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Chronic fibrotic tissue disrupts various organ functions. Despite significant advances in therapies, mortality and morbidity due to heart failure remain high, resulting in poor quality of life. Beyond the cardiomyocyte-centric view of heart failure, it is now accepted that alterations in the interstitial extracellular matrix (ECM) also play a major role in the development of heart failure. Here, we show that protein kinase N (PKN) is expressed in cardiac fibroblasts. Furthermore, PKN mediates the conversion of fibroblasts into myofibroblasts, which plays a central role in secreting large amounts of ECM proteins via p38 phosphorylation signaling. Fibroblast-specific deletion of PKN led to a reduction of myocardial fibrotic changes and cardiac dysfunction in mice models of ischemia-reperfusion or heart failure with preserved ejection fraction. Our results indicate that PKN is a therapeutic target for cardiac fibrosis in heart failure., (© 2024. The Author(s).)

Junctional epidermolysis bullosa (JEB) is an intractable cutaneous disorder in humans causing skin fragility and blistering due to mutations in genes encoding essential molecules adhering epidermis and dermis including collagen XVII. However, the pathogenesis still remains to be not fully understood perhaps because of a lack of appropriate animal models. Here, we report novel mutant rats suffering from JEB, which was confirmed to be caused by a frameshift mutation of Col17a1 gene, as a rat model for investigating the underlying mechanism of pathogenesis. The mutant rats completely lacked the expression of collagen XVII and had blisters leading to infantile deaths as a homozygous condition, although their skin was apparently normal at birth by light microscopic evaluation except that immunohistochemical examination could not detect collagen XVII in any organs. These observations suggest that collagen XVII is not essential for the development of skin during the prenatal period but is indispensable for keeping epidermal-dermal connections stable after birth. Subsequent electron microscopic examinations further revealed an absence of hemidesmosomal inner plaques being composed of BP230, a binding partner of collagen XVII, and plectin in Col17a1-null newborns, albeit mRNA expressions of these molecules seemed to be unaffected at least during the fetal period. These results suggest that the lack of collagen XVII induces attenuation of hemidesmosomal inner plaques, which in turn destabilizes the epidermis-dermis connection and results in deterioration of epidermal physiology with formation of blisters after birth., (Copyright © 2024. Published by Elsevier Inc.)

Background: The effect of early parenteral nutrition (EPN) therapy on brain development in extremely premature infants at a gestational age (GA) of 22-25 weeks remains unknown., Objectives: This study investigated the effect of EPN therapy on GA 22 to 25 weeks of gestation using magnetic resonance imaging (MRI) global brain abnormality score (GBAS)., Subjects: Forty-six preterm infants born before 26 weeks of gestation were divided into the GA 22-23 weeks (GA 22-23; n = 18) and GA 24-25 weeks (GA 24-25; n = 28) group., Methods: Each infant received ≥3.0 g/kg/day of amino acids from day 1 of life and ≥1.0 g/kg/day of lipid emulsion the next day. Weight change during hospitalization, GBAS at discharge, and developmental quotient (DQ) until three years old were compared between the groups., Results: GA 22-23 showed long-term postnatal weight loss, but weight at 41 weeks of postmenstrual age did not differ between the groups. The GBAS score was not significantly different, but the head circumference was smaller in GA 22-23 than in GA 24-25 until 2 years old. The DQ at 1-1.5 years old was lower in GA 22-23 than that of GA 24-25; however, there was no significant difference in DQ after 2 years old between the groups., Conclusions: The effect of nutritional support with EPN therapy in premature neonates born at <24 weeks of gestation may still be inadequate. GBAS is useful for assessing brain development in very preterm infants, and the importance of nutritional support during the first few weeks of life should continue to be explored., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: Bacterial translocation across the gut barrier has been implicated in the pathogenesis of systemic lupus erythematosus (SLE), though underlying mechanisms remain unclear. This study aimed to investigate the role of translocated bacteria in the context of molecular mimicry by utilizing lupus model mice and blood samples from untreated SLE patients., Methods: Bacterial translocation was evaluated using nonselective cultured mesenteric lymph nodes (MLNs) from B6SKG mice, a lupus model characterized by impaired TCR signalling and gut dysbiosis. The relationships of detected pathobionts with autoantibody production were examined using in vivo experiments, enzyme-linked immunosorbent assay, immunoblotting, and epitope mapping., Results: Culture-based bacterial profiling in MLNs demonstrated that Lactobacillus murinus was enriched in B6SKG mice with elevated anti-dsDNA IgG levels. Subcutaneous injection of heat-killed L. murinus induced anti-dsDNA IgG production without altering T- or B cell subset composition. Immunoblotting and mass spectrometry analysis identified a peptide ATP-binding cassette (ABC) transporter as a molecular mimicry antigen, with its cross-reactivity in lupus mice confirmed by serological assays and in vivo immunization. The L. murinus ABC transporter exhibited surface epitopes that were cross-reactive with sera from lupus mice and patients. The ABC transporter from R. gnavus, known for its pathogenic role in lupus patients, had a similar epitope sequence to that of the L. murinus ABC transporter and reacted with lupus sera., Conclusion: ABC transporters from gut bacteria can serve as cross-reactive antigens that may promote anti-dsDNA antibody production in genetically susceptible mice. These findings underscore the role of commensal-derived molecular mimicry and bacterial translocation in lupus pathogenesis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The environmental contaminant perchlorate raises concern for hypothyroidism-related brain disorders in children. This study investigated the effects of developmental perchlorate exposure on hippocampal neurogenesis and oligodendrocyte (OL) development. Pregnant Sprague-Dawley rats were administered with ammonium perchlorate (AP) in drinking water at concentrations of 0 (control), 300, and 1000 ppm from gestation day 6 until weaning [postnatal day (PND) 21]. On PND 21, offspring displayed decreased serum triiodothyronine and thyroxine concentrations at 1000 ppm and thyroid follicular epithelial cell hyperplasia at ≥300 ppm (accompanying increased proliferation activity at 1000 ppm). Hippocampal neurogenesis indicated suppressed proliferