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Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide despite advances in cancer therapeutics. In several gynecological cancers, anti-Müllerian hormone receptor type 2 (AMHR2) mediates AMH-induced growth inhibition and is expressed at high levels. Furthermore, 5%-8% of NSCLCs exhibit high AMHR2 expression, suggesting that AMH may inhibit the progression of some lung cancers. However, the clinical relevance of AMHR2 expression and its role in lung cancer is not fully clarified., Methods: Immunostaining was performed on 79 surgical specimens of NSCLC. The Cancer Genome Atlas RNA-seq data for lung adenocarcinoma were analyzed, and gene ontology and gene set enrichment analyses were performed. In cellular experiments, AMHR2-overexpressing NSCLC cell lines were established, and the role of the AMH-AMHR2 pathway in cell proliferation with recombinant human AMH protein treatment was examined., Results: A total of 13 cases (16.5%) were positive for immunostaining in lung adenocarcinoma tissues; no positive signals were detected in lung squamous carcinoma tissues. Gene expression variation analysis using The Cancer Genome Atlas data showed that the expression of genes related to the cell cycle was downregulated in the AMHR2-high group. Cellular experiments showed that activation of the AMH-AMHR2 pathway suppressed cell proliferation., Conclusion: In lung adenocarcinoma tissues with high expression of AMHR2, activation of the AMH-AMHR2 pathway may suppress cell proliferation., (© 2024 The Authors. Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Background: Kounis syndrome is defined as the concurrence of acute coronary syndromes in the setting of allergic or anaphylactic reactions. It primarily affects men aged 40-70 years and is often associated with chest pain. This syndrome is often unrecognized and undiagnosed in clinical practice due to a low level of awareness. Herein, we present a case of type I Kounis syndrome in a young woman without chest pain., Case Presentation: A 28-year-old Japanese woman with a history of atopic dermatitis received a glycyrrhizin, glutathione, and neurotropin preparation (a preparation of inflamed skin extract from rabbits inoculated with vaccinia virus) at a dermatology clinic to treat pruritus caused by atopic dermatitis. Immediately after the administration, the patient developed abdominal pain and generalized body wheals. The patient was diagnosed with anaphylaxis and was transported to our hospital. She had no chest pain on arrival at our hospital; however, a 12-lead electrocardiogram showed ST elevation in leads I, aVL, V2, and V3, and an echocardiogram showed decreased wall motion in the anterior and lateral walls of the left ventricle. Sublingual nitroglycerin administration improved ST-segment elevation and left ventricular wall motion abnormalities. The patient underwent emergency coronary angiography, which revealed no significant stenosis, and was diagnosed with type I Kounis syndrome., Conclusion: Kounis syndrome without chest pain is rare in young women. Since it can be fatal in cases with severe allergic symptoms such as anaphylaxis, the possibility of concurrent acute coronary syndrome should be considered when treating systemic allergic reactions, regardless of age, sex, or the presence or absence of chest symptoms., (© 2024. The Author(s).)

Design of metal cofactor ligands is essential for controlling the reactivity of metalloenzymes. We investigated a carbene transfer reaction catalyzed by myoglobins containing iron porphyrin cofactors with one and two trifluoromethyl groups at peripheral sites (FePorCF 3 and FePor(CF 3 ) 2 , respectively), native heme and iron porphycene (FePc). These four myoglobins show a wide range of Fe(II)/Fe(III) redox potentials in the protein of +147 mV, +87 mV, +42 mV and -198 mV vs. NHE, respectively. Myoglobin reconstituted with FePor(CF 3 ) 2 has a more positive potential, which enhances the reactivity of a carbene intermediate with alkenes, and demonstrates superior cyclopropanation of inert alkenes, such as aliphatic and internal alkenes. In contrast, engineered myoglobin reconstituted with FePc has a more negative redox potential, which accelerates the formation of the intermediate, but has low reactivity for inert alkenes. Mechanistic studies indicate that myoglobin with FePor(CF 3 ) 2 generates an undetectable active intermediate with a radical character. In contrast, this reaction catalyzed by myoglobin with FePc includes a detectable iron-carbene species with electrophilic character. This finding highlights the importance of redox-focused design of the iron porphyrinoid cofactor in hemoproteins to tune the reactivity of the carbene transfer reaction., (© 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Background/aim: The frequency rate of injection site reactions (ISR) due to fosaprepitant meglumine (Fos APR) has been shown to vary depending on the types of combined anticancer drug. This study aimed to elucidate the impact of Fos APR on ISR in patients receiving paclitaxel and carboplatin, with and without bevacizumab therapy (TC±Bev)., Patients and Methods: This study focused on patients with gynecologic cancer (n=93) who received TC±Bev administration at Fujita Health University Hospital from March 2016 to February 2020, and monitored up to six cycles. The patients were randomly assigned to the Fos APR group (n=47) and the Aprepitant (APR) group (n=46). Using Visual Infusion Phlebitis (VIP) scores, ISR was evaluated by comparing the VIP scores of all cycles using a linear mixed model. The risk factors that contribute to the occurrence of vascular pain throughout all cycles were also examined., Results: The VIP scores of all cycles showed a near significant intergroup difference (p=0.071). Factors that affected the development of vascular pain included Fos APR and age (p=0.027 and 0.049, respectively). Regarding age, patients aged <65 years had a higher risk. Four patients underwent a switch from the originally assigned neurokinin-1 receptor antagonist; in all of these cases, Fos APR was changed to APR for vascular pain., Conclusion: Fos APR may increase the risk for ISR associated with TC±Bev therapy for gynecological cancer., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Small cell lung cancer (SCLC) is the most aggressive type of lung cancer. The overall survival has not improved significantly over the last decades because no major therapeutic breakthroughs have been achieved for over 15 years., Methods: We analyzed a genome-wide loss-of-function screening database to identify vulnerabilities in SCLC for the development of urgently needed novel therapies., Results: We identified SKP2 (encoding S-phase kinase-associated protein 2) and CKS1B (encoding CDC28 protein kinase regulatory subunit 1B) as the two most essential genes in that order in SCLC. Notably, SKP2 and CKS1B comprise the p27 binding pocket of the E3 ubiquitin ligase SCF SKP2 complex. Immunohistochemistry on tissue microarrays revealed that SKP2 was expressed in >95% of samples at substantially higher levels than that observed for commonly used neuroendocrine markers. As expected, SCLC cell lines were sensitive to SKP2 inhibition. Furthermore, SKP2 or CKS1B knockdown induced apoptosis in RB1 mutant cells, whereas it induced senescence in RB1 wild-type cells., Conclusion: Although the mechanism underlying SKP2 knockdown-induced growth inhibition differs between RB1-wild-type and -mutant SCLC, SKP2 can be considered a novel therapeutic target for patients with SCLC regardless of the RB1 mutation status. Our findings indicate that SKP2 is a potential novel clinical diagnostic marker and therapeutic target in SCLC., Competing Interests: Declaration of competing interest Ken Tajima received research funding from Novartis. Kazuhisa Takahashi received research funding from Chugai Pharm, MSD, Ono Pharm, and Bristol-Myers Squibb. Additionally, Kazuhisa Takahashi acknowledges donations from Eli Lilly Japan, Teijin Pharm, Chugai Pharm, Nippon Boehringer Ingelheim, Kyorin Pharm, Taiho Pharm, and Sanofi. The other authors have no conflicts of interest., (Copyright © 2024 [The Author]. Published by Elsevier B.V. All rights reserved.)

