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Introduction: Vancomycin requires a population pharmacokinetic (popPK) model to estimate the area under the concentration-time curve (AUC), and an AUC-guided dosing strategy is necessary. This study aimed to develop a popPK model for vancomycin using a real-world database pooled from a nationwide web application (PAT)., Methods: In this retrospective study, the PAT database between December 14, 2022 and April 6, 2023 was used to develop a popPK model. The model was validated and compared with six existing models based on the predictive performance of datasets from another PAT database and the Kumamoto University Hospital. The developed model determined the dosing strategy for achieving the target AUC., Results: The modeling populations consisted of 7146 (13,372 concentrations from the PAT database), 3805 (7540 concentrations from the PAT database), and 783 (1775 concentrations from Kumamoto University Hospital) individuals. A two-compartment popPK model was developed that incorporated creatinine clearance as a covariate for clearance and body weight for central and peripheral volumes of distribution. The validation demonstrated that the popPK model exhibited the smallest mean absolute prediction error of 5.07, outperforming others (ranging from 5.10 to 5.83). The dosing strategies suggested a first dose of 30 mg/kg and maintenance doses adjusted for kidney function and age., Conclusions: This study demonstrated the updating of PAT through the validation and development of a popPK model using a vast amount of data collected from anonymous PAT users., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Integrins are transmembrane receptors that facilitate cell adhesion to the extracellular matrix and neighboring cells. Aberrant expression of integrins has been associated with tumor progression and metastasis in various cancer types. Integrin alpha-5 (ITGA5) is an integrin subtype that serves as a receptor for fibronectin, fibrinogen, and fibrillin-1. The purpose of this study was to elucidate how ITGA5 expression plays a role in human non-small cell lung cancer (NSCLC). Our clinical data, along with data retrieved from The Cancer Genome Database (TCGA), revealed that high ITGA5 expression in NSCLC patients was associated with a lower recurrence-free survival and overall survival. In our in vitro functional assays, ITGA5 overexpression in human NSCLC cell lines resulted in increased cell size, adhesion, and migration properties, while knockdown of ITGA5 restored the phenotypes. Correspondingly, knockdown and inhibition of ITGA5 in endogenously high-expressing NSCLC cell lines resulted in decreased cell size, adhesion, migration, and proliferation. The antiproliferative effect was also confirmed by a reduction in Ki-67 without discernible changes in apoptosis. Collectively, these findings reveal the significant role of ITGA5 in various functional behaviors in NSCLC, providing a potential therapeutic target for NSCLC patients with high ITGA5 expression., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Since homologous recombination deficiency (HRD) is relatively uncommon in pancreatic cancer (PC), its impact on time-to-treatment failure (TTF) among patients undergoing systemic chemotherapy for unresectable and recurrent PC remains uncertain., Methods: Among patients with unresectable and recurrent PC enrolled in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database by July 2023, a total of 1394 patients who underwent first-line chemotherapy with either gemcitabine plus nab-paclitaxel (GnP) or FOLFIRINOX (FFX) and received tissue-based CGP tests after disease progression were included in this study. HRD was defined as the presence of germline or somatic genetic mutations in homologous recombination repair (HRR)-related genes such as ATM, BARD1, BRIP1, BRCA1/2, CHEK2, CDK12, PALB, and RAD51C/D. We investigated the correlation between HRD and TTF among patients treated with GnP and FFX., Results: First-line chemotherapy consisted of GnP in 69% of the cases and FFX in 31%. The CGP tests used were NCC OncoPanel and FoundationOne CDx in 26% and 74%, respectively. HRR-related genetic abnormalities were identified in 107 patients (7.6%): BRCA2 (n = 51), ATM (n = 34), BRCA1 (n = 9), PALB2 (n = 9), among others. In the GnP cohort, the median TTF was comparable between the HRD and non-HRD groups (5.3 vs 4.6 months, P = 0.44). Conversely, in the FFX cohort, it was significantly longer in the HRD group compared to the non-HRD group (7.3 vs. 4.7 months, p < 0.01)., Conclusions: Our findings suggest that HRR-related genetic abnormalities might be predictive of TTF in platinum-based chemotherapy for PC., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no conflict of interest., (© 2024. The Author(s).)

Introduction: Teicoplanin (TEIC) is typically administered as a loading dose over 36-48 h. Achieving an effective concentration quickly is expected to treat severe infections, such as sepsis and methicillin-resistant Staphylococcus aureus infections. We aimed to identify the TEIC loading dose to be completed within 24 h, targeting the concentration of 15-30 μg/mL and factors affecting the loading dose by utilizing the decision tree (DT) model., Methods: Patients treated with TEIC between January 2017 and December 2022 who met the 24-h loading dose regimen were enrolled. A LD 22.5 (corrected TEIC loading dose targeting concentration of 22.5 μg/mL) was determined, factors affecting the concentration were extracted, and a DT model was constructed. The validity of the DT was assessed using the coefficient of determination (R 2 ) in the DT and population pharmacokinetics (PopPK) models for LD 22.5 ., Result: A total of 149 patients were divided into training (n = 104, 70 %) and test groups (n = 45, 30 %). We indicated an average of 14.5 mg/kg for LD 22.5 and extracted four factors (estimated glomerular filtration rate, age, albumin, and C-reactive protein) from the DT model. The R 2 values were 0.724, 0.695, 0.681, and 0.653 for the DT models (training and test groups) and two PopPK models, respectively., Conclusion: We established a 24-h loading dose regimen targeting the TEIC concentration of 15-30 μg/mL and identified four factors affecting the loading dose by using DT. By following the indicated DT algorithm flowchat, optimal decisions regarding the loading dose could be made for TEIC therapy., Competing Interests: Declaration of interest None., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

N ω -hydroxy-l-arginine amidinohydrolase (EC:3.5.3.25), an enzyme in the d-cycloserine (d-CS) biosynthetic pathway of Streptomyces lavendulae, catalyzes the hydrolysis of an arginase inhibitor, N ω -hydroxy-l-arginine, to produce l-ornithine and hydroxyurea, despite being homologous to arginase. Like arginase, the enzyme (DcsB) possesses two manganese ions (Mn A and Mn B ) essential for the enzymatic reaction at the bottom of the cavity formed within the molecule. However, one of the Mn A ligands in DcsB is Cys86, whereas the corresponding residues in arginase are histidine. In this study, we determined the crystal structure of Mn-free DcsB to elucidate the installation mechanism of the manganese ions. The flipping of the His111 residue after the formation of the coordination bond to the second manganese ion may facilitate the installation of Mn B and the closing of the cavity entrance to retain Mn A and Mn B at the active site. Copper ions, which are known to be a positive regulator of many secondary metabolites in Streptomyces species, were found to irreversibly inactivate the catalytic activity of DcsB. Mass spectrometric and crystallographic analyses of the Cu(II)-treated DcsB indicated that Cys86 is oxidized to sulfinic acid. The d-CS biosynthesis in the producing microorganism may be negatively regulated by the concentration of intracellular copper ions, which mediates the oxidative stress., (© 2024 Federation of European Biochemical Societies.)

Aim: Oral care is one of the most neglected nursing practices owing to a lack of training, standard nursing oral care guidelines and low confidence and skills. There is little evidence to inform the development of oral care training and guidelines, which ideally should be done in collaboration with oral health professionals. Further, there is a lack of research, particularly in New Zealand, with nursing staff caring for care-dependent older people, including those ageing in their own homes. This pilot study aimed to determine the impact of oral care training on nursing staff knowledge, attitudes and confidence in supporting community-dwelling older peoples' oral care., Method: Mixed methods design comprising delivery of an oral healthcare and assessment training intervention by a team comprising nursing and oral health professionals, pre- and post-intervention questionnaires (N = 14) and a post-intervention focus group with community-based nursing staff (N = 5)., Results: Staff knowledge significantly improved (p = 0.046) following interprofessional collaborative training, but attitude and confidence scores did not (p = 0.127), although focus group responses suggested that participants' confidence was heightened. Participants expressed the need to implement oral care practices to benefit clients' health, clarify roles and identify oral care as a core competency. They sought to make individual- and organisational-level practice changes accordingly., Conclusion: Oral care training based on interprofessional collaboration and education enhances nursing staff knowledge but not their confidence in oral care provision. Ongoing, hands-on practical training for nursing staff in collaboration with oral health professionals has the potential to advance nursing oral-care practice and improve care-dependent older peoples' oral care., Implication for Practice: Oral care training and education with oral health professionals is effective to enhance nursing staff knowledge and awareness in oral health care. However, transforming knowledge into nursing oral care practice requires hands on practical training and ongoing collaboration with oral health professionals to improve care-dependent older people's oral health care., (© 2024 John Wiley & Sons Ltd.)

