1, PDC5, PDC6, ARO10, and THI3 encoding enzymes that decarboxylate α-ketoisocaproic acid to isovaleraldehyde. Among these genes, THI3 is the main gene involved in isoamyl alcohol biosynthesis. Decreased production of isoamyl alcohol has been reported in yeast strains with disrupted THI3 (Δthi3). However, it has also been reported that high THI3 expression did not enhance decarboxylase activity. Therefore, the involvement of THI3 in isoamyl alcohol biosynthesis remains unclear. In this study, we investigated the role of THI3 in isoamyl alcohol biosynthesis. While reproducing previous reports of reduced isoamyl alcohol production by the Δthi3 strain, we observed that the decrease in isoamyl alcohol production occurred only at low yeast nitrogen base concentrations in the medium. Upon investigating individual yeast nitrogen base components, we found that the isoamyl alcohol production by the Δthi3 strain reduced when thiamine concentrations in the medium were low. Under low-thiamine conditions, both thiamine and thiamine diphosphate (TPP) levels decreased in Δthi3 cells. We also found that the decarboxylase activity of cell-free extracts of the Δthi3 strain cultured in a low-thiamine medium was lower than that of the wild-type strain, but was restored to the level of the wild-type strain when TPP was added. These results indicate that the loss of THI3 lowers the supply of TPP, a cofactor for decarboxylases, resulting in decreased isoamyl alcohol production., (Copyright © 2023. Published by Elsevier B.V.)

Objective: Sinonasal malignant tumors (SNMT) are relatively rare among head and neck malignant tumors. Most are squamous cell carcinomas, and malignant melanomas, olfactory neuroblastomas, adenoid cystic carcinomas, sarcomas, and others also occur. The most common primary site of nasal sinus squamous cell carcinoma is the maxillary sinus. In recent years, a decrease in incidence of maxillary sinus squamous cell carcinoma (MSSCC) has been reported along with a decrease in the incidence of sinusitis. MSSCC is treated with a combination of surgery, radiation, and chemotherapy. Treatment decisions are made according to the progression of the disease, the patient's general condition, and the patient's own wishes. There are variations in treatment policies among facilities due to the specialty of staff and cooperation with other departments at each facility. We conducted a multi-institutional retrospective study to compare outcomes by treatment strategy., Methods: In this study, 340 patients with SNMT who were treated at 13 Hospitals (Head and Neck Oncology Group (Kyoto-HNOG) ) during the 12-year period from January 2006 to December 2017 were included. There were 220 patients with squamous cell carcinoma, 32 with malignant melanoma, 21 with olfactory neuroblastoma, and 67 with other malignancies. Of the squamous cell carcinomas, 164 were of maxillary sinus origin. One hundred and forty cases of MSSCC that were treated radically were included in the detailed statistical analysis., Results: There were 5 cases of cStage I, 9 cases of cStage II, 36 cases of cStage III, 74 cases of cStage IVa, and 16 cases of cStage IVb. There were 92 cases without clinical lymph node metastasis (cN(-)) and 48 cases with clinical lymph node metastasis(cN(+)). Primary tumors were treated mainly by surgery in 85 cases (Surg) and by radical radiation therapy (with or without chemotherapy) of 6-70 Gy in 55 cases(non-Surg). The 5-year overall/disease-free survival rate (OS/DFS) for MSSCC was 65.1%/51.6%. Old age, renal dysfunction, and clinical T progression were independent risk factors for OS, and renal dysfunction was an independent risk factor for DFS. In cN(-) patients, OS and DFS were significantly better in Surg group than in non-Surg group. In cN(+) patients, there was no significant difference in OS and DFS between Surg and non-Surg groups., Conclusion: For patients with MSSCC without lymph node metastasis, aggressive surgery on the primary tumor contributes to improved prognosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests, (Copyright © 2023. Published by Elsevier B.V.)