Purpose: The quick establishment of adequate vascular access is essential for the technical success of mechanical thrombectomy (MT). Focusing on shifts in aortic arch geometry and aging-related changes, we propose an imaging parameter for predicting access difficulty using chest CT., Methods: Patients with acute anterior circulation large-vessel occlusion who underwent MT from April 2020 to September 2021 were included in this retrospective multicenter observational study. The distance from the sternum to the ascending aorta (S-AAD) was defined as the surrogate marker of access difficulty. Access was defined as difficult when the time from femoral sheath placement to guiding catheter induction (guiding time: GT) ≥ 30 minutes, and the patients were dichotomized into groups with short GT (sGT: GT < 30 min) and long GT (lGT: GT ≥ 30 min)., Results: One hundred fifteen patients were included. There were 12 patients (10.4 %) in lGT group. The median (IQR) S-AAD was 11.9 mm (6.3, 18.3 mm) in sGT group and 6.6 mm (4.0, 10.3 mm) in lGT group, and a significant difference in S-AAD was observed (P = 0.026). In multivariate analyses, dyslipidemia and S-AAD < 5 mm were significantly associated with difficult access (OR, 5.938 [95 % CI, 1.468, 24.022], P = 0.012 for dyslipidemia; OR, 5.147 [95 % CI, 1.267, 20.917], P = 0.022 for S-AAD < 5 mm)., Conclusion: S-AAD is a simple and reliable imaging parameter to predict access difficulty. This parameter may be helpful in selecting the appropriate devices and access routes in preinterventional practice., Competing Interests: Competing interests The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In normal-pressure hydrocephalus, disturbances in cerebrospinal fluid (CSF) circulation occur; therefore, understanding CSF dynamics is crucial. The two-dimensional phase-contrast (2D-PC) method, a common approach for visualizing CSF flow on MRI, often presents challenges owing to prominent vein signals and excessively high contrast, hindering the interpretation of morphological information. Therefore, we devised a new imaging method that utilizes T 2 -weighted high-signal intensification of the CSF and saturation pulses, without requiring specialized imaging sequences. This sequence utilized a T 2 -weighted single-shot fast spin-echo combined with multi-phase imaging synchronized with a pulse wave. Optimal imaging conditions (repetition time, presence/absence of fast recovery, and echo time) were determined using self-made contrast and single-plate phantoms to evaluate signal-to-noise ratio, contrast ratio, and spatial resolution. In certain clinical cases of hydrocephalus, confirming CSF flow using 2D-PC was challenging. However, our method enabled the visualization of CSF flow, proving to be useful in understanding the pathophysiology of hydrocephalus., (© 2024. The Author(s), under exclusive licence to Japanese Society of Radiological Technology and Japan Society of Medical Physics.)

Background: Predictive biomarkers for nivolumab in recurrent or metastatic head and neck squamous cell carcinoma (RMHNSCC) have not yet been established., Methods: The tumor proportion score (TPS), combined positive score (CPS), and soluble forms of programmed cell death ligand-1 (PD-L1) and programmed cell death ligand-2 (PD-L2) were retrospectively analyzed in patients with RMHNSCC treated with nivolumab., Results: The positivity rates for TPS (PD-L1), CPS (PD-L1), TPS (PD-L2), and CPS (PD-L2) were 73.8%, 78.2%, 56.4%, and 78.2%, respectively. Patients with high TPS (PD-L1), CPS (PD-L1), or CPS (PD-L1 and PD-L2) showed significantly prolonged progression-free survival. Favorable overall survival was associated with high CPS (PD-L1 and PD-L2) and low soluble PD-L1 and PD-L2 levels. The expressions of tissue and soluble PD-L1/2 were not correlated., Conclusions: Our study revealed that compared to PD-L1 expression alone, dual expression of PD-L1 and PD-L2 in tissue or soluble form could be feasible biomarkers in patients with RMHNSCC who received nivolumab., (© 2024 Wiley Periodicals LLC.)

Background: Total gastrectomy with D2 dissection including splenectomy (TGS) is usually selected for locally resectable scirrhous gastric cancer (SGC), which was established in the era of surgery alone. However, it remains unclear whether TGS for SGC is justified in the era of effective adjuvant chemotherapy., Methods: This study included 112 SGC patients, consisting of 60 cases treated between January 2000 and December 2006 (Former group), and 52 cases treated between January 2007 and December 2016 (Latter group). We collected clinicopathological data and then examined the survival and the therapeutic value indexes., Results: The background characteristics were well-balanced, except for sex and physical status. The Latter group might be characterized by frequent female (P = 0.037) and poorer physical status (P = 0.048). Adjuvant chemotherapy was administered to 86.5% of the Latter group and was 11.7% of the Former group (P < 0.001). The 5-year-overall survival rate of the Latter group was 58.7% (95% confidence interval: 43.5-71.1), seems better than that of the Former group (44.5%; 95% confidence interval 31.7-56.6) (hazard ratio = 0.758, P = 0.291). Improvement of the index from the Former group was observed in the Latter group at almost all stations. The ratio of the index between two groups was 1.42 at the D1 station and 1.67 at the D2 station. Index of splenic hilar node ranked similarly high in both groups., Conclusion: The therapeutic value index was improved in almost all nodal stations by S-1 adjuvant chemotherapy, especially in D2 nodes. TGS would be more important for locally resectable SGC in the era of effective adjuvant chemotherapy., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Non-alcoholic fatty liver disease (NAFLD) and its advanced stage, non-alcoholic steatohepatitis (NASH), have become increasingly prevalent owing to the rise in metabolic syndromes. Accurate assessment of hepatic fat deposition and inflammation is crucial for diagnosing and managing NAFLD/NASH. We investigated the influence of Gd-EOB-DTPA, (EOB) on proton-density fat fraction (PDFF) measurements using chemical shift-encoded magnetic resonance imaging (CSE-MRI) at 3-T. In total, 431 patients who underwent EOB contrast-enhanced MRI were included. PDFF measurements were obtained from pre- and post-contrast CSE-MRI. Linear regression and Bland-Altman analyses were performed to assess the correlation and agreement between pre- and post-EOB PDFF measurements. Relative enhancement (RE) of the liver was calculated as an EOB uptake index. There was a significant decrease in PDFF following EOB administration compared with the pre-contrast values (P < 0.0001), which was observed across all PDFF ranges (< 10% and ≥ 10%). Linear regression analysis revealed high correlation between pre- and post-EOB PDFF measurements. Bland-Altman analysis indicated a small bias between pre- and post-EOB PDFF values. Subgroup analysis based on RE showed a significant difference in ΔPDFF between patients with high RE (> 120%) and those with lower RE levels. EOB administration resulted in a slight decrease in PDFF measurements obtained using CSE-MRI at 3-T. We were able to generalize and clarify that the PDFF of the liver on 3D CSE-MRI at 3-T was slightly decreased after EOB administration as we used a larger group of patients compared to previous studies., (© 2024. The Author(s), under exclusive licence to Japanese Society of Radiological Technology and Japan Society of Medical Physics.)

Background:  We evaluated the pharmacokinetics (PK) of low-dose (15 mg) edoxaban in very elderly patients (≥80 years) with nonvalvular atrial fibrillation (NVAF) and high bleeding risk., Methods:  This subanalysis of the phase 3, randomized, double-blind, placebo-controlled, multicenter ELDERCARE-AF study evaluated edoxaban plasma concentrations and compared them with the Japanese population of the ENGAGE AF-TIMI 48 and Japanese severe renal impairment (SRI) studies., Results:  The PK analysis population included 451 patients, 53.8% of whom concomitantly used antiplatelet drugs, 41.0% had SRI, and 38.0% had low body weight. Edoxaban plasma concentrations at trough and 1 to 3 hours post-dose in ELDERCARE-AF were 17.3 ± 13.9 ( n  = 427) and 93.3 ± 57.8 ng/mL ( n  = 447), respectively. These values were slightly higher than the 15 mg group in ENGAGE AF-TIMI 48 ( n  = 79; 12.4 ± 12.1 and n  = 115; 78.7 ± 45.0 ng/mL, respectively), lower than the ENGAGE AF-TIMI 48 high-dose reduced to 30 mg group ( n  = 83; 25.1 ± 36.6 and n  = 111; 150 ± 91.6 ng/mL, respectively), but similar to the Japanese SRI study ( n  = 39; 18.4 ± 11.2 and n  = 40; 96.8 ± 48.3 ng/mL, respectively). ELDERCARE-AF patients with SRI and low body weight (≤45 kg) had higher concentrations than those without, and those taking antiplatelet drugs had lower concentrations than those who were not., Conclusion:  PK data support edoxaban 15 mg once daily for very elderly NVAF patients with high bleeding risk, with caution for patients with SRI and/or low body weight., Competing Interests: T.Y. received personal fees from Daiichi Sankyo Co., Ltd. during the conduct of the study; grants and personal fees from Daiichi Sankyo Co., Ltd., Bayer Yakuhin, Ltd., and Bristol Myers Squibb K.K.; personal fees from Pfizer Japan Inc., Nippon Boehringer Ingelheim Co., Ltd., Ono Pharmaceutical Co., Ltd., Toa Eiyo Ltd., Novartis Pharma K.K., and Otsuka Pharmaceutical Co., Ltd. outside the submitted work. Y.I., M.F., and T.H. are employees of Daiichi Sankyo Co., Ltd. S.H. is an employee of Certara, Inc. K.O. received grants and personal fees from Daiichi Sankyo Co., Ltd. during the conduct of the study; personal fees from Daiichi Sankyo Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Bristol-Myers Squibb K.K., Medtronic Japan Co., Ltd., Johnson and Johnson K.K., and Bayer Yakuhin, Ltd. outside the submitted work., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Background and Objective: Lymphangioleiomyomatosis (LAM) is a rare neoplastic disease associated with the functional tumour suppressor genes TSC1 and TSC2 and causes structural destruction in the lungs, which could potentially increase the risk of lung cancer. However, this relationship remains unclear because of the rarity of the disease., Methods: We investigated the relative risk of developing lung cancer among patients diagnosed with LAM between 2001 and 2022 at a single high-volume centre in Japan, using data from the Japanese Cancer Registry as the reference population. Next-generation sequencing (NGS) was performed in cases where tumour samples were available., Results: Among 642 patients diagnosed with LAM (sporadic LAM, n = 557; tuberous sclerosis complex-LAM, n = 80; unclassified, n = 5), 13 (2.2%) were diagnosed with lung cancer during a median follow-up period of 5.13 years. All patients were female, 61.5% were never smokers, and the median age at lung cancer diagnosis was 53 years. Eight patients developed lung cancer after LAM diagnosis. The estimated incidence of lung cancer was 301.4 cases per 100,000 person-years, and the standardized incidence ratio was 13.6 (95% confidence interval, 6.2-21.0; p = 0.0008). Actionable genetic alterations were identified in 38.5% of the patients (EGFR: 3, ALK: 1 and ERBB2: 1). No findings suggested loss of TSC gene function in the two patients analysed by NGS., Conclusion: Our study revealed that patients diagnosed with LAM had a significantly increased risk of lung cancer. Further research is warranted to clarify the carcinogenesis of lung cancer in patients with LAM., (© 2024 Asian Pacific Society of Respirology.)