Background: Considerable interobserver variability exists in diagnosis of ovarian high-grade endometrioid carcinoma (HGEC) and high-grade serous carcinoma (HGSC) due to histopathological similarities. While homologous recombination deficiency (HRD) correlates with drug sensitivity in HGSC, the molecular features of HGEC are unclear., Methods: Fresh-frozen samples from 15 ovarian HGECs and 274 ovarian HGSCs in the JGOG-TR2 cohort were submitted to targeted DNA sequencing, RNA sequencing, DNA methylation array, and SNP array. We additionally analyzed 555 ovarian HGSCs from TCGA-OV and 287 endometrial high-grade carcinomas from TCGA-UCEC., Results: Unsupervised clustering using copy number signatures identified four distinct tumor groups (C1, C2, C3 and C4). C1 (n = 41) showed CCNE1 amplification and poor survival. C2 (n = 160) and C3 (n = 59) showed high BRCA1/2 alteration frequency with low and moderate ploidy, respectively. C4 (n = 22) was characterized by favorable outcome, higher HGEC proportion, no BRCA1/2 alteration or CCNE1 amplification, and low levels of HRD score, ploidy, intra-tumoral heterogeneity, cell proliferation rate, and WT1 gene expression. Notably, C4 exhibited a normal endometrium-like DNA methylation profile, thus, defined as "HGEC-type" tumors, which were also identified in TCGA-OV and TCGA-UCEC., Conclusions: Ovarian "HGEC-type" tumors present a non-HRD status, favorable prognosis, and endometrial differentiation, possibly constituting a subset of clinically diagnosed HGSCs., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The Great Salt Lake, located in Utah, USA, is a saltwater lake with no outlet and is surrounded by vast mountains and salt deserts. We aimed to use Great Salt Lake-derived processed mineral water (hereafter termed as GSL-MW) for maintaining oral health. Therefore, we examined its radical scavenging activity as an antioxidant and its cytoprotective effect on human gingival fibroblasts (hGFs). The scavenging activity against O 2 •- radicals was determined by an electron spin resonance (ESR)-spin trapping technique using two kinds of O 2 •- generation systems; however, we could not reach any concrete conclusion because of the interference caused by GSL-MW in both systems. Detection of ·OH radicals using the ESR-spin trapping technique and kinetic analyses using double-reciprocal plots (corresponding to Lineweaver-Burk plots that are used to represent enzyme kinetics) revealed that GSL-MW has the ability to scavenge ·OH radicals. GSL-MW also showed a weak 2,2-diphenyl-1-picrylhydrazyl (DPPH; a stable radical)-scavenging activity. Regarding the cytoprotective effects, subconfluent hGFs pretreated with 10× and 100× dilutions of GSL-MW for 3 min and then exposed to harsh environmental conditions, such as pure water or 100 μM H 2 O 2 for 3 min, showed enhanced cell viability rate. Moreover, 10× and 100× dilutions of GSL-MW reduced oxidative damage in confluent hGFs exposed to 12.5 and 25 mM H 2 O 2 . Our findings show that GSL-MW has antioxidant potential and cytoprotective effects on hGFs, suggesting that GSL-MW can be used to maintain oral health.

Objective: Days of antibiotic spectrum coverage (days of ASC: DASC) is a metric for antibiotic usage calculated by ASC scores for spectrum and addresses limitations of days of therapy (DOT), which does not include spectrum. This study aims to investigate whether ASC-related metrics offer different aspects compared to aggregated DOT for all antibiotics (DOT total ) and to assess their correlation in evaluating the impact of antimicrobial stewardship team (AST) programs., Design: Retrospective., Setting: A single center within an 845-bed hospital., Methods: Trends in DOT total , DASC, and the DASC/DOT ratio, representing the average spectrum coverage per therapy day, were analyzed pre- and post-AST programs (April 2018) from January 2015 to December 2023, using interrupted time series analysis. Independent of the DASC/DOT, we also advocated ASC-stratified DOT (ASDOT), which facilitates comprehensive evaluation of DOT across ASC scores of <6, 6-10, and >10, representing narrow-, intermediate-, and broad-spectrum antibiotics., Results: Among inpatients, AST programs significantly moderated the increasing trends of these metrics. Specifically, although the rates of increase in DOT total and DASC were slowed or plateaued, the DASC/DOT ratio decreased ( P < 0.001). ASDOT metrics revealed a decrease and subsequent plateau in DOT total for the broad- and intermediate-spectrum antibiotics, with an increase observed for the narrow-spectrum antibiotics ( P < 0.001 for each). DASC did not provide additional insights in the outpatient's population., Conclusions: The study demonstrates that ASC-related metrics may yield different and useful conclusions about the effectiveness of AST programs for inpatients.

Background: The most effective dosing strategy of meropenem for patients undergoing continuous renal replacement therapy (CRRT) remains uncertain. This study aimed to analyze the population pharmacokinetics (popPKs) of unbound meropenem and establish an appropriate dosing approach., Methods: This prospective study involved 19 patients for the development of a popPK model and an additional 10 for its validation. Ethical approval was obtained., Results: The clearance of unbound meropenem was influenced by the sequential organ failure assessment (SOFA) score [=2.22 × (SOFA score/12)^1.88] and the effluent flow rate from the CRRT device, with an interindividual variability of 44.5%. The volume of distribution was affected by the simplified acute physiology score II [=23.1 × (simplified acute physiology score II/52)^1.54]. Monte Carlo simulations suggested meropenem doses ranging from 1.0 to 3.0 g/d using continuous infusion to achieve a target time above the 4 times of minimum inhibitory concentration of the unbound form (% f T >4×MIC ) of 100% for definitive therapy. For empirical therapy, a dose of 1.0 g/d using continuous infusion was recommended to target % f T >MIC of 100%., Conclusions: This study developed a popPK model for unbound meropenem in patients undergoing CRRT and formulated dosing guidelines., Clinical Trial Registration: UMIN000024321., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Channelrhodopsins are microbial light-gated ion channels that can control the firing of neurons in response to light. Among several cation channelrhodopsins identified in Guillardia theta (GtCCRs), GtCCR4 has higher light sensitivity than typical channelrhodopsins. Furthermore, GtCCR4 shows superior properties as an optogenetic tool, such as minimal desensitization. Our structural analyses of GtCCR2 and GtCCR4 revealed that GtCCR4 has an outwardly bent transmembrane helix, resembling the conformation of activated G-protein-coupled receptors. Spectroscopic and electrophysiological comparisons suggested that this helix bend in GtCCR4 omits channel recovery time and contributes to high light sensitivity. An electrophysiological comparison of GtCCR4 and the well-characterized optogenetic tool ChRmine demonstrated that GtCCR4 has superior current continuity and action-potential spike generation with less invasiveness in neurons. We also identified highly active mutants of GtCCR4. These results shed light on the diverse structures and dynamics of microbial rhodopsins and demonstrate the strong optogenetic potential of GtCCR4., Competing Interests: Declaration of interests O.N. is a co-founder and scientific advisor for Curreio, Inc. This research was funded by Daiichi Sankyo Co., Ltd. S.H., S.S., S.P.T., and H.K. have a patent related to this work (U.S. Patent No. 12,030,917,　 Japan Patent No. 7492777)., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