Aim: To examine whether serum β2-microglobulin (β2-MG) could improve the prediction performance for kidney failure with replacement therapy (KFRT) among patients with diabetic nephropathy (DN)., Methods: Patients with biopsy-proven DN at Nara Medical University Hospital were included. The exposure of interest was log-transformed serum β2-MG levels measured at kidney biopsy. The outcome variable was KFRT. Multivariable Cox regression models and competing-risk regression models, with all-cause mortality as a competing event, were performed. Model fit by adding serum β2-MG levels was calculated using the Akaike information criterion (AIC). The net reclassification improvement (NRI) and integrated discrimination improvement (IDI) indexes were used to evaluate the improvement of predictive performance for 5-year cumulative incidence of KFRT by serum β2-MG levels., Results: Among 408 patients, 99 developed KFRT during a median follow-up period of 6.7 years. A higher serum β2-MG level (1-unit increase in log-transformed serum β2-MG level) was associated with a higher incidence of KFRT, even after adjustments for previously known clinical and histological risk factors (hazard ratio [95% confidence interval {CI}]: 3.30 [1.57-6.94] and subdistribution hazard ratio [95% CI]: 3.07 [1.55-6.06]). The addition of log-transformed serum β2-MG level reduced AIC and improved the prediction of KFRT (NRI and IDI: 0.32 [0.09-0.54] and 0.03 [0.01-0.56], respectively)., Conclusions: Among patients with biopsy-proven DN, serum β2-MG was an independent predictor of KFRT and improved prediction performance. In addition to serum creatinine, serum β2-MG should probably be measured for DN., (© 2023 John Wiley & Sons Ltd.)

This study aimed to investigate the essential role of the kicking action in front crawl. To achieve this objective, we examined the relationships of the hand propulsive force and trunk inclination with swimming velocity over a wide range of velocities from 0.75 m·s -1 to maximum effort, including the experimental conditions of arm stroke without a pull buoy. Seven male swimmers performed a 25 m front crawl at various speeds under three swimming conditions: arm stroke with a pull buoy, arm stroke without a pull buoy (AWOB) and arm stroke with a six-beat kick (SWIM). Swimming velocity, hand propulsive force and trunk inclination were calculated using an underwater motion-capture system and pressure sensors. Most notably, AWOB consistently exhibited greater values than SWIM for hand propulsive force across the range of observed velocities ( p  < 0.05) and for trunk inclination below the severe velocity ( p  < 0.05), and these differences increased with decreasing velocity. These results indicate that 1) the kicking action in front crawl has a positive effect on reducing the pressure drag acting on the trunk, thereby allowing swimmers to achieve a given velocity with less hand propulsive force, and 2) this phenomenon is significant in low-velocity ranges.

In this study, information on injectable anticancer drug use and additional fee for enhanced collaboration (AEC) and additional fee for specific drug management guidance 2 (ASD2) claims from the NDB Open Data Japan (NODJ) dataset and the number of patients with cancer according to sex and age from the National Cancer Registry (NCR) dataset were integrated and evaluated to determine the current status and challenges in pharmacist interventions for patients receiving cancer treatment. The NODJ data, including receipt data billed from 2020 to 2021, were obtained from the Ministry of Health, Labour and Welfare website. The use of injectable anticancer drugs decreased relative to the number of cancer patients aged ≥ 75 years compared to those aged < 75 years. Regarding injectable anticancer drug use, the number of AEC claims was similar between men and women, but the number of ASD2 claims was lower in men than in women. The number of times community pharmacists claimed their ASD2 was approximately 5% of the number of times hospital pharmacists claimed their AEC. This study revealed that several patients did not receive sufficient guidance from community pharmacists compared to hospital pharmacists, suggesting a potential insufficiency in the collaboration between the two groups., Competing Interests: MI is an employee of Kifune Pharmacy. The other authors declare no conflicts of interest., (© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