Purpose: The purpose of the study was to evaluate the efficacy and safety of pre-emptive transcatheter arterial embolization (P-TAE) of aortic side branches to prevent type II endoleak in patients with abdominal aortic aneurysm after endovascular abdominal aneurysm repair (EVAR)., Materials and Methods: This multicenter, prospective, single-arm trial enrolled 100 patients with abdominal aortic aneurysm from nine hospitals between 2018 and 2021. There were 85 men and 15 women, with a mean age of 79.6 ± 6.0 (standard deviation) years (range: 65-97 years). P-TAE was attempted for patent aortic side branches, including the inferior mesenteric artery, lumbar arteries, and other branches. The primary endpoint was late type II endoleak incidence at 6 months post-repair. Secondary endpoints included changes in aneurysmal sac diameter at 6- and 12 months, complications, re-intervention, and aneurysm-related mortality. Aneurysm sac changes at 6- and 12 months was compared between the late and no-late type II endoleak groups., Results: Coil embolization was successful in 80.9% (321/397) of patent aortic side branches, including 86.3% of the inferior mesenteric arteries, 80.3% of lumbar arteries, and 55.6% of other branches without severe adverse events. Late type II endoleak incidence at 6 months was 8.9% (8/90; 95% confidence interval: 3.9-16.8%). Aneurysm sac shrinkage > 5 mm was observed in 41.1% (37/90) and 55.3% (47/85) of the patients at 6- and 12-months post-EVAR, respectively. Patients with late type II endoleak had less aneurysm sac shrinkage than those without type II endoleak at 12 months (-0.2 mm vs. -6.0 mm; P = 0.040). No patients required re-intervention for type II endoleak, and no aneurysm-related mortalities occurred., Conclusion: P-TAE is safe and effective in preventing type II endoleak, leading to early sac shrinkage at 12 months following EVAR., Competing Interests: Declaration of competing interests The authors declare no actual or potential conflict of interest related to this study., (Copyright © 2024 Société française de radiologie. Published by Elsevier Masson SAS. All rights reserved.)

Background: The 3Rs (Reduction, Refinement, Replacement) principle is driving the need for alternative methods in animal testing. Despite advancements in in vitro testing, complex systemic toxicity tests still necessitate in vivo approaches. The aim of this study was to develop a developmental toxicity test protocol using the Iberian ribbed newt ( Pleurodeles waltl ) as a model organism, integrating AI image analysis for embryo selection to improve test accuracy and reproducibility., Methods: We established a developmental toxicity test protocol based on the zebrafish test. Gonadotropin was administered to induce ovulation, and in vitro fertilization was performed. Embryos were imaged at 5-6 and 6-7 h post-fertilization. AI image analysis was utilized to assess embryo viability. The test chemical was administered 24-48 h post-fertilization, and morphological changes were observed daily until day 8. Additionally, a time-lapse photography system was constructed to monitor embryonic development., Results: Out of 24 cultured embryos, 75% developed normally to the late tail bud stage or initial hatching stage, whereas 25% experienced developmental arrest or death. AI image analysis achieved high accuracy in classifying embryos, with overall accuracies of 92.0% and 92.9% for two learning models. The AI system demonstrated higher precision in the selection of viable embryos compared to visual inspection., Conclusion: The Iberian ribbed newt presents a viable alternative model for developmental toxicity testing, adhering to the 3Rs principles. The integration of AI image analysis substantially enhances the accuracy and reproducibility of embryo selection, providing a reliable method for evaluating developmental toxicity in pharmaceuticals., Competing Interests: The authors declare no conflict of interest., (©2024 Tottori University Medical Press.)

Chemical structures of protein surfaces govern intermolecular interaction, and protein functions include specific molecular recognition, transport, self-assembly, etc. Therefore, the relationship between the chemical structure and protein functions provides insights into the understanding of the mechanism underlying protein functions and developments of new biomaterials. In this study, we analyze protein surface features, including surface amino acid populations and secondary structure ratios, instead of entire sequences as input for the classifier, intending to provide deeper insights into the determination of protein classes (cytosol or secreted). We employed a random forest-based classifier for the prediction of protein locations. Our training and testing data sets consisting of secreted and cytosol proteins were constructed using filtered information from UniProt and 3D structures from AlphaFold. The classifier achieved a testing accuracy of 93.9% with a feature importance ranking and quantitative boundary values for the top three features. We discuss the significance of these features quantitatively and the hidden rules to determine the protein classes (cytosol or secreted).

Objective: We assessed microvessel flow within peripheral nerves using nerve sonography in patients with peripheral neuropathy., Methods: This study included consecutive patients with peripheral neuropathy who were admitted to our hospital. The patients were divided into two groups: inflammatory neuropathies for immune-mediated neuropathies, such as Guillain - Barré syndrome and chronic inflammatory demyelinating polyneuropathy, and the rest were defined as non-inflammatory neuropathies. We assessed nerve size and intraneural blood flow at four sites on each median and ulnar nerve. Blood flow was evaluated using color Doppler imaging, advanced dynamic flow (ADF), and superb microvascular imaging (SMI) techniques., Results: Thirty-nine patients (median age, 60.0 years; 20 male) were enrolled in this study. An increase in intraneural blood flow was observed in five patients when evaluated by color Doppler, five patients by ADF, and 13 patients by SMI. An overall analysis of the three methods showed that intraneural blood flow was significantly higher in patients with inflammatory neuropathy than in those with non-inflammatory neuropathy (54.2% vs. 0%, p = 0.0005)., Conclusions: Intraneural hypervascularization is more frequent in patients with inflammatory neuropathy than in those with non-inflammatory neuropathy., Significance: Evaluation of microvessel flow within peripheral nerves may contribute to the diagnosis of peripheral neuropathy., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Extracellular vesicles (EVs) can transfer antigens and immunomodulatory molecules, and such EVs released by antigen-presenting cells equipped with immunostimulatory functions have been utilized for vaccine formulations. A prior high-throughput screening campaign led to the identification of compound 634 ( 1 ), which enhanced EV release and increased intracellular Ca 2+ influx. Here, we performed systematic structure-activity relationship (SAR) studies to investigate the scaffold for its potency as a vaccine adjuvant. Synthesized compounds were analyzed in vitro for CD63 reporter activity (a marker for EV biogenesis) in human THP-1 cells, induction of Ca 2+ influx, IL-12 production, and cell viability in murine bone-marrow-derived dendritic cells. The SAR studies indicated that the ester functional group was requisite, and the sulfur atom of the benzothiadiazole ring replaced with a higher selenium atom ( 9f ) or a bioisosteric ethenyl group ( 9h ) retained potency. Proof-of-concept vaccination studies validated the potency of the selected compounds as novel vaccine adjuvants.