We surveyed the status of the secondary finding (SF) disclosure in comprehensive genome profiling (CGP) in 2020. The situation has changed: increase in the number of hospitals that provide CGP, an update to the Comprehensive Tumor Genomic Profiling: Materials for Review of Secondary Findings (CTGPMRSF), and the addition of a liquid biopsy test, FoundationOne ® Liquid CDx (F1L). Moreover, the actual situation was unclear because the 2020 survey did not include all designated and cooperative hospitals. Herein, we conducted a questionnaire survey of all designated-core, designated, and cooperative hospitals to identify the current status and challenges concerning SF in the CGP in 2022. A total of 82.1% of the hospitals responded and 77.7% of the response was from cooperative hospitals. Approximately 80% of the hospitals used CTGPMRSF. SF disclosure, confirmatory test implementation, and SF confirmation rates were 12.4%, 31.6%, and 46.6% for FoundationOne ® CDx (F1CDx), respectively, and 6.8%, 31.8%, and 70.7% for F1L, respectively. The implementation rate of the confirmatory test was substantially higher in hospitals with genetic experts and in hospitals that could conduct confirmatory tests on the same day. Our survey provides insight into how SF is handled in Japan. The percentage of cases leading to confirmatory tests has gradually increased, although challenges such as insurance coverage limitations and varied understanding of SF among patients and healthcare providers persist. With the increasing use of whole-genome analysis, our findings will provide valuable insights into establishing an effective SF disclosure system., (© 2024. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Background: AWaRe (Access, Watch, Reserve) classification proposed by the World Health Organization (WHO) holds potential for assessing antimicrobial stewardship programs (ASPs). However, increase in antibiotics for non-infectious treatment might undermine the effectiveness of using the AWaRe classification for assessing ASPs. The study aimed to evaluate the antimicrobial usage by AWaRe classification and specify issues for assessing ASPs., Methods: The retrospective study was conducted in a single center within an 845-bed hospital. Antimicrobial usage data for outpatients were obtained from medical records used for billing purposes. Antimicrobials for non-infectious treatment were defined by smaller dose of macrolides, tetracyclines with pemphigoid, rifaximin, and prophylactic sulfamethoxazole-trimethoprim (ST) agent., Results: The usage of antimicrobials for non-infectious treatment increased from 25.3 % to 50.1 % for the ratio of the amount to defined daily doses (DDDs) and from 46.3 % to 65.9 % for prescription days between January 2015 and March 2024. The usage of prophylactic sulfamethoxazole-trimethoprim (ST) agents increased by 2.4 times, and the usage of rifaximin increased by more than 100 times. Macrolides for non-infectious treatment was stable or fluctuated while that for infection treatment decreased to that amount for non-infectious treatment. The ratios for Access increased from 31.9 % to 58 % and 42 % to 78 % by excluding the antimicrobials for non-infectious treatment., Conclusions: The findings suggested that the AWaRe classification might not be appropriate for assessing ASPs and comparing them among hospitals., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Aim: Yokukansan is one of the most frequently used herbal medicines that can improve the behavioral and psychological symptoms of dementia. In this exploratory study, we investigated whether yokukansan affects the steady-state blood concentrations of donepezil, risperidone, and the major metabolites of both drugs in a real-world clinical setting., Methods: A non-randomized, open-label, single-arm study examining drug-drug interactions was conducted. Fifteen dementia patients taking donepezil for at least 4 weeks and eight schizophrenia patients taking risperidone for at least 2 weeks were orally administered 2.5 g of yokukansan three times a day before or between meals, and blood samples were collected before and 8 weeks after starting co-treatment with yokukansan. Plasma concentrations of donepezil, risperidone, and each metabolite were measured using high-performance liquid chromatography-tandem mass spectrometry and compared before and after the 8-week administration of yokukansan., Results: The plasma concentrations of donepezil and its metabolites (6-O-desmethyl-donepezil, 5-O-desmethyl-donepezil, and donepezil-N-oxide), risperidone, and its metabolite paliperidone did not differ before and after the 8-week treatment with yokukansan., Conclusions: The findings of this study show that the concomitant use of yokukansan may have little clinical impact on the steady-state blood levels of donepezil and risperidone in patients with dementia or schizophrenia., (© 2024 The Author(s). Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Background: Comprehensive cancer genomic profiling tests have recently been used clinically to guide optimal treatment. Currently approved tests use DNA from tissue or plasma samples to analyze a few hundred genes. RNA panels complement DNA panels to detect fusion and exon skipping., Methods: Between April 2017 and March 2022, we analyzed non-small cell lung cancer samples using Todai OncoPanel, a matched tumor/normal pair panel targeting both DNA and RNA. Publicly available genomic data was downloaded from the Center for Cancer Genomics and Advanced Therapeutics database on 2022/11/3., Results: Sixty non-small cell lung cancer (NSCLC) samples were analyzed. With the DNA panel, 32 samples (53%) had TP53 loss-of-function mutations. Among adenocarcinoma, 17 (33%) had EGFR activating mutations, and 6 (12%) had ERBB2 activating mutations. One BRCA1 and one BRCA2 pathogenic germline variant were also detected. With the RNA panel, 11 fusion genes were detected, all in adenocarcinoma. Specifically, EML4-ALK and KIF5B-RET were detected from one sample each, and 9 others were all novel fusions with unknown pathogenicity. In addition, 4 of 60 (7%) NSCLC samples harbored MET exon 14 skipping. Analysis of the Center for Cancer Genomics and Advanced Therapeutics database found 37 MET exon 14 splice site mutations in 1514 NSCLC samples (2%, p = 0.039)., Conclusions: Analysis of NSCLC with Todai OncoPanel detected many druggable targets. Its RNA panel may detect MET exon 14 skipping with high sensitivity., Competing Interests: Declaration of competing interest Hidenori Kage Shinji Kohsaka, Kenji Tatsuno, Hiroyuki Aburatani, Hiroyuki Mano, and Katsutoshi Oda received research funds from Konica Minolta, Inc. Shinji Kohsaka, Kenji Tatsuno, Hiroyuki Aburatani, Hiroyuki Mano received patent royalties from Konica Minolta, Inc. Katsutoshi Oda received honoraria from Chugai Pharmaceutical Co. The other authors have no conflicts of interest., (Copyright © 2024 [The Author]. Published by Elsevier B.V. All rights reserved.)

Objective: Treatment with immune checkpoint inhibitors (ICIs) has shown clinical benefit for a wide range of cancer types. The neutrophil-to-lymphocyte ratio (NLR) reportedly correlates with survival time or progression-free survival in patients treated with ICIs. However, NLR has not yet been assessed in patients with brain metastases (BMs) receiving stereotactic radiosurgery (SRS) combined with concurrent ICIs. The authors investigated the predictive impact of NLR on the survival data of patients with BMs who received SRS with concurrent ICIs., Methods: The clinical records of patients who had undergone SRS with concurrent ICIs for BMs between January 2015 and August 2023 were retrospectively analyzed. NLR was calculated using the data obtained from the last examination prior to SRS. The optimal NLR cutoff value was identified by receiver operating characteristic (ROC) curve analysis for time-to-event data (overall survival [OS] ≤ 18 months). OS and intracranial disease progression-free survival (IC-PFS) rates were compared between the two NLR groups., Results: Of the 185 eligible patients included, 132 were male. The median (IQR) patient age was 69 (61-75) years. The primary cancers were lung, genitourinary, skin, breast, gastrointestinal, and others in 132, 23, 22, 2, 2, and 4 patients, respectively. The post-SRS median OS and IC-PFS times for the entire cohort were 18.4 (95% CI 14.0-23.1) months and 9.2 (95% CI 6.9-10.8) months, respectively. ROC curve analysis identified the optimal NLR cutoff value for 18-month OS to be 5.0 (area under the curve 0.64, Youden index 0.31). Kaplan-Meier analysis revealed that patients with high NLR (> 5) had a significantly shorter OS (median survival time 10.9 months for 48 patients vs 22.2 months for 137 patients, HR 2.0, 95% CI 1.3-3.0, p < 0.001). Similarly, a significant difference in median IC-PFS was noted: 4.8 months with high NLR versus 10.7 months with low NLR (HR 1.7, 95% CI 1.2-2.5, p = 0.003)., Conclusions: The authors found elevated pre-SRS NLR (> 5) to be associated with shorter OS and IC-PFS after SRS with concurrent ICIs for BMs. NLR is a simple, cost-effective, and widely accessible biomarker, which can thus be used for managing patients with BMs receiving SRS concurrently with ICIs. Further investigation in other large datasets is, however, required to validate these findings.