The "duckweed-microbes co-cultivation method" is a microbial isolation technique that effectively recovers diverse microbes, including rarely cultivated bacterial phyla, from environmental samples. In this method, aseptic duckweed and microbes collected from an environmental sample are co-cultivated for several days, and duckweed-associated microbes are then isolated from its roots using a conventional agar plate-based cultivation method. We herein propose several improvements to the method in order to specifically obtain members of the rarely cultivated bacterial phylum, Verrucomicrobiota. In systems using river water as the inoculum, the marked enrichment of Verrucomicrobiota was observed after 10 days of co-cultivation, particularly in the roots and co-cultivated media. We also successfully isolated 44 strains belonging to subdivisions 1, 3, and 4 of the phylum Verrucomicrobiota from these systems. This was achieved by changing the concentration of nitrogen in the co-cultivation medium, which is known to affect duckweed growth and/or metabolism, and by subjecting the fronds and co-cultivated media as well as the roots after co-cultivation to microbial isolation.

Dispensing errors pose a significant health risk, with drug name similarity being a potential contributory factor. To determine the impact of drug name similarity on dispensing errors within clinical settings, we analyzed 563 dispensing errors at an acute hospital in Japan from April 2015 to June 2018. Drug name similarity between two drugs was classified into Name-Similar and Name-Dissimilar groups using the m2-vwhtfrag index, the value of the drug name similarity. Drug efficacy similarity was categorized into Efficacy-Same, Efficacy-Close, and Efficacy-Far. The drug name similarity and drug efficacy similarity of all possible pair combinations were obtained and similarly classified. The proportion of the number of pairs with dispensing errors per the total number of drug pairs in the hospital's drug formulary in each category was calculated. The highest proportion of the number of pairs with dispensing errors was 36% for the Efficacy-Same and Name-Similar group, and the lowest proportion was 0.022% for the Efficacy-Far and Name-Dissimilar group. The proportion of the number of pairs with dispensing errors was significantly higher in the Name-Similar category than in the Name-Dissimilar category for all drug efficacy categories. Our results indicate that drug name similarity increases the risk of dispensing errors, and that m2-vwhtfrag is a useful indicator to assess dispensing errors in clinical practice. Such drug name and efficacy similarity evaluations can help identify factors causing dispensing errors, and predict the risk of dispensing errors for newly adopted drugs, considering the relationship with the whole drug formulary in the hospital dispensary.

Background: Late laryngopharyngeal cancers after transoral surgery include not only local recurrences but also metachronous multiple cancers., Methods: We compared clinical information, surgical outcomes, and late laryngopharyngeal cancers in patients who underwent transoral nonrobotic surgery for laryngopharyngeal squamous cell carcinoma without lymph node metastases between 2015 and 2021 in a multicenter retrospective study., Results: Four hundred and fifty-seven patients were included. Positive surgical margins were found in 121 patients (26.5%). Twenty-two patients (4.8%) received additional treatment. Positive horizontal margins of invasive carcinoma (p = 0.003) and positive horizontal margins of carcinoma in situ only (p = 0.032) were independent risk factors for local recurrence, and prior radiotherapy (p = 0.001) for metachronous multiple cancers. Local control was significantly worse without additional treatment (p = 0.049), but there was no significant difference in survival., Conclusions: Patients with positive margins had an increased frequency of local recurrence, but salvage therapy was effective., (© 2023 Wiley Periodicals LLC.)

Purpose: Mucosal melanoma of the head and neck (MMHN) is a rare condition. This study aimed to investigate oncological outcomes of surgical intervention in patients with MMHN., Materials and Methods: The study included 34 patients with MMHN who underwent surgical resection as initial treatment at 10 institutions in Japan between July 2005 and June 2015. Results: The 5-year overall survival (OS), local control rate (LCR), disease-free survival (DFS), and disease-specific survival (DSS) rates were 48.7%, 53.4%, 32.4%, and 55.1%, respectively. Based on multivariate analysis, no independent prognostic factors for the 5-year OS and DSS were found. Based on univariate analysis, the 5-year LCR was worse in patients with lesions in the nasal cavity and paranasal sinuses than in the oral cavity and pharynx. However, no differences in oncological outcomes were identified in relation to primary sites, and postoperative radiotherapy (PORT) and adjuvant systemic therapy did not contribute to improvements in the 5-year OS., Conclusions: No independent prognostic factors for the 5-year OS or DSS were identified. Regional or distant recurrences are often identified, regardless of local control with surgical resection. Difficult control of MMHN with conventional therapeutic strategies, such as surgical intervention, PORT, and systemic therapy, has been suggested.