Rapid and accurate identification of Staphylococcus aureus (SA) in blood culture specimens is crucial for timely clinical intervention. Traditional Gram staining methods, although widely accessible and cost-effective, exhibit variable sensitivities and specificities in the BACTEC system. We aimed to develop and validate the "STAPH score," a novel semi-quantitative scoring system that integrates Gram stain morphology and time to positivity to differentiate SA from coagulase-negative staphylococci (CoNS) in blood cultures. We analyzed 148 blood culture specimens from septic patients. Each specimen was assessed independently by two examiners using Gram staining and the STAPH score, which assigns points based on five parameters: cluster size, time to positivity, aerobic enlargement, pint (three-dimensional appearance), and the presence of hemorrhage. Sensitivity and specificity were calculated for various cutoff points. Cohen's kappa coefficient was used to assess inter-examiner agreement. Of the 148 specimens, 49 (33.1%) were identified as SA and 99 (66.9%) as CoNS. At a STAPH score cutoff of 3 points, the sensitivity was 93.9% (95% confidence interval [CI], 83.1%-98.7%) and specificity was 91.9% (95% CI, 84.7%-96.4%). The kappa coefficient at this cutoff was 0.67 (95% CI, 0.55-0.79). A STAPH score <3 effectively ruled out SA with 100% sensitivity, whereas a score of 5 confirmed SA with 100% specificity. The STAPH score is a reliable and efficient tool for the rapid identification of SA in blood cultures within the BACTEC system. By combining Gram staining observations with time to positivity, this method enhances diagnostic accuracy, reduces subjectivity, and supports timely clinical decision-making.IMPORTANCEThe rapid and accurate identification of Staphylococcus aureus (SA) in blood cultures is vital for timely and appropriate clinical intervention. This study introduces the "STAPH score," a novel semi-quantitative scoring system that combines Gram stain morphology and time to positivity. By providing a reliable and efficient method to differentiate SA from coagulase-negative staphylococci, the STAPH score enhances diagnostic accuracy and reduces subjectivity in microscopic examinations. This score, applicable within the BACTEC system, addresses the limitations of traditional Gram staining methods and expensive molecular techniques. The implementation of the STAPH score in clinical practice can lead to faster diagnosis, improved patient outcomes, and optimized antimicrobial therapy. This method is particularly valuable in resource-limited settings where advanced diagnostic tools may not be available.

Neuroimaging databases for neuro-psychiatric disorders enable researchers to implement data-driven research approaches by providing access to rich data that can be used to study disease, build and validate machine learning models, and even redefine disease spectra. The importance of sharing large, multi-center, multi-disorder databases has gradually been recognized in order to truly translate brain imaging knowledge into real-world clinical practice. Here, we review MRI databases that share data globally to serve multiple psychiatric or neurological disorders. We found 42 datasets consisting of 23,293 samples from patients with psychiatry and neurological disorders and healthy controls; 1245 samples from mood disorders (major depressive disorder and bipolar disorder), 2015 samples from developmental disorders (autism spectrum disorder, attention-deficit hyperactivity disorder), 675 samples from schizophrenia, 1194 samples from Parkinson's disease, 5865 samples from dementia (including Alzheimer's disease), We recognize that large, multi-center databases should include governance processes that allow data to be shared across national boundaries. Addressing technical and regulatory issues of existing databases can lead to better design and implementation and improve data access for the research community. The current trend toward the development of shareable MRI databases will contribute to a better understanding of the pathophysiology, diagnosis and assessment, and development of early interventions for neuropsychiatric disorders., (© 2024 The Author(s). Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Fruit maturity at harvest is a major factor in determining its quality. In this study, external skin color of grape has been utilized to predict their chemical content and, in turn, the maturity of the fruit. Measurements of the chemical content such as Brix and acidity were made on ten bunches of "Shine Muscat" grapes at three different harvest periods (immature, mature, and overmature). Using a machine vision system, color and UV-excited fluorescence images of grape berries and bunches were taken during the respective harvest stages. Acquired images were processed using ImageJ to obtain RGB values. Rratio and a*/b* are strongly related to Brix and sugar-to-acid ratio of grape fruit, with regression coefficients of 0.5626 and 0.5180, repectively. It was found that a* color index was the best predictor of grape bunch maturity. Furthermore, discriminant analysis has shown that color images of grape berries perform better than 365 nm fluorescence images., 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 Elsevier Ltd. All rights reserved.)

Surface-enhanced Raman scattering (SERS) is widely recognized as a remarkably powerful analytical technique that enables trace-level detection of organic molecules on a metal surface in aqueous systems with negligible spectral interference of water. This insensitivity of SERS to liquid water is violated in a restrictive manner under specific electrochemical conditions. However, the origin of such different SERS sensitivities to liquid water remains unclear. Here, we show that hydrogen-bond networks of water play a pivotal role in losing SERS enhancement for liquid water, and SERS detection of water requires local defects in the hydrogen-bond networks, which are formed around hydration shells of solute ions or on a polarized electrode surface. This work gives a new perspective on in situ SERS investigations in aqueous systems, including electrochemical and biological reactions.

Adipocyte-cancer cell interactions promote tumor development and progression. Previously, we identified adipsin (CFD) and its downstream effector, hepatocyte growth factor (HGF), as adipokines that enhance adipocyte-breast cancer stem cell interactions. Here, we show that adipsin-dependent adipocyte maturation and the subsequent upregulation of HGF promote tumor invasion in breast cancers. Mature adipocytes, but not their precursors, significantly induced breast tumor cell migration and invasion in an adipsin expression-dependent manner. Promoters of tumor invasion, galectin 7 and matrix metalloproteinases, were significantly upregulated in cancer cells cocultured with mature adipocytes; meanwhile, their expression levels in cancer cells cocultured with adipocytes were reduced by adipsin knockout (Cfd KO) or a competitive inhibitor of CFD. Tumor growth and distant metastasis of mammary cancer cells were significantly suppressed when syngeneic mammary cancer cells were transplanted into Cfd KO mice. Histological analyses revealed reductions in capsular formation and tumor invasion at the cancer-adipocyte interface in the mammary tumors formed in Cfd KO mice. These findings indicate that adipsin-dependent adipocyte maturation may play an important role in adipocyte-cancer cell interaction and breast cancer progression., (© 2024. The Author(s).)

Introduction: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disorder that principally targets the central nervous system, specifically the spinal cord and optic nerves. NMOSD is often associated with thyroid pathologies such as Graves' disease or Hashimoto's thyroiditis. Thyroid eye disease (TED) is an autoimmune condition characterized by inflammation and hypertrophy of the extraocular muscles. Dysthyroid optic neuropathy (DON), a critical complication of TED, may lead to irreversible visual loss. We report a case of DON complicated by NMOSD., Case Presentation: We report a case of an autoimmune disease presenting as DON in a 44-year-old Japanese woman with a history of Graves' disease, who experienced reduced visual acuity and orbital pain. Brain magnetic resonance imaging disclosed hypertrophy of the rectus muscles, compressing the optic nerve bilaterally. Consequently, she was diagnosed with DON and underwent three courses of steroid semi-pulse therapy and left orbital decompression surgery, alleviating optic nerve compression. Nevertheless, the visual prognosis remained poor. A subsequent serological test showed positive for aquaporin-4 antibody. Treatment with satralizumab, an interleukin-6 receptor monoclonal antibody, was initiated in conjunction with steroids to suppress the autoimmune response and reduce NMOSD relapse risk. Following this treatment, no NMOSD recurrences were reported., Conclusion: This case highlights the necessity of considering the possible coexistence of DON and NMOSD in patients with autoimmune diseases., Competing Interests: The authors report no conflicts of interest regarding this report., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Shiga toxin (Stx)-producing Escherichia coli (STEC) causes serious gastrointestinal illness, including hemorrhagic colitis and hemolytic uremic syndrome. Two types of Stxs (Stx1 and Stx2) are known and both are encoded by bacteriophages (Stx phages), but the production of Stx2 is known to be a major risk factor for severe STEC infections. The production of Stx2, but not Stx1, is tightly coupled with the induction of Stx phages, and Stx2 production levels vary between STEC strains even within the same serotype. Here, we analyzed the genomic diversity of all Stx phages in 71 strains representing the entire O145:H28 lineage, one of the often highly pathogenic STECs, and the relationship between the variations in Stx phage genomes and the levels of Stx2 production by host strains. Our analysis reveals highly dynamic natures of Stx phages in O145:H28, including the independent acquisition of similar Stx phages by different sublineages, the recent transfer of Stx phage between different sublineages, and the frequent gain and loss of Stx phages in some sublineages. We also show the association of the Stx2 phage types with the Stx2 production levels of host strains: strains carrying short-tailed Stx2 phages exhibited significantly higher Stx2 production levels than those carrying long-tailed Stx2 phages. Detailed analyses of the Stx2 phage genomes revealed that both of short- and long-tailed phages exhibited sequence diversification and they were divided into two groups, respectively, based on the sequence similarity of the phage early region encoding genes responsible for phage induction, short-tailed phages contained early regions clearly different in genetic organization from those in long-tailed phages. Therefore, the variations in the early regions between short-and long-tailed Stx2 phages appeared to be linked to a striking difference in Stx2 production levels in their host strains. These results broaden our understanding of the diversification and dynamism of Stx phages in O145:H28 and the association of Stx2 phage types with the Stx2 production level in this STEC lineage., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Nakamura, Taniguchi, Gotoh, Isobe, Kimata, Igawa, Kitahashi, Takahashi, Nomoto, Iwabuchi, Morimoto, Iyoda and Hayashi.)