Background: Previous studies reported the mutational landscape in extramammary Paget's disease (EMPD); however, the prognostic implications of genetic alterations remain unexplored. While CDKN2A loss is known to be associated with tumor progression or poor prognosis in some types of cancer, its significance in EMPD has not been investigated., Objectives: To examine the association between common genetic alterations and prognosis in EMPD., Methods: This is a retrospective cohort study analyzing EMPD cases registered until January 2024 in the Center for Cancer Genomics and Advanced Therapeutics database, which is a nationwide database recording clinical data and comprehensive genomic profiling (CGP) test results in Japan., Results: A total of 167 cases were recorded in the database, with CDKN2A loss being the most frequent genetic variant. Survival analysis was conducted on 127 cases. Survival from chemotherapy initiation was analyzed with adjusting for length bias inherent in the database using the Kaplan-Meier estimator, an established adjustment method. Cases with BRCA2-mutant tumors (n=18) had a worse prognosis than those with BRCA2-wild-type tumors (n=109; HR=2.97, 95% CI 1.46-6.01, p=0.003). Additionally, CDKN2A-mutant group (n=72) had a significantly worse prognosis than those with CDKN2A-wild-type group (n=55; HR=1.81, 95% CI 1.06-3.07, p=0.029). Most CDKN2A variants were pathogenic, primarily characterized by loss, while most BRCA2 variants were variants of uncertain significance. In the analysis of survival from CGP enrollment based on Eastern Cooperative Oncology Group performance status (ECOG-PS), cases with ECOG-PS 1 at the time of CGP enrollment had significantly poorer prognosis than those with ECOG-PS 0 (p=0.034; median survival time, 531 vs. 259 days)., Conclusions: Somatic CDKN2A variant, mainly exhibiting loss, may be associated with poor prognosis in EMPD. Cases with BRCA2-mutant cancer might also have a worse prognosis in EMPD. In addition, CGP testing before PS deteriorates is preferable, considering the observed median survival of individuals undergoing CGP tests in an ECOG-PS-1 condition was less than 9 months., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

The cellular origin of clear cell ovarian carcinoma (CCOC), a major histological subtype of ovarian carcinoma remains elusive. Here, we explored the candidate cellular origin and identify molecular subtypes using integrated genomic/epigenomic analysis. We performed whole exome-sequencing, microarray, and DNA methylation array in 78 CCOC samples according to the original diagnosis. The findings revealed that ARID1A and/or PIK3CA mutations were mutually exclusive with DNA repair related genes, including TP53, BRCA1, and ATM. Clustering of CCOC and other ovarian carcinomas (n = 270) with normal tissues from the fallopian tube, ovarian surface epithelium, endometrial epithelium, and pelvic peritoneum mesothelium (PPM) in a methylation array showed that major CCOC subtypes (with ARID1A and/or PIK3CA mutations) were associated with the PPM-lile cluster (n = 64). This cluster was sub-divided into three clusters: (1) mismatch repair (MMR) deficient with tumor mutational burden-high (n = 2), (2) alteration of ARID1A (n = 51), and (3) ARID1A wild-type (n = 11). The remaining samples (n = 14) were subdivided into (4) ovarian surface epithelium-like (n = 11) and (5) fallopian tube-like (considered as high-grade serous histotype; n = 3). Among these, subtypes (1-3) and others (4 and 5) were found to be associated with immunoreactive signatures and epithelial-mesenchymal transition, respectively. These results contribute to the stratification of CCOC into biological subtypes., (© 2024. The Author(s).)

Background: The workplace is an ideal-and priority-setting for health promotion activities. Developing and implementing workplace health promotion interventions, including oral health promotion activities, can help create health-supporting workplace environments., Objective: To pilot workplace oral health promotion activities among staff working in the aged care sector, report their impact and explore participants' views on the factors that contribute to participation and effectiveness., Methods: This study comprised three phases: (i) the development and face validation of the resources, (ii) a 3-h educational session and (iii) five interview sessions with participants 4-6 weeks following the education session. The recorded interviews were transcribed verbatim and analysed thematically., Results: Eleven community-aged care workforce were invited to five feedback sessions. Ten participants were female and ranged in age from 18 to 64. All participants gave favourable comments about the content and delivery of the training session and accompanying resources. The participants felt that the benefits of WOHP include improved staff knowledge, awareness and oral care routine, the ability to share (and put into practice) the gained knowledge and information with their dependants, a lower risk of having poor oral health that adversely affects their well-being and work tasks, and potentially beneficial impacts on the organization's staff roster. Their attendance in the WOHP was facilitated by being paid to attend and scheduling the sessions during work time. Future WOHP suggestions include the possibility of a one-stop dental check-up at the workplace or staff dental care discounts from local dental practitioners and combining oral health with other health promotion activities., Conclusions: Planning and implementing WOHP was deemed acceptable and feasible in this study context and successfully achieved short-term impacts among community-aged care workers. Appropriate times and locations, organizational arrangements and a variety of delivery options contributed to successful programme planning and implementation., (© 2023 The Authors. Community Dentistry and Oral Epidemiology published by John Wiley & Sons Ltd.)

Neurolymphomatosis (NL) is a rare complication of non-Hodgkin's lymphoma, characterized by the infiltration of lymphoma cells into the peripheral nerves. A 54-year-old woman initially presented with right facial palsy without any other significant symptoms and was diagnosed with Bell's palsy. Despite initial improvement, her condition recurred, prompting further evaluation. Magnetic resonance imaging (MRI) revealed contrast enhancement from the tympanic segment to the surface of the masseter muscle along the right facial nerve and an adjacent mass lesion. Biopsy of the mass revealed a diagnosis of T-cell/histiocyte-rich large B-cell lymphoma. Chemotherapy resulted in complete resolution of facial palsy. Follow-up MRI confirmed the absence of contrast enhancement along the facial nerve. Facial palsy was considered to be caused by NL. This case was classified as that of primary NL because the facial palsy was the first manifestation of a hematologic malignancy. Recurrent facial palsy, which is atypical in Bell's palsy, led to further evaluation with MRI, which finally resulted in the diagnosis of malignant lymphoma. In cases of recurrent facial palsy, clinicians should consider various diagnoses, including that of NL, and advocate early imaging tests and biopsy, if possible, for accurate diagnosis and improved outcomes., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Objective: Anaplastic thyroid carcinoma (ATC) is considered a very aggressive carcinoma and has been difficult to treat with therapeutic strategies. This study examines the landscape of genomic alteration in ATC, including the BRAF V600E mutation, and its clinical implications., Design, Patients and Mesurement: A retrospective observational study was conducted using collected at the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) in Japan, utilizing comprehensive genomic profiling data from 102 ATC cases. Additionally, AACR-GENIE data from 267 cases were analysed for validation. Statistical methods, including the conditional Kendall tau statistic and χ 2 tests, were employed for survival analysis and gene mutation comparisons., Results: Among 102 ATCs, BRAF, RAS, and other driver mutations were found in 83 cases (81.2%). The prevalence of BRAF V600E mutations was as high as 60%. Co-mutation analysis identified different genomic profiles in the BRAF, RAS, and wild-type groups. Despite the diverse molecular backgrounds, no significant differences in clinical variables and overall survival were observed. The analysis considering left-side amputation suggested that RAS mutations had a poorer prognosis. In the BRAF/RAS wild-type group, FGFR1 and NF1 were identified as driver mutations, with an accumulation of copy number variations and less TERT promoter mutations. This molecular subgrouping was also supported by the AACR-GENIE data., Conclusions: Comprehensive genomic analysis of ATC in Japan revealed distinct molecular subgroups, highlighting the importance of BRAF V600E mutations, particularly V600E, as potential therapeutic targets and suggest the relevance of tailor-made therapeutic strategies based on genomic profiling., (© 2024 The Author(s). Clinical Endocrinology published by John Wiley & Sons Ltd.)

Competing Interests: Declaration of competing interest No conflict of interest has been declared by the authors.

Resistance-associated substitutions (RASs) of hepatitis C virus (HCV) affect the efficacy of direct-acting antivirals (DAAs). In this study, we aimed to clarify the susceptibility of the coexistence of nonstructural (NS) 5A Q24K/L28M/R30Q (or R30E)/A92K RASs, which were observed in patients with DAAs re-treatment failure and to consider new therapeutic agents. We used a subgenomic replicon system in which HCV genotype 1B strain 1B-4 was electroporated into OR6c cells derived from HuH-7 cells (Wild-type [WT]). We converted WT genes to NS5A Q24K/L28M/R30Q/A92K or Q24/L28K/R30E/A92K. Compared with the WT, the Q24K/L28M/R30Q/A92K RASs was 36,000-fold resistant to daclatasvir, 440,000-fold resistant to ledipasvir, 6300-fold resistant to velpatasvir, 3100-fold resistant to elbasvir, and 1.8-fold resistant to pibrentasvir. Compared with the WT, the Q24K/L28M/R30E/A92K RASs was 640,000-fold resistant to daclatasvir and ledipasvir, 150,000-fold resistant to velpatasvir, 44,000-fold resistant to elbasvir, and 1500-fold resistant to pibrentasvir. The Q24K/L28M/R30E/A92K RASs was 816.3 times more resistant to pibrentasvir than the Q24K/L28M/R30Q/A92K RASs. Furthermore, a combination of pibrentasvir and sofosbuvir showed therapeutic efficacy against these RASs. Combination regimens may eradicate HCV with NS5A Q24K/L28M/R30E/A92K RASs., (© 2024. The Author(s).)