As industrial shochu yeast is a diploid strain, obtaining a strain with mutations in both allelic genes was considered difficult. We investigated a method for disrupting two copies of a homozygous gene with a single transformation. We designed a disruption cassette containing an intact LYS5 flanked by nonfunctional ura3 gene fragments divided into the 5'- and 3'-regions. These fragments had overlapping sequences that enabled LYS5 removal as well as URA3 regeneration through loop-out. Furthermore, both ends of the disruption cassette had an additional repeat sequence that allowed the cassette to be removed from the chromosome through loop-out. First, 45 bases of 5'- and 3'-regions of target gene sequences were added on both ends of this cassette using polymerase chain reaction; the resultant disruption cassette was introduced into a shochu yeast strain (ura3/ura3 lys5/lys5); then, single allele disrupted strains were selected on Lys drop-out plates; and after cultivation in YPD medium, double-disrupted strains, in which replacement of another allelic gene with disruption cassette by loss of heterozygosity and regeneration of URA3 in one of the cassettes by loop-out, were obtained by selection on Ura and Lys drop-out plates. The disruption cassettes were removed from the double-disrupted strain via loop-out between repeat sequences in the disruption cassette. The strains that lost either URA3 or LYS5 were counter-selected on 5-fluoroorotic acid or α-amino adipic acid plates, respectively. Using this method, we obtained leu2/leu2 and leu2/leu2 his3/his3 strains in shochu yeast, demonstrating the effectiveness and repeatability of this gene disruption technique in diploid yeast Saccharomyces cerevisiae., (Copyright © 2023 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

Home healthcare services provided by community pharmacists are essential for maintaining community care, especially in Japan's aging population. Personnel shortage in pharmacies is occasionally cited as the reason why pharmacies are unable to provide home healthcare services. This study examined the relationship between the number of pharmacists in each pharmacy and the provision of home healthcare services. The number of full-time and part-time pharmacists per pharmacy has a positive impact on the provision of home healthcare services. Moreover, the larger the number of pharmacists per pharmacy, the easier it is for the pharmacy to provide home healthcare services. With regard to pharmacies with one full-time pharmacist, there are more pharmacies that provide home healthcare services when the population density of municipalities where the pharmacy is located is high. However, the impact of the number of pharmacists on population density became obscure when the number of full-time pharmacists per pharmacy was three or more. Taken together, these findings indicate that the provision of home healthcare services by pharmacies is related to the number of pharmacists per pharmacy and the population density of the area. This could have implications for widening regional disparities in home healthcare services.

In this study, we investigated the changes in composition, microstructure, and starch molecular structure of shochu koji during preparation. We observed that the gelatinized and outer part of starch was decomposed in priority during the early and middle preparation stages. The gap between the starch granules increased with the delayed time. Finally, the koji microstructure became spongy. Shochu koji mold produced two α-amylases in different expression manners. Acid-labile α-amylase was produced in the early and middle preparation stages. Acid-stable α-amylase and saccharification power were produced in the middle and late stages. Throughout the koji preparation, reducing sugars content reached approximately 13-20 % of the total sugar content, with glucose representing over 70 % of the reducing sugars. α-Glucan fragments with C chains of degree of polymerization (DP) 4-73 were observed in the early and middle stages (<23 h), indicating the degradation of amylopectin at long B chains. In the latter stage, the amount of C chains of DP 6-30 decreased, while the longer C chains (DP 30<) did not change. These results showed that acid-labile α-amylase, acid-stable α-amylase, and saccharification enzymes including glucoamylase and α-glucosidase work preferentially on the amorphous regions of starch granules, and cooperative action of these enzymes during koji preparation contributes to the formation of the observed microstructure. Our study is the first report on the decomposition schemes of starch and the microstructure forming process in shochu koji., Competing Interests: The authors declare that they have no conflict of interest., (2023 by The Japanese Society of Applied Glycoscience.)