A series of isostructural reticular frameworks with systematic differences on chemical structures allows us to disclose correlations between specific structural factors and properties, providing insights for designing novel porous materials. However, even slight differences in the molecular structure often lead to non-isostructural polymorphic frameworks particularly in the case of hydrogen-bonded organic frameworks (HOFs) because the structures of HOFs are based on a subtle balance of reversible interactions. In this study, we found that three simple analogues of tetracarboxylic acids with naphthalene, quinoxaline, and pyrazinopyrazine cores (NT, QX, and PP, respectively) yielded isostructural solvated HOFs (NT-1, QX-1, and PP-1, respectively), where hydrogen-bonded sql-networked sheets were slip-stacked with closely similar manners. More importantly, these isostructural HOFs underwent structural transformations in different manners upon removal of the guest solvents. Comparison of the crystal structures of the HOFs before and after the transformation revealed that intermolecular interactions of the core significantly affected on rearrangements of hydrogen bonds in the transformation. The results suggest the potential to control the properties and functions of isostructural HOFs by elements in the core., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Background: Vancomycin regimens are designed to achieve an area under the concentration-time curve/minimum inhibitory concentration (AUC/MIC) ratio ranging between 400 and 600 µg·h/mL in the steady state. However, in cases of critical infections such as bacteremia requiring an early treatment approach, the clinical course may be affected by the AUC/MIC before reaching the steady state, that is, the AUC/MIC values 24 h after the first dose (first 24-h AUC/MIC). This study evaluated the relationship between the first 24-h AUC/MIC and the clinical course of methicillin-resistant Staphylococcus aureus (MRSA) infection., Methods: We retrospectively reviewed the records of patients with MRSA bacteremia in a university hospital between 2015 and 2022. The first 24-h AUC/MIC cutoff was set at 300 µg·h/mL based on the results of early response, and eligible patients were divided into groups with a first 24-h AUC/MIC either < 300 µg·h/mL (< 300 group, n = 32) or ≥ 300 µg·h/mL (≥ 300 group, n = 38). The primary endpoint was the rate of treatment efficacy, and the secondary endpoints were time to clinical and bacteriological improvement and 30-day survival rate., Results: Treatment efficacy and 30-day survival rates were not significantly different between the two groups (78.1% vs. 79.0%, P = 0.933 and 83.9% vs. 87.2%, P = 0.674, respectively). Among patients who showed treatment efficacy, the median time to clinical and bacteriological improvement was 11.5 days and 8.0 days in the < 300 and ≥ 300 groups, respectively; compared to the ≥ 300 group, the < 300 group had a significantly longer time to improvement (P = 0.001)., Conclusions: The first 24-h AUC/MIC had no effect on the treatment efficacy and 30-day survival rates. However, the time to clinical and bacteriological improvement was significantly prolonged in the < 300 group, indicating that the first 24-h AUC/MIC does not affect the rate of therapeutic efficacy but may affect the treatment period., Competing Interests: The authors declare that they have no competing interest., (Copyright 2024, Higashi et al.)

Although antibiotics are most frequently prescribed for respiratory tract infections, effective interventions for their proper use by physicians have not been fully established. We assessed the impact of educational films on the rates of antibiotic prescriptions for respiratory tract infections using fictitious scenarios. In this nationwide web-based survey prospective study, a total of 1100 physicians were included. The physicians were required to view educational short films and determine the need for prescribing antibiotics in 10 fictitious scenarios involving adults diagnosed with different acute respiratory tract infectious diseases. The antibiotic prescription rates for each scenario were compared before and after viewing the educational short film. The rates of antibiotic prescription significantly decreased after viewing the educational film, especially in cases with a narrowly defined common cold (from 51% to 15%), mild pharyngolaryngitis (from 71% to 25%), and acute bronchitis without chronic respiratory underlying diseases (from 63% to 23%). Alternatively, a slight decrease in rates was observed in cases with moderate or severe rhinosinusitis (from 94% to 79%), moderate or severe acute pharyngitis (from 88% to 69%), and acute bronchitis with chronic lung disease (from 70% to 58%), for which antibiotics are recommended. Educational short films may encourage the proper use of antibiotics for respiratory tract infections; however, the possibility of undertreatment in patients requiring antibiotics must be considered.

Competing Interests: Declaration of competing interest The authors have no conflicts of interest directly relevant to the content of this article.

Background/aim: Self-expandable metallic stent (SEMS) placement is becoming the standard bridge-to-surgery (BTS) strategy for potentially curable left-sided obstructive colorectal cancer (OCRC). The study objective was to evaluate the effectiveness of SEMS placement as a BTS strategy for both right- and left-sided OCRC., Patients and Methods: We retrospectively compared the short- and long-term outcomes of patients with OCRC who underwent placement of a SEMS versus a trans-nasal/anal decompression tube (DCT). The cohort comprised 57 patients with stage II/III right-sided OCRC (DCT, n=20; SEMS, n=8) or left-sided OCRC (DCT, n=9; SEMS, n=20). The short-term outcomes were the incidence of postoperative complications, rate of laparoscopic surgery, rate of stoma construction, and postoperative hospital stay; long-term outcomes were the 3-year overall survival (OS) and relapse-free survival (RFS)., Results: The SEMS group had a higher rate of laparoscopic surgery (85.7% vs. 6.9%, p<0.001), lower rate of stoma construction (10.7% vs. 34.5%, p=0.03), and shorter postoperative hospital stay (14 vs. 17 days, p=0.04) than the DCT group. Both groups had a similar incidence of postoperative complications. The 3-year OS and RFS were also similar in the DCT and SEMS groups for both right-sided OCRC (OS, 75.0% vs. 87.5%, HR=1.51, 95% CI=0.22-10.25, p=0.7; RFS, 65.0% vs. 50.0%, HR=0.97, 95% CI=0.28-3.36, p=0.9) and left-sided OCRC (OS, 88.8% vs. 90.0%, HR=1.19, 95% CI=0.10-14.29, p=0.9; RFS, 77.8% vs. 85.0%, HR=1.03, 95% CI=0.16-6.5, p=0.9)., Conclusion: SEMS placement is a reasonable BTS strategy for left- and right-sided OCRC that achieves comparable short- and long-term outcomes to DCT insertion., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: The sex-specific effect of the visceral-to-subcutaneous fat ratio (VSR) before gastrectomy on postoperative survival in patients with gastric cancer (GC) remains unclear. This study measured the preoperative VSR in patients with GC and analyzed its relationship with 5-year overall survival (OS) and relapse-free survival (RFS) by sex., Patients and Methods: This prospective study included 540 patients with GC undergoing gastrectomy. Preoperative visceral and subcutaneous fat volumes were measured using computed tomography, and the VSR was calculated. A cutoff value for the VSR was established using 5-year survival data, and its association with survival was analyzed using the Kaplan-Meier method, log-rank tests, and multivariate regression analysis., Results: Among the 459 patients analyzed (300 males and 159 females), OS and RFS were significantly lower in the low-VSR group than in the high-VSR group in males (OS: 76.2% vs. 88.1%, p=0.01; RFS: 74.6% vs. 86.0%, p=0.02). In females, no difference in OS was observed between the groups, whereas the high-VSR group had significantly lower RFS than that of the low-VSR group (RFS: 74.7% vs. 88.9%, p=0.01). Multivariate analysis showed that a low VSR was an independent poor predictor of OS in males and a high VSR was an independent poor predictor of RFS in females., Conclusion: In patients with GC, the sex-dependent preoperative VSR was a potentially useful predictor of postoperative survival., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Helicobacter pylori ( H. pylori ), a bacterium which chronically infects the stomach of approximately half the world's population, is a risk factor for the development of gastric cancer (GC). However, the underlying mechanism whereby H. pylori infection induces GC development remains unclear. Intermittent injection of the H. pylori cytotoxin-associated gene A antigen (CagA) protein into its host cell inhibits nuclear translocation of BRCA1/BRCA2, DNA repair proteins involved in the development of breast cancer/ovarian cancer. Interestingly, hereditary breast and ovarian cancer (HBOC) syndrome is associated with GC development. Here, we aimed to clarify the molecular link between H. pylori infection, BRCA1/2 pathogenic variants (PVs), GC and higher GC incidence in HBOC families., Methods: We retrospectively reviewed data from Japanese patients undergoing precision treatment using cancer genomic medicine., Results: We found a higher GC incidence in HBOC families having germline pathogenic variants (GPVs) of BRCA1/2 (2.95% vs. 0.78% in non-HBOC families). Next, we found that 96.1% of H. pylori -infected patients received cancer genomic medicine for advanced GC, and > 16% advanced GC patients had gBRCA2 PVs. Furthermore, expressing wild-type BRCA1/2 in Gan mice (a mouse model of human GC) inhibited GC development. Thus, gBRAC1/2 PVs and H. pylori infection synergistically increase the risk of GC development., Conclusion: Our study highlights the need to investigate the potential of therapeutic agents against BRCA1/2 PVs to avoid the development of GC in HBOC families. In addition, our results suggest that poly (ADP-ribose) polymerase (PARP) inhibitors could potentially inhibit GC development and progression with gBRCA1/2 PVs., Competing Interests: The authors state no competing interest., (Copyright 2024, Hayashi et al.)