Background: Treating refractory status epilepticus (RSE) remains a challenge. Thiamylal can be used as a second- or third-line treatment; however, its potential to induce cytochrome P450 (CYP) activity may reduce the concentration of antiepileptic drugs (AEDs) administered prior to thiamylal. This report details a case of RSE patient treated with thiamylal, with monitored concentrations of thiamylal and other AEDs., Case Presentation: A 72-year-old healthy man developed RSE. Despite the administration of various AEDs, his seizures were not resolved. Thiamylal was then administered at an initial bolus dose of 2.1 mg/kg, followed by a continuous infusion of 4.2-5.2 mg/kg/h. The initial thiamylal concentration was observed at 7.8 μg/mL, increasing to 35.2 μg/mL before decreasing after dose reduction and cessation. Concurrently, the concentration of concomitant carbamazepine decreased from 5.59 μg/mL to 2.1 μg/mL and recovered as thiamylal concentration decreased. Lesser impacts were noted for other AEDs., Conclusions: This case report underscored the efficacy of thiamylal in treating RSE. However, it also highlighted the need for clinicians to closely monitor the concentrations of concurrent AEDs, especially carbamazepine, during thiamylal therapy., (© 2024. The Author(s).)

Background: Teicoplanin is used to treat serious Gram-positive bacterial infections. However, the optimal trough concentrations for pediatric patients remain unclear owing to the lack of monitoring guidelines. This study aimed to determine the optimal teicoplanin trough concentration for treating Gram-positive bacterial infections in children., Methods: A systematic review was conducted using 4 databases. Stepwise cutoffs within the range of 10-30 mcg/mL were used for efficacy and safety. Studies were included if they reported treatment success rates and/or all-cause mortality, nephrotoxicity, hepatotoxicity, and thrombocytopenia according to the trough concentration., Results: The meta-analysis included 12 studies involving 830 pediatric patients. Teicoplanin cutoff values of 10, 15, 20, and 30 mcg/mL were reported in 9, 8, 9, and 2 studies, respectively. Trough concentrations <10 mcg/mL significantly reduced the treatment success rate, with an odds ratio of 0.07 and a 95% confidence interval ranging from 0.01 to 0.40. The overall treatment success rate was 50.0% versus 95.7% observed at concentrations ≥10 mcg/mL. However, no significant difference was observed at the 15-, 20-, and 30-mcg/mL cutoffs, when compared with lower concentrations. Trough concentrations <20 mcg/mL were associated with a decreased risk of nephrotoxicity (odds ratio = 0.21; 95% confidence interval, 0.08-0.55). However, hepatotoxicity and thrombocytopenia showed no significant associations with trough concentration ranges between 10 and 30 mcg/mL., Conclusions: Although further prospective studies are required for validation, the authors' findings suggest that 10- to 20-mcg/mL teicoplanin is the optimal trough concentration for enhanced clinical success and reduced toxicity in pediatric patients., Competing Interests: K. Matsumoto received grant support funding from Meiji Seika Pharma Co., Ltd., and Sumitomo Pharma Co., Ltd., and speaker honoraria from Meiji Seika Pharma Co., Ltd. The other authors have no conflicts of interest to declare., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

To develop novel bovine lactoferrin (bLF) peptides targeting bLF-tumour necrosis factor (TNF) receptor-associated factor 6 (TRAF6) binding sites, we identified two peptides that could target bLF-TRAF6 binding sites using structural analysis. Moreover, another peptide that could bind to the TRAF6 dimerization area was selected from the bLF sequence. The effects of each peptide on cytokine expression in lipopolysaccharide (LPS)-stimulated osteoblasts (ST2) and on osteoclastogenesis were examined using an LPS-treated co-culture of primary bone marrow cells (BMCs) with ST2 cells and a single culture of osteoclast precursor cells (RAW-D) treated with soluble receptor activator of NF-κB ligand. Finally, the effectiveness of these peptides against LPS-induced alveolar bone destruction was assessed. Two of the three peptides significantly suppressed LPS-induced TNF-α and interleukin-1β expression in ST2 cells. Additionally, these peptides inhibited and reversed LPS-induced receptor activator of NF-κB ligand (RANKL) upregulation and osteoprotegerin (OPG) downregulation, respectively. Furthermore, both peptides significantly reduced LPS-induced osteoclastogenesis in the BMC-ST2 co-culture and RANKL-induced osteoclastogenesis in RAW-D cells. In vivo, topical application of these peptides significantly reduced the osteoclast number by downregulating RANKL and upregulating OPG in the periodontal ligament. It is indicated that the novel bLF peptides can be used to treat periodontitis-associated bone destruction., (© 2024 The Author(s). Chemical Biology & Drug Design published by John Wiley & Sons Ltd.)

Background: This study aimed to compare the incidence and severity of cervical kyphosis before and after surgery between patients with adolescent idiopathic scoliosis (AIS) with major thoracolumbar/lumbar curves (Lenke type 5C group) and those with major thoracic curves (Lenke type 1A group). Further, factors associated with cervical spinal alignment changes after surgery in the two groups were examined. Methods: This study included consecutive patients with AIS who underwent posterior spinal fusion for Lenke type 1A and 5C curves and who were followed up for at least 1 year. To measure changes in sagittal alignment, all patients underwent radiography before, immediately after, and at 1 year after surgery. The correlation coefficients change the value of the C2-C7 angle before and after surgery (ΔC2-ΔC7) and other spinopelvic parameters were examined. Results: In total, 19 of 30 patients in the Lenke type 1A group and 21 of 36 in the Lenke type 5C group presented with cervical kyphosis preoperatively. Hence, the incidence of cervical kyphosis did not significantly differ between the two groups. Further, the two groups had significantly higher thoracic kyphosis (TK) and greater C2-C7 angles postoperatively. The TK of the Lenke type 5C group further increased at 1 year postoperatively. The Lenke 1A type group presented with a significant re-decrease in the C2-C7 angle at 1 year postoperatively. However, the C2-C7 angle of the Lenke type 5C group did not change. The ΔTK was closely associated with the ΔC2-ΔC7 in the Lenke type 1A group, but not in the Lenke type 5C group. Conclusions: In thoracic AIS, postoperative cervical alignment should achieve an adequate TK and promote correction of the coronal plane curve. Moreover, selective corrective surgery can improve postoperative cervical alignment in lumbar AIS., Competing Interests: The authors declare no conflict of interest.

Glucose, a key component of traditional Japanese fermented foods, is derived from rice starch via saccharification by hydrolytic enzymes produced by Aspergillus oryzae . The δ 13 C value of glucose reflects that of its rice source. However, the influence of saccharification parameters (glucose concentration, degradation temperature, and reaction time) on glucose δ 13 C values is unclear. Here, we investigated the influence of saccharification on the δ 13 C value of glucose. Our experiments showed a significant difference in the δ 1 ³C value of glucose (-27.0 ± 0.1 ‰) obtained from saccharification compared to the ingredient rice (-27.1 ± 0.1 ‰) and remaining solid residue (-27.1 ± 0.1 ‰); however, it did not differ significantly from those of rice koji (-27.0 ± 0.1 ‰) and steamed rice (-27.1 ± 0.1 ‰), despite all values being within 0.1 ‰. Notably, glucose concentration, degradation temperature, and reaction time did not significantly affect glucose δ 13 C values. These findings demonstrate the remarkable preservation of glucose δ 13 C values. The δ 13 C values remain aligned with the original δ 13 C value of the rice, even with up to 60 % degradation during A. oryzae saccharification. This persistence of the δ 13 C value throughout the process offers a potential tool for authenticating the origin of rice-fermented beverages based on the δ 13 C value of their glucose component., Competing Interests: 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., (© 2024 The Authors.)