The cycle of life and death and Earth's carbon cycle(s) are intimately linked, yet how bacterial cells, one of the largest pools of biomass on Earth, are recycled back into the carbon cycle remains enigmatic. In particular, no bacteria capable of scavenging dead cells in oxygen-depleted environments have been reported thus far. In this study, we discover the first anaerobes that scavenge dead cells and the two isolated strains use distinct strategies. Based on live-cell imaging, transmission electron microscopy, and hydrolytic enzyme assays, one strain (designated CYCD) relied on cell-to-cell contact and cell invagination for degrading dead food bacteria where as the other strain (MGCD) degraded dead food bacteria via excretion of lytic extracellular enzymes. Both strains could degrade dead cells of differing taxonomy (bacteria and archaea) and differing extents of cell damage, including those without artificially inflicted physical damage. In addition, both depended on symbiotic metabolic interactions for maximizing cell degradation, representing the first cultured syntrophic Bacteroidota. We collectively revealed multiple symbiotic bacterial decomposition routes of dead prokaryotic cells, providing novel insight into the last step of the carbon cycle., (© 2023. The Author(s), under exclusive licence to International Society for Microbial Ecology.)

A putative methyltransferase, LaeA, controls citric acid production through epigenetic regulation of the citrate exporter gene, cexA, in the white koji fungus Aspergillus luchuensis mut. kawachii. In this study, we investigated the role of another epigenetic regulator, heterochromatin protein 1, HepA, in citric acid production. The ΔhepA strain exhibited reduced citric acid production in liquid culture, although to a lesser extent compared to the ΔlaeA strain. In addition, the ΔlaeA ΔhepA strain showed citric acid production similar to the ΔlaeA strain, indicating that HepA plays a role in citric acid production, albeit with a less-significant regulatory effect than LaeA. RNA-seq analysis revealed that the transcriptomic profiles of the ΔhepA and ΔlaeA strains were similar, and the expression level of cexA was reduced in both strains. These findings suggest that the genes regulated by HepA are similar to those regulated by LaeA in A. luchuensis mut. kawachii. However, the reductions in citric acid production and cexA expression observed in the disruptants were mitigated in rice koji, a solid-state culture. Thus, the mechanism by which citric acid production is regulated differs between liquid and solid cultivation. Further investigation is thus needed to understand the regulatory mechanism in koji., (Copyright © 2023 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

Fast magic-angle spinning (MAS) solid-state NMR spectroscopy is a powerful tool for gaining structural and dynamic information on solid proteins. To access such information site-specifically, the signal assignment process is unavoidable. In the assignment process, Cα and Cβ chemical shifts are of paramount importance in identifying the type of amino acid residues. Conventionally, however, recording the Cβ chemical shift of solid proteins with relatively short transverse relaxation time is often limited by the long delay required for the magnetization transfer to Cβ spins and its evolution, that is, by the sensitivity drop. In this article, we propose a new method that encodes the Cβ chemical shifts onto the intensities of the scalar-coupled Cα signals by combining an optimal control-based spin manipulation pulse and a spin-state filter. This reduces the total required transverse evolution to less than half of that for the previously proposed method, opening up the concept of the Cβ-encoding nearest-neighbor NMR, for the first time, to solid proteins. Also, the total measurement time was shorter than that required for the explicit Cβ shift evolution. We demonstrate the sequential signal assignment for microcrystalline protein GB1, and then discuss the prospects for more challenging proteins.