Changes in the gut microbiome have pivotal roles in the pathogenesis of acute graft-versus-host disease (aGVHD) after allogenic haematopoietic cell transplantation (allo-HCT) 1-6 . However, effective methods for safely resolving gut dysbiosis have not yet been established. An expansion of the pathogen Enterococcus faecalis in the intestine, associated with dysbiosis, has been shown to be a risk factor for aGVHD 7-10 . Here we analyse the intestinal microbiome of patients with allo-HCT, and find that E. faecalis escapes elimination and proliferates in the intestine by forming biofilms, rather than by acquiring drug-resistance genes. We isolated cytolysin-positive highly pathogenic E. faecalis from faecal samples and identified an anti-E. faecalis enzyme derived from E. faecalis-specific bacteriophages by analysing bacterial whole-genome sequencing data. The antibacterial enzyme had lytic activity against the biofilm of E. faecalis in vitro and in vivo. Furthermore, in aGVHD-induced gnotobiotic mice that were colonized with E. faecalis or with patient faecal samples characterized by the domination of Enterococcus, levels of intestinal cytolysin-positive E. faecalis were decreased and survival was significantly increased in the group that was treated with the E. faecalis-specific enzyme, compared with controls. Thus, administration of a phage-derived antibacterial enzyme that is specific to biofilm-forming pathogenic E. faecalis-which is difficult to eliminate with existing antibiotics-might provide an approach to protect against aGVHD., (© 2024. The Author(s).)

Purpose: Three-dimensional contrast-enhanced magnetic resonance imaging (3D-Ce-MRI) is a most powerful tool for evaluation of neoadjuvant chemotherapy (NAC). However, the use of contrast agent is invasive, expensive, and time consuming, Thus, contrast agent-free imaging is preferable. We aimed to investigate the tumor volume change after NAC using maximum intensity projection diffusion-weighted image (MIP-DWI) and 3D-Ce-MRI., Method: We finally enrolled 55 breast cancer patients who underwent NAC in 2018. All MRI analyses were performed using SYNAPSE VINCENT® medical imaging system (Fujifilm Medical, Tokyo, Japan). We evaluated the tumor volumes before, during, and after NAC. Tumor volume before NAC on 3D-Ce-MRI was termed Pre-CE and those during and after NAC were termed Post-CE. The observer raised the lower end of the window width until the tumor was clearly visible and then manually deleted the non-tumor tissues. A month thereafter, the same observer who was blinded to the 3D-Ce-MRI results randomly evaluated the tumor volumes (Pre-DWI and Post-DWI) using MIP-DWI with the same method. Tumor volume change between ΔCE (Pre-CE - Post-CE/Pre-CE) and ΔDWI (Pre-DWI - Post-DWI/Pre-DWI) and the processing time for both methods (Time-DWI and Time-CE) were compared., Results: We enrolled 55 patients. Spearman's rho between ΔDWI and ΔCE for pure mass lesions, and non-mass enhancement (NME) was 0.89 (p < 0.01), 0.63(p < 0.01) respectively. Time-DWI was significantly shorter than Time-CE (41.3 ± 21.2 and 199.5 ± 98.3 respectively, p < 0.01)., Conclusions: Non-contrast-enhanced Breast MRI enables appropriate and faster evaluation of tumor volume change after NAC than 3D-Ce-MRI especially for mass lesions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The identification of epitope peptides from tumor-associated antigens (TAAs) is informative for developing tumor-specific immunotherapy. However, only a few epitopes have been detected in mouse TAAs of head and neck cancer (HNSCC)., Methods: Novel mouse c-Met-derived T-cell epitopes were predicted by computer-based algorithms. Mouse HNSCC cell line-bearing mice were treated with a c-Met peptide vaccine. The effects of CD8 and/or CD4 T-cell depletion, and vaccine combination with immune checkpoint inhibitors (ICIs) were evaluated. Tumor re-inoculation was performed to assess T-cell memory., Results: We identified c-Met-derived short and long epitopes that elicited c-Met-reactive antitumor CD8 and/or CD4 T-cell responses. Vaccination using these peptides showed remarkable antitumor responses via T cells in which ICIs were not required. The c-Met peptide-vaccinated mice rejected the re-inoculated tumors., Conclusions: We demonstrated that novel c-Met peptide vaccines can induce antitumor T-cell response, and could be a potent immunotherapy in a syngeneic mouse HNSCC model., (© 2024 Wiley Periodicals LLC.)

Purpose: To clarify the genetic and clinical features of Japanese patients with ABCA4-associated retinopathy., Design: Retrospective, multicenter cohort study., Methods: Patients with retinal degeneration and biallelic ABCA4 variants were recruited from 13 different hospitals. Whole exome sequencing analysis was used for genetic testing. Comprehensive ophthalmic examinations were performed on matched patients. The primary outcome measure was identifying multimodal retinal imaging findings associated with disease progression., Results: This study included 63 patients: 19 with missense/missense, 23 with missense/truncation, and 21 with truncation/truncation genotypes. In total, 62 variants were identified, including 29 novel variants. Six patients had a mild phenotype characterized by foveal-sparing or preserved foveal structure, including 4 with missense/missense and 2 with missense/truncation genotypes. The p.Arg212His variant was the most frequent in patients with mild phenotypes (4/12 alleles). Clinical findings showed a disease duration-dependent worsening of the phenotypic stage. Patients with the truncation/truncation genotype exhibited rapid retinal degeneration within a few years and definite fundus autofluorescence imaging patterns, including hyper autofluorescence at the macula and few or no flecks., Conclusions: Our results indicate that missense/missense or missense/truncation genotypes, including the p.Arg212His variant, are associated with a relatively mild phenotype. In contrast, the truncation/truncation genotype causes rapid and severe retinal degeneration in Japanese patients with ABCA4-associated retinopathy. These data are vital in predicting patient prognosis, guiding genetic counseling, and stratifying patients for future clinical trials., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Precut papillotomy is performed in cases of difficult biliary cannulation, but identification of the biliary orifice is difficult. Texture and color enhancement imaging (TXI) can enhance the structure, color, and brightness. This study compared TXI and white light imaging (WLI) in visibility of biliary orifices., Methods: We retrospectively examined 20 patients who underwent bile duct cannulation using both WLI and TXI after precut papillotomy at our center between 2021 and 2022. On WLI and TXI images displayed in random order, bile duct orifice on precut-incision surface of each image was independently evaluated by eight evaluators. Single-indication accuracy rate of biliary orifices, visibility score rated on a 4-grade scale, and color difference between the biliary orifice and the surrounding tissue were examined., Results: The single-indication accuracy rate was higher in TXI compared to WLI (50.6% vs. 35.6%, odds ratio 2.26 [95% CI: 1.32-3.89], p = .003). The time to indicate the biliary orifice was comparable between TXI and WLI (median, 9.7 s [range, 2.6-43] vs. 10.9 s [1.5-64], p = .086). Furthermore, the visibility score was higher in TXI than in WLI (median, 3 [interquartile range, 2-3] vs. 2 [2, 3], p < .001), and the color difference between the biliary orifice and surrounding tissue in TXI was more pronounced than in WLI (median, 22.9 [range, 9.39-55.2] vs. 18.0 [6.48-43.0]; p < .001)., Conclusions: TXI enhanced the color difference and visibility of the biliary orifice after precut and improved single-indication accuracy rate, suggesting that it could be useful for biliary cannulation after precut papillotomy., (© 2024 Japanese Society of Hepato‐Biliary‐Pancreatic Surgery.)