Background: Cefiderocol is a siderophore cephalosporin antibiotic with bactericidal activity against carbapenem-resistant Enterobacterales. However, an efficient dosing strategy is yet to be developed. This study aimed to evaluate efficient lower-dose regimens and estimate potential drug cost reductions., Methods: This simulation study used a virtual population of 10,000 resampled individuals based on a reported population pharmacokinetic model. The target index for maximal bactericidal activity was the time for the unbound cefiderocol concentration to be above the minimum inhibitory concentration (TAM&#95;unbound) of 100%, which was determined using a minimum inhibitory concentration distribution or specific value., Results: The probability of achieving 100% TAM&#95;unbound with the standard, low- (reduced by 1 g or one dose), and extended low- (reduced by 2 g or 2 doses) dose regimens was nearly 100%. The lowest probability of achieving 100% TAM&#95;unbound with the extended low-dose regimen at a creatinine clearance range of 90-120 mL/min was 86.4%. The probability of achieving TAM&#95;unbound of 100% was more than 90% for MIC of ≤0.5 mcg/mL with the extended low-dosing regimen. Furthermore, using an efficient dosing regimen reduced the medical costs over a 10-day treatment period for 10 patients, from $122,826.50 to $62,665.69 $ and ¥12,598,187 $ to ¥5,451,173 in the United States and Japan, respectively., Conclusionss: A lower dosing regimen for cefiderocol could result in substantial reductions in drug costs while still achieving 100% TAM&#95;unbound., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

A 62-year-old man visited his primary care physician with the complaints of loss of appetite and fatigue. He was admitted to our hospital based on a diagnosis of acute kidney injury, Fanconi syndrome as indicated by hypokalemia, hypouricemia, hypophosphatemia, elevated glucose levels in urine, and aminoaciduria. He had been taking multiple supplements, including Red Yeast Rice Cholesterol Help®, for one and a half years. After admission, all the supplements were stopped. Blood samples were collected; however, the samples were negative for diseases that could cause Fanconi syndrome. Renal biopsy revealed renal proximal tubular damage, mainly characterized by simplification of the proximal tubular epithelium. The mycotoxin, citrinin, which is reported to be produced by the mold used for producing red yeast rice, but not the mold Monascus pilosus used for Red Yeast Rice Cholesterol Help ® , reportedly causes proximal tubular damage. However, although the causative agent has not been identified, it was thought that a substance similar to citrinin, produced by the mold used for Red Yeast Rice Cholesterol Help®, caused proximal tubular damage, leading to acute kidney injury and Fanconi syndrome. Hence, all supplements were stopped, and the patient was treated with oral potassium and phosphorus preparations, leading to gradual recovery of his kidney function. We herein report the first case of acute kidney injury and Fanconi syndrome in a patient taking multiple health supplements, including Red Yeast Rice Cholesterol Help®. Early discontinuation of the oral supplements was probably useful in improving the patient's kidney function., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

The effect of shear flows on the thermal conductivity of polymer melts is investigated using a reversed nonequilibrium molecular-dynamics (RNEMD) method. We extended the original RNEMD method to simultaneously produce spatial gradients of temperature and flow velocity in a single direction. This method enables accurate measurement of the thermal conductivity in the direction transverse to shear flow. The Weissenberg number defined with the shear rate and the relaxation time of the polymer conformation can uniformly differentiate the occurrence of shear rate dependence of the thermal conductivity across different chain lengths. The stress-thermal rule (STR) (i.e., the linear relationship between anisotropic parts of the stress tensor and the thermal conductivity tensor) holds for entangled polymer melts even under shear flows but not for unentangled polymer melts. Furthermore, once entanglements form in polymer chains, the stress-thermal coefficient in the STR remains independent of the polymer chain length. These observations align with the theoretical foundation of the STR, which focuses on energy transmission along the network structure of entangled polymer chains [B. van den Brule, Rheol. Acta 28, 257 (1989)0035-451110.1007/BF01329335]. However, under driven shear flows, the stress-thermal coefficient is notably smaller than that measured in the literature for a quasiquiescent state without external forces. Although the mechanism of the STR in shear flows has yet to be fully elucidated, our study confirmed the validity of the STR in shear flows. This allows us to use the STR as a constitutive equation for computational thermofluid dynamics of polymer melts, thus having broad engineering applications.

Approximately 30% of steroid-resistant nephrotic syndromes are attributed to monogenic disorders that involve 27 genes. Mutations in KANK family members have also been linked to nephrotic syndrome; however, the precise mechanism remains elusive. To investigate this, podocyte-specific Kank1 knockout mice were generated to examine phenotypic changes. In the initial assessment under normal conditions, Kank1 knockout mice showed no significant differences in the urinary albumin-creatinine ratio, blood urea nitrogen, serum creatinine levels, or histological features compared to controls. However, following kidney injury with adriamycin, podocyte-specific Kank1 knockout mice exhibited a significantly higher albumin-creatinine ratio and a significantly greater sclerotic index than control mice. Electron microscopy revealed more extensive foot process effacement in the knockout mice than in control mice. In addition, KANK1 -deficient human podocytes showed increased detachment and apoptosis following adriamycin exposure. These findings suggest that KANK1 may play a protective role in mitigating podocyte damage under pathological conditions.

Bacteria have two routes for the l-methionine biosynthesis. In one route called the direct sulfuration pathway, acetylated l-homoserine is directly converted into l-homocysteine. The reaction using H 2 S as the second substrate is catalyzed by a pyridoxal 5'-phosphate-dependent enzyme, O -acetylhomoserine sulfhydrylase (OAHS). In the present study, we determined the enzymatic functions and the structures of OAHS from Lactobacillus plantarum ( Lp OAHS). The Lp OAHS enzyme exhibited the highest catalytic activity under the weak acidic pH condition. In addition, crystallographic analysis revealed that the enzyme takes two distinct structures, open and closed forms. In the closed form, two acidic residues are sterically clustered. The proximity may cause the electrostatic repulsion, inhibiting the formation of the closed form under the neutral to the basic pH conditions. We concluded that the pH-dependent regulation mechanism using the two acidic residues contributes to the acidophilic feature of the enzyme., Importance: In the present study, we can elucidate the pH-dependent regulation mechanism of the acidophilic OAHS. The acidophilic feature of the enzyme is caused by the introduction of an acidic residue to the neighborhood of the key acidic residue acting as a switch for the structural interconversion. The strategy may be useful in the field of protein engineering to change the optimal pH of the enzymes. In addition, this study may be useful for the development of antibacterial drugs because the l-methionine synthesis essential for bacteria is inhibited by the OAHS inhibitors. The compounds that can inhibit the interconversion between the open and closed forms of OAHS may become antibacterial drugs., Competing Interests: The authors declare no conflict of interest.

Mastitis causes significant economic losses to the dairy industry due to decreased milk production in infected cows. Identification of mastitis-causing pathogens, such as streptococci, is necessary for selecting an effective antibiotic for treating mastitis. Although bacterial cultivation is widely used for pathogen identification, it requires more than 24 hr to complete. Contrarily, Lateral flow assays are simple, rapid, and inexpensive testing procedures. In this study, the effectiveness of an immunochromatographic test kit for detecting streptococci in milk samples from cows with clinical mastitis was evaluated as an alternative to bacterial cultivation. The performance of the immunochromatographic test kit for detecting mastitis-causing pathogens was compared with that of bacterial cultivation and real-time quantitative polymerase chain reaction (qPCR). The sensitivity and specificity of the immunochromatographic test kit were 0.800 and 0.875, respectively, compared with bacterial cultivation. Additionally, the κ statistic values of the immunochromatographic test kit was 0.667, indicating substantial agreement with the results of bacterial cultivation. Statistically, sensitivity and specificity of the immunochromatographic kit and real-time qPCR did not differ significantly; thus, the immunochromatographic test kit detected mastitis-causing streptococci as effectively as real-time qPCR. Therefore, the immunochromatographic kit is a rapid, inexpensive, and simple method for detecting streptococci and contributes to the timely selection of appropriate antibiotics for treatment and promotes early recovery from mastitis.

In the past few years, the face mask has been recommended for the prevention of exposing others to COVID-19. Wearing a face mask may have the potential to increase dyspnea and discomfort during exercise; however, controversy exists on whether wearing face masks during exercise affects exercise performance, perception, and mood in runners. We investigated the physiological and perceptual responses of healthy male adults who had experienced long-distance running while exercising at different intensities. Nine healthy young adults who were long-distance runners wearing surgical face mask conducted an incremental treadmill protocol. The protocol was three 6-min stages (20%, 40%, and 60% of maximal heart rate, respectively). The rating of perceived exertion (RPE) and the feeling scale (FS) were measured. RPE was higher in mask condition than in unmask condition (No mask vs. Face mask, light; 8.22 vs. 8.78, p = 0.615, middle; 10.00 vs. 10.78, p = 0.345, high; 12.33 vs. 13.67, p = 0.044.), while FS was not different between conditions. The present study shows that wearing a mask may increase rating of perceived exertion and discomfort when the exercise intensity exceeds a certain threshold in healthy male adults who have experienced long-distance running., (© 2024 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

The PTPRQ gene has been identified as one of the genes responsible for non-syndromic sensorineural hearing loss (SNHL), and assigned as DFNA73 and DFNB84. To date, about 30 causative PTPRQ variants have been reported to cause SNHL. However, the detailed clinical features of PTPRQ -associated hearing loss (HL) remain unclear. In this study, 15,684 patients with SNHL were enrolled and genetic analysis was performed using massively parallel DNA sequencing (MPS) for 63 target deafness genes. We identified 17 possibly disease-causing PTPRQ variants in 13 Japanese patients, with 15 of the 17 variants regarded as novel. The majority of variants identified in this study were loss of function. Patients with PTPRQ -associated HL mostly showed congenital or childhood onset. Their hearing levels at high frequency deteriorated earlier than that at low frequency. The severity of HL progressed from moderate to severe or profound HL. Five patients with profound or severe HL received cochlear implantation, and the postoperative sound field threshold levels and discrimination scores were favorable. These findings will contribute to a greater understanding of the clinical features of PTPRQ -associated HL and may be relevant in clinical practice.

Objectives: In recent years, Vancomycin (VCM) dosing design using area under the concentration-time curve (AUC) has been recommended as a measure of efficacy and safety, but there are fewer reports on pediatric patients than on adults. In this study, we evaluated the threshold of AUC for AKI occurrence in pediatric patients and investigated the factors that contribute to the occurrence of AKI., Methods: Pediatric patients aged 1-15 years on VCM treatment who underwent TDM at Kagoshima University Hospital from April 2016 to March 2022 were included in the computation of AUC using pediatric population pharmacokinetic parameters., Results: The ROC curve showed that the AUC threshold for the risk of developing AKI was 583.0 μg・h/mL, and the AUC-ROC curve was 0.873 (sensitivity 0.930, specificity 0.750). Univariate analysis showed that factors associated with AKI incidence were the duration of VCM administration, ICU admission, and AUC SS . Concomitant medications identified as risk factors for AKI incidence were tazobactam/piperacillin, liposomal amphotericin B, calcineurin inhibitors, contrast agents, and H 2 -receptor blockers. The multivariate analysis showed that AUC ≧ 583.0 μg・h/mL (odds ratio 20.14, 95% CI 3.52-115.22, p < 0.001) and H 2 -receptor blockers (odds ratio 8.70, 95% confidence interval = 1.38-54.87, p = 0.02) were independent factors for AKI incidence., Conclusions: We showed that in pediatric patients receiving VCM, the risk of AKI increases as AUC increases. The findings imply that concurrent use of VCM and H 2 -receptor blockers may increase the risk of AKI., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Kazuaki Matsumoto reports a relationship with Meiji Seika Pharma Co., Ltd that includes: funding grants. Kazuaki Matsumoto reports a relationship with Sumitomo Pharma Co., Ltd that includes: funding grants. Kazuaki Matsumoto reports a relationship with Meiji Seika Pharma Co., Ltd that includes: speaking and lecture fees. co-author is the editor of Journal of Infection and Chemotherapy – Kazuaki Matsumoto., (Copyright © 2023 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: We aimed to evaluate patient-reported outcomes (PROs) of stereotactic radiosurgery (SRS) for TN in terms of treatment efficacy and toxicity., Methods: We retrospectively analyzed patients who underwent Gamma Knife SRS for idiopathic or classic TN between January 2013 and February 2022. Questionnaires regarding pain relief, treatment toxicity, and post-SRS treatment were sent between late 2022 and early 2023, and the responses received were analyzed. The Faces Pain Scale (FPS, 0: best, 5: worst) was used for quantitative evaluation., Results: Responses were received from 51 patients (76%). The mean pre-SRS FPS score was 4.1 (standard deviation (SD) 1.1). Forty-three patients (83%) reported initial pain relief and the best post-SRS FPS score was 1.1 (SD 1.5) (P < 0.001). At a median follow-up of 50 months, the FPS score was still 1.1 (SD 1.6) (P < 0.001). Analysis of factors contributing to durable pain relief showed neurovascular compression to be associated with FPS score improvement (Odds ratio 5.7, 95% CI 1.1-29.7, P = 0.038). Facial dysesthesia had a mean pre-SRS FPS score of 1.7 (SD 2.0) and a mean score of 1.4 (SD 1.7) at the last follow-up (P = 0.32). Eight patients (15%) received post-SRS interventions and 21 (40%) no longer required pharmacotherapy without post-SRS intervention. Forty-four patients (85%) reported being satisfied with SRS., Conclusions: We analyzed PROs of SRS for TN using the FPS and showed SRS to be a safe and effective treatment modality achieving long lasting pain relief., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Competing Interests: Conflicts of interest None disclosed.

Aims: Amikacin requires therapeutic drug monitoring for optimum efficacy; however, the optimal model-informed precision dosing strategy for the area under the concentration-time curve (AUC) of amikacin is uncertain. This simulation study aimed to determine the efficient blood sampling points using the Bayesian forecasting approach for early achievement of the target AUC range for amikacin in critically ill patients., Methods: We generated a virtual population of 3000 individuals using 2 validated population pharmacokinetic models identified using a systematic literature search. AUC for each blood sampling point was evaluated using the probability of achieving a ratio of estimated/reference AUC at steady state in the 0.8-1.2 range., Results: On day 1, the 1-point samplings for population pharmacokinetic models showed a priori probabilities of 26.3 and 45.6%, which increased to 47.3 and 94.4% at 23 and 15 h, respectively. Using 2-point sampling at the peak (3 and 4 h) and trough (24 h) on day 1, these probabilities further increased to 72.3 and 99.5%, respectively. These probabilities were comparable on days 2 and 3, regardless of 3 and 6 sampling points or estimated glomerular filtration rate. These results indicated the higher predictive accuracy of 2-point sampling than 1-point sampling on day 1 for amikacin AUC estimation. Moreover, 2-point sampling was a more reasonable approach than rich sampling., Conclusions: This study contributes to the development of an efficient model-informed precision dosing strategy for early targeting of amikacin AUC in critically ill patients., (© 2024 British Pharmacological Society.)

Carcinoid syndrome is caused by the release of serotonin and other substances, which commonly occurs due to liver metastasis of neuroendocrine tumors. It rarely occurs due to liver metastasis of neuroendocrine carcinoma. We report the case of a patient with liver metastasis of neuroendocrine carcinoma who suffered from acute abdominal pain and diarrhea triggered by hemodialysis. Various differential diagnoses were considered, but we concluded these symptoms to be probably caused by exacerbation of carcinoid syndrome, as the serum 5HIAA level was markedly elevated, and a drug with anti-serotonin activity was effective. Prochlorperazine maleate, which has anti-serotonin activity, was effective for these symptoms, and the patient was able to continue maintenance hemodialysis, which contributed to his quality of life and prognosis. We speculated the mechanism of carcinoid exacerbation was that substances such as serotonin had entered the systemic circulation via the increased extrahepatic shunt of the portal venous blood flow, entering the inferior vena cava and that this condition had been triggered by hemodialysis via the same mechanism as portal systemic encephalopathy., (© 2023. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Chimeric antigen receptor (CAR) designs that incorporate pharmacologic control are desirable; however, designs suitable for clinical translation are needed. We designed a fully human, rapamycin-regulated drug product for targeting CD33+ tumors called dimerizaing agent-regulated immunoreceptor complex (DARIC33). T cell products demonstrated target-specific and rapamycin-dependent cytokine release, transcriptional responses, cytotoxicity, and in vivo antileukemic activity in the presence of as little as 1 nM rapamycin. Rapamycin withdrawal paused DARIC33-stimulated T cell effector functions, which were restored following reexposure to rapamycin, demonstrating reversible effector function control. While rapamycin-regulated DARIC33 T cells were highly sensitive to target antigen, CD34+ stem cell colony-forming capacity was not impacted. We benchmarked DARIC33 potency relative to CD19 CAR T cells to estimate a T cell dose for clinical testing. In addition, we integrated in vitro and preclinical in vivo drug concentration thresholds for off-on state transitions, as well as murine and human rapamycin pharmacokinetics, to estimate a clinically applicable rapamycin dosing schedule. A phase I DARIC33 trial has been initiated (PLAT-08, NCT05105152), with initial evidence of rapamycin-regulated T cell activation and antitumor impact. Our findings provide evidence that the DARIC platform exhibits sensitive regulation and potency needed for clinical application to other important immunotherapy targets.

Introduction: Human pose estimation, a computer vision technique that identifies body parts and constructs human body representations from images and videos, has recently demonstrated high performance through deep learning. However, its potential application in clinical photography remains underexplored. This study aimed to establish photographic parameters for patients with adolescent idiopathic scoliosis (AIS) using pose estimation and to determine correlations between these photographic parameters and corresponding radiographic measures., Methods: We conducted a study involving 42 patients with AIS who had undergone spinal correction surgery and conservative treatment. Preoperative photographs were captured using an iPhone 13 Pro mounted on a tripod positioned at the head of an X-ray tube. From the outputs of pose estimation, we derived five photographic parameters and subsequently conducted a statistical analysis to assess their correlations with relevant conventional radiographic parameters., Results: In the sagittal plane, we identified significant correlations between photographic and radiographic parameters measuring trunk tilt angles. In the coronal plane, significant correlations were found between photographic parameters measuring shoulder height and trunk tilt and corresponding radiographic measurements., Conclusions: The results suggest that pose estimation, achievable with common mobile devices, offers potential for AIS screening, early detection, and continuous posture monitoring, effectively mitigating the need for X-ray radiation exposure. Level of Evidence: 3., Competing Interests: Conflicts of Interest: The authors declare that there are no relevant conflicts of interest., (Copyright © 2024 The Japanese Society for Spine Surgery and Related Research.)

Histone modification, a major epigenetic mechanism regulating gene expression through chromatin remodeling, introduces dynamic changes in chromatin architecture. Protein arginine methyltransferase 6 (PRMT6) is overexpressed in various types of cancer, including prostate, lung and endometrial cancer (EC). Epigenome regulates the expression of endogenous retrovirus (ERV), which activates interferon signaling related to cancer. The antitumor effects of PRMT6 inhibition and the role of PRMT6 in EC were investigated, using epigenome multi‑omics analysis, including an assay for chromatin immunoprecipitation sequencing (ChIP‑seq) and RNA sequencing (RNA‑seq). The expression of PRMT6 in EC was analyzed using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and immunohistochemistry (IHC). The prognostic impact of PRMT6 expression was evaluated using IHC. The effects of PRMT6‑knockdown (KD) were investigated using cell viability and apoptosis assays, as well as its effects on the epigenome, using ChIP‑seq of H3K27ac antibodies and RNA‑seq. Finally, the downstream targets identified by multi‑omics analysis were evaluated. PRMT6 was overexpressed in EC and associated with a poor prognosis. PRMT6‑KD induced histone hypomethylation, while suppressing cell growth and apoptosis. ChIP‑seq revealed that PRMT6 regulated genomic regions related to interferons and apoptosis through histone modifications. The RNA‑seq data demonstrated altered interferon‑related pathways and increased expression of tumor suppressor genes, including NK6 homeobox 1 and phosphoinositide‑3‑kinase regulatory subunit 1, following PRMT6‑KD. RT‑qPCR revealed that eight ERV genes which activated interferon signaling were upregulated by PRMT6‑KD. The data of the present study suggested that PRMT6 inhibition induced apoptosis through interferon signaling activated by ERV. PRMT6 regulated tumor suppressor genes and may be a novel therapeutic target, to the best of our knowledge, in EC.

In Japan, comprehensive genomic profiling (CGP) tests have been reimbursed under the national health care system for solid cancer patients who have finished standard treatment. More than 50,000 patients have taken the test since June 2019. We performed a nation-wide questionnaire survey between March 2021 and July 2022. Questionnaires were sent to 80 designated Cancer Genomic Medicine Hospitals. Of the 933 responses received, 370 (39.7%) were web based and 563 (60.3%) were paper based. Most patients (784, 84%) first learned about CGP tests from healthcare professionals, and 775 (83.1%) gave informed consent to their treating physician. At the time of informed consent, they were most worried about test results not leading to novel treatment (536, 57.4%). On a scale of 0-10, 702 respondents (75.2%) felt that the explanations of the test result were easy to understand (7 or higher). Ninety-one patients (9.8%) started their recommended treatment. Many patients could not receive recommended treatment because no approved drugs or clinical trials were available (102/177, 57.6%). Ninety-eight patients (10.5%) did not wish their findings to be disclosed. Overall satisfaction with the CGP test process was high, with 602 respondents (64.5%) giving a score of 7-10. The major reason for choosing 0-6 was that the CGP test result did not lead to new treatment (217/277, 78.3%). In conclusion, satisfaction with the CGP test process was high. Patients and family members need better access to information. More patients need to be treated with genomically matched therapy., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Pseudomonas aeruginosa bacteremia is associated with a high mortality rate, and meropenem (MEPM) is commonly used to treat it. However, the relationship between the time above the minimum inhibitory concentration ( f T >MIC ) of MEPM and its therapeutic efficacy in P. aeruginosa bacteremia has not been explored. This study aimed to investigate this relationship by defining the target % f T >MIC of MEPM as 75%. The retrospective study spanned 14 years and included hospitalized patients treated with MEPM for P. aeruginosa bacteremia. Monte Carlo simulation was used to calculate the probability of target attainment (PTA) for each patient, and the threshold for a PTA of 75% f T >MIC associated with in-hospital survival was determined using receiver operating characteristic (ROC) curves. The ROC curve-derived PTA associated with improved in-hospital survival was 65.0%, a significant finding in multivariate logistic regression analysis adjusted for patient background factors (odds ratio: 20.49, 95% confidence interval: 3.02-245.23, p = 0.005). This result suggests a dosing regimen that achieves a PTA of at least 65% when the target f T >MIC of MEPM for treating P. aeruginosa bacteremia is defined as 75%.

Malignant giant cell tumor of bone (GCTB) is identified by the presence of multinucleated giant cells, with an aggressive behavior and a high risk of metastasis, which has not been genetically characterized in detail. H3 histone family member 3A ( H3F3A ) gene mutations are highly recurrent and specific in GCTB. The present study analyzed the clinical information and genomic sequencing data of eight cases of malignant GCTB (out of 384 bone sarcoma samples) using an anonymized genomic database. There were 5 males and 3 females among the cases, with a median age of 33 years at the time of the initial diagnosis. H3F3A G34W and G34L mutations were detected in 3 patients and 1 patient, respectively. In 75% of cases without H3F3A mutation, mitogen-activated protein kinase (MAPK) signaling pathway gene alterations were found (KRAS single nucleotide variant, KRAS amplification, nuclear respiratory factor 1 -BRAF fusion). Moreover, the collagen type I alpha 2 chain -ALK fusion was detected in remaining one case. The most frequent gene alterations were related to cell cycle regulators, including TP53 , RB1 , cyclin-dependent kinase inhibitor 2A/B and cyclin E1 (75%, 6 of 8 cases). On the whole, the present study discovered recurrent MAPK signaling gene alterations or other gene alterations in cases of malignant GCTB. Of note, two fusion genes should be carefully validated following the pathology re-review by sarcoma pathologists. These two fusion genes may be detected in resembling tumors, which contain giant cells, apart from malignant GCTB. The real-world data used herein provide a unique perspective on genomic alterations in clinicopathologically diagnosed malignant GCTB., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Tsuda et al.)

The aim of the present study was to develop a semi-quantitative urine pregnancy test for mares based on the Cuboni reaction and to verify the reliability of this test. The urine specimens were hydrolyzed by heating in the presence of hydrochloric acid. The resulting free estrogens were extracted from the urine matrix using toluene. Sulfuric acid was added to the toluene extract and the mixture was heated again. The lower layer in the test tube containing sulfuric acid was used for fluorescence measurements with excitation at 355 nm and measurement at 535 nm. The fluorometric Cuboni test revealed that the fluorescence counts in urine samples collected after the second trimester of gestation were significantly higher than those obtained from barren mares. The levels of estrogens, including equilin, estrone and estardiol-17β exhibited a dose-dependent increase in fluorescence counts, whereas other steroids, such as progesterone, testosterone, and cortisol, did not affect fluorescence. Heat treatment of urine samples with hydrochloric acid significantly increased the fluorescence counts in those collected after the second trimester of gestation compared to non-pregnant samples, implying the presence of large amounts of conjugated estrogens in pregnant mare urine. Fluorescence counts in urine samples obtained during pregnancy showed a positive relationship with estrone concentrations as measured by enzyme immunoassay. The results of the present study showed that the fluorometric Cuboni test facilitates urine fluorescence counts depending on the urinary estrogen content and is capable of discriminating between pregnancy and non-pregnancy states beyond the second trimester of gestation in mares.