Aims: Interleukin-16 (IL-16) has been reported to mediate left ventricular myocardial fibrosis and stiffening in patients with heart failure with preserved ejection fraction (HFpEF). We sought to elucidate whether IL-16 has a distinct impact on pathophysiology and prognosis across different subphenotypes of acute HFpEF., Methods and Results: We analysed 211 patients enrolled in a prospective multicentre registry of acute decompensated HFpEF for whom serum IL-16 levels after stabilization were available (53% female, median age 81 [interquartile range 75-85] years). We divided this sub-cohort into four phenogroups using our established clustering algorithm. The study endpoint was all-cause death. Patients were subclassified into phenogroup 1 ('rhythm trouble' [n = 69]), phenogroup 2 ('ventricular-arterial uncoupling' [n = 49]), phenogroup 3 ('low output and systemic congestion' [n = 41]), and phenogroup 4 ('systemic failure' [n = 52]). After a median follow-up of 640 days, 38 patients had died. Among the four phenogroups, phenogroup 2 had the highest IL-16 level. The IL-16 level showed significant associations with indices of cardiac hypertrophy, diastolic dysfunction, and congestion only in phenogroup 2. Furthermore, the IL-16 level had a significant predictive value for all-cause death only in phenogroup 2 (C-statistic 0.750, 95% confidence interval 0.606-0.863, P = 0.017), while there was no association between the IL-16 level and the endpoint in the other phenogroups., Conclusions: Our results indicated that the serum IL-16 level had a significant association with indices that reflect the pathophysiology and prognosis of HFpEF in a specific phenogroup in acute HFpEF., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background and Objectives: The total thrombus-formation analysis system (T-TAS) can quantitatively analyse the contribution of platelets to haemostasis using reconstituted blood samples. However, it is unsuitable in cases with low platelet counts. We introduced a haemodilution (HD) chip with a shallow chamber depth, adapted to low platelet counts and high shear conditions (1500 s -1 )., Materials and Methods: Blood samples were prepared by mixing red blood cell products, standard human plasma and platelet products; the final platelet count was 50 × 10 3 /μL. Aggregation tests were performed by using the aggregation inducers collagen, adenosine diphosphate (ADP) and ristocetin. Samples with 2-, 4- and 9-day-old platelet products (N = 10) were evaluated., Results: The HD chip enabled the stable analysis of the haemostatic function of all samples at a platelet count of 50 × 10 3 /μL. Haemostatic function was correlated with ADP aggregation (time to 10 kPa [T 10 ]: r = -0.53; area under the curve for 30 min: r = 0.40) and storage period (T 10 : r = 0.44)., Conclusion: The HD chip-mounted T-TAS can stably analyse haemostatic function under low platelet counts and high shear conditions; this approach is expected to serve as a bridge to in vivo haemostatic tests with experimental animals., (© 2024 International Society of Blood Transfusion.)

Objective: To analyse the impact of histological discordance of subtypes (subtypes or divergent differentiation [DD]) in specimens from transurethral resection (TUR) and radical cystectomy (RC) on the outcome of the patients with bladder cancer receiving RC., Patients and Methods: We analysed data for 2570 patients from a Japanese nationwide cohort with bladder cancer treated with RC between January 2013 and December 2019 at 36 institutions. The non-urinary tract recurrence-free survival (NUTR-FS) and overall survival (OS) stratified by TUR or RC specimen histology were determined. We also elucidated the predictive factors for OS in patients with subtype/DD bladder cancer., Results: At median follow-up of 36.9 months, 835 (32.4%) patients had NUTR, and 691 (26.9%) died. No statistically significant disparities in OS or NUTR-FS were observed when TUR specimens were classified as pure-urothelial carcinoma (UC), subtypes, DD, or non-UC. Among 2449 patients diagnosed with pure-UC or subtype/DD in their TUR specimens, there was discordance between the pathological diagnosis in TUR and RC specimens. Histological subtypes in RC specimens had a significant prognostic impact. When we focused on 345 patients with subtype/DD in TUR specimens, a multivariate Cox regression analysis identified pre-RC neutrophil-lymphocyte ratio and pathological stage as independent prognostic factors for OS (P = 0.016 and P = 0.001, respectively). The presence of sarcomatoid subtype in TUR specimens and lymphovascular invasion in RC specimens had a marginal effect (P = 0.069 and P = 0.056, respectively)., Conclusion: This study demonstrated that the presence of subtype/DD in RC specimens but not in TUR specimens indicated a poor prognosis. In patients with subtype/DD in TUR specimens, pre-RC neutrophil-lymphocyte ratio and pathological stage were independent prognostic factors for OS., (© 2024 BJU International.)

Purpose: The aim of this study was to describe the efficacy of Descemet membrane endothelial keratoplasty (DMEK) in patients with corneal endothelial decompensation secondary to a forceps-induced corneal birth injury., Methods: This was a retrospective, noncomparative, interventional case series. Four eyes of 4 patients (1 female and 3 males; mean age, 64.0 ± 4.7 years) with corneal endothelial decompensation due to forceps-induced corneal birth injury were included. DMEK was performed in all cases, using a combined technique, including the use of intraoperative optical coherence tomography, vital staining of Descemet membrane of both host and donor, removal of scarred Descemet membrane with side-port forceps and vitreous cutter to smoothen the posterior corneal surface, epithelial peeling, and illumination for visualization. The examination included preoperative and postoperative ophthalmologic examinations: best-corrected visual acuity (converted to logarithm of the minimum angle of resolution [logMAR]), intraocular pressure, endothelial cell density (ECD), and central corneal thickness., Results: No postoperative complications were noted, and corneal transparency was maintained during follow-up (mean follow-up period, 32.0 ± 27.0 months; range, 3-71 months). The mean best-corrected visual acuity was 0.52 ± 0.35 logMAR preoperatively and 0.15 ± 0.09 logMAR at the last visit. The mean postoperative ECD was 1632 ± 631 cells/mm 2 (mean ECD at baseline, 3167 cells/mm 2 ). Central corneal thickness decreased from 640 ± 67 μm preoperatively to 576 ± 58 μm postoperatively., Conclusions: This study suggests that DMEK can be performed uneventfully in eyes with a forceps-induced corneal birth injury. The combination of surgical techniques may be an effective approach for DMEK., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background & Aims: Gastric cancer is often accompanied by a loss of mucin 6 (MUC6), but its pathogenic role in gastric carcinogenesis remains unclear., Methods: Muc6 knockout (Muc6 -/- ) mice and Muc6-dsRED mice were newly generated. Tff1Cre, Golph3 -/- , R26-Golgi-mCherry, Hes1 flox/flox , Cosmc flox/flox , and A4gnt -/- mice were also used. Histology, DNA and RNA, proteins, and sugar chains were analyzed by whole-exon DNA sequence, RNA sequence, immunohistochemistry, lectin-binding assays, and liquid chromatography-mass spectrometry analysis. Gastric organoids and cell lines were used for in vitro assays and xenograft experiments., Results: Deletion of Muc6 in mice spontaneously causes pan-gastritis and invasive gastric cancers. Muc6-deficient tumor growth was dependent on mitogen-activated protein kinase activation, mediated by Golgi stress-induced up-regulation of Golgi phosphoprotein 3. Glycomic profiling revealed aberrant expression of mannose-rich N-linked glycans in gastric tumors, detected with banana lectin in association with lack of MUC6 expression. We identified a precursor of clusterin as a binding partner of mannose glycans. Mitogen-activated protein kinase activation, Golgi stress responses, and aberrant mannose expression are found in separate Cosmc- and A4gnt-deficient mouse models that lack normal O-glycosylation. Banana lectin-drug conjugates proved an effective treatment for mannose-rich murine and human gastric cancer., Conclusions: We propose that Golgi stress responses and aberrant glycans are important drivers of and promising new therapeutic targets for gastric cancer., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objectives: We retrospectively examined the initial experience and learning curve after the introduction of thrombectomy with the combined technique using an aspiration catheter and a stent retriever as first-line attempt for acute ischemic stroke., Methods: Consecutive patients undergoing thrombectomy for acute ischemic stroke at our institution between January 2020 and December 2022 were divided into 3 groups according to the year of thrombectomy. Patient characteristics and procedural, safety, and clinical outcomes were compared between the three year periods to determine predictors of favorable clinical outcome., Results: In 2020, 2021, and 2022, the numbers of patients were 74, 70, and 90, respectively, with similar patient characteristics across the three years; successful recanalization rates were 79.7%, 97.1%, and 93.3%, respectively (P < 0.01 for the first 2 years); median procedure times were 67, 43, and 32 minutes, respectively (P < 0.01 for the first 2 years and P = 0.018 for the last 2 years); first pass effect rates were 20.3%, 41.4%, and 44.4%, respectively (P < 0.01 for the first 2 years); symptomatic intracranial hemorrhage rates were 14.9%, 2.9%, and 1.1%, respectively (P = 0.018 for the first 2 years); and percentages of modified Rankin Scale score 0-2 at 90 days were 24.3%, 42.9%, and 41.1%, respectively (P = 0.022 for the first 2 years). Procedure time (P = 0.038) and successful recanalization (P = 0.041) were independent predictors of favorable clinical outcome., Conclusions: The learning curve effect of the combined technique may be associated with better clinical outcome due to increased successful recanalization rates, shortened procedure time, and reduced symptomatic intracranial hemorrhage., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Lomentospora prolificans is a rare, filamentous fungus, that causes a disseminated infection in immunocompromised individuals. Disseminated infections caused by the fungus are difficult to diagnose early. It is resistant to multiple antifungal agents and has a high mortality rate. We encountered a case in which the involvement of this fungus was indicated by a history of antifungal prophylaxis and an elevated serum 1,3-beta-D-glucan (BDG) level. A 76-year-old female with myelodysplastic syndrome that developed into overt leukemia was administered oral posaconazole as antifungal prophylaxis. She was admitted to the hospital to determine the cause of her fever, where no new abnormalities other than an elevated serum BDG level were observed. Unfortunately, the patient died due to acute respiratory failure on the same day of admission. The day after her death, L. prolificans was detected in a blood culture taken upon her admission. L. prolificans should be suspected based on the history of antifungal prophylaxis and an elevated serum BDG level, as these are risk factors for infection by this pathogen. Blood cultures are useful to provide a diagnosis. If treated early, before it is detected in culture, the mortality rate can be decreased., 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.)

Endothelial transplantation has recently been accepted worldwide, in the long history of corneal transplantation. The introduction of endothelial keratoplasty (Descemet stripping automated endothelial keratoplasty and Descemet membrane endothelial keratoplasty) has enabled us to expand the surgical indications owing to the low incidence of rejection and quick recovery of visual function. New technologies have been developed to ensure stable postoperative outcomes with a shorter learning curve, such as transplantation using cultured human endothelial cells and induced pluripotent stem cells (iPS) or new devices such as artificial endothelium. This review discusses the history and characteristics of corneal transplantation alongside new treatment options that may offer hope for patients with endothelial disease in the future., (© 2024. The Author(s).)

The problem of antimicrobial resistance (AMR) is not limited to the medical field but is also becoming prevalent on a global scale in the environmental field. Environmental water pollution caused by the discharge of wastewater into aquatic environments has caused concern in the context of the sustainable development of modern society. However, there have been few studies focused on the treatment of hospital wastewater, and the potential consequences of this remain unknown. This study evaluated the efficacy of the inactivation of antimicrobial-resistant bacteria (AMRB) and antimicrobial resistance genes (AMRGs) in model wastewater treatment plant (WWTP) wastewater and hospital effluent based on direct ultraviolet (UV) light irradiation provided by a conventional mercury lamp with a peak wavelength of 254 nm and an ultraviolet light-emitting diode (UV-LED) with a peak emission of 280 nm under test conditions in which the irradiance of both was adjusted to the same intensity. The overall results indicated that both UV- and UV-LED-mediated disinfection effectively inactivated the AMRB in both wastewater types (>99.9% after 1-3 min of UV and 3 min of UV-LED treatment). Additionally, AMRGs were also removed (0.2-1.4 log 10 for UV 254 nm and 0.1-1.3 log 10 for UV 280 nm), and notably, there was no statistically significant decrease ( p < 0.05) in the AMRGs between the UV and UV-LED treatments. The results of this study highlight the importance of utilizing a local inactivation treatment directly for wastewater generated by a hospital prior to its flow into a WWTP as sewage. Although additional disinfection treatment at the WWTP is likely necessary to remove the entire quantity of AMRB and AMRGs, the present study contributes to a significant reduction in the loads of WWTP and urgent prevention of the spread of infectious diseases, thus alleviating the potential threat to the environment and human health risks associated with AMR problems.

Objectives: Impaired B-cell reconstitution after allogeneic hematopoietic cell transplantation (allo-HCT) contributes to the pathogenesis of chronic graft-versus-host disease (cGVHD). Therefore, methods to consistently achieve effective B cell lymphogenesis are required. We assessed the long-term effects of posttransplantation cyclophosphamide (PTCy) use on immune reconstitution in clinical settings, an emerging strategy to suppress allogeneic immunological inflammation early after allo-HCT and prevent subsequent GVHD., Methods: We comprehensively analyzed peripheral immune cell subsets and measured serum immunoglobulin G (IgG) or cytokine levels in 39 patients who survived for >1 year after allo-HCT., Results: The absolute counts of B1 and IgM memory B cells were significantly lower in patients with severe cGVHD than in those without. The absolute count and percentage (among total CD19+ B cells) of switched memory B cells and serum IgG levels were significantly higher in patients transplanted with PTCy than in those transplanted with conventional GVHD prophylaxis. Interestingly, increased percentages of switched memory B cells and serum IgG levels were observed only in patients transplanted with PTCy and not in those transplanted with umbilical cord blood., Conclusions: PTCy administration can mediate favorable memory B-cell reconstitution long after allo-HCT and may therefore suppress cGVHD., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The association of computed tomography (CT)-derived skeletal muscle index (SMI) and skeletal muscle radiodensity (SMD) with postoperative prognosis in patients with gastric cancer (GC) remains unknown. Therefore, the present study aimed to assess the association between SMI and SMD with 5-year overall survival (OS) and recurrence-free survival (RFS) in patients with GC. SMI and SMD were measured preoperatively in patients who underwent gastrectomy. Patients were categorized into Groups 1 (high SMI and SMD), 2 (high SMI or SMD) and 3 (low SMI and SMD). OS and RFS rates were assessed using Kaplan-Meier analysis and the log-rank test. Among 459 patients, OS and RFS rates were significantly lower in the low-SMD group than in the high-SMD group (OS, 83.4% vs. 88.8%, respectively; P=0.04 and RFS, 80.5% vs. 87.2%, respectively; P=0.02). OS and RFS rates were also significantly lower in Group 3 than in Groups 2 and 1 (P=0.006). Multivariate analysis revealed that a low SMI and SMD (Group 3) was a significant independent prognostic factor for OS [hazard ratio (HR), 2.32; 95% confidence interval (CI), 1.17-4.59; P=0.016] and RFS (HR, 2.28; 95% CI, 1.19-4.37; P=0.013). In summary, low SMI and SMD values may be useful postoperative prognostic indicators for patients with GC., Competing Interests: The authors declared that they have no competing interests., (Copyright: © 2024 Hashimoto et al.)

Purpose: To determine the superiority of intensity-modulated radiation therapy (IMRT) over three-dimensional conformal radiation therapy (3DCRT) in patients who underwent intra-arterial chemoradiotherapy for oral cancer., Methods: We retrospectively analyzed patients with locally advanced oral cancer curatively treated with intra-arterial chemoradiotherapy at a single institution between 2010 and 2021. All patients treated after May 2015 underwent IMRT. Docetaxel (12 mg/m 2 /week) and nedaplatin (5 mg/m 2 /day) were administered through a shallow temporal artery using a catheter., Results: In total, 143 patients (IMRT: 71; 3DCRT: 72) were included in this study. The 5-year overall survival (OS) and progression-free survival (PFS) rates were 75.7 % and 59.8 %, respectively, with no significant differences between the irradiation methods. In multivariate analysis, cervical lymph node metastasis (LNM) was the only significant poor prognostic factor contributing to OS, PFS, locoregional control (LRC), and local control (LC). In multivariate subgroup analysis of LNM cases (n = 90), IMRT contributed to favorable LRC (hazard ratio [HR]=0.4, P = 0.01) and LC (HR=0.4, P = 0.006). There was no difference in the incidence of grade ≥2 osteonecrosis of the jaw (4.2 % vs. 12.5 %, P = 0.13), xerostomia (75 % vs. 82 %, P = 0.316), or dysgeusia (80 % vs. 82 %, P = 0.834) between the IMRT and 3DCRT groups. However, the rates of xerostomia at 6 months and dysgeusia at 3 months were lower in the IMRT group (both P < 0.001)., Conclusion: IMRT neither improved patient survival nor significantly reduced the incidence of osteonecrosis of the jaw. However, it demonstrated favorable LRC and LC in patients with LNM, suggesting an advantage in early recovery from xerostomia and dysgeusia., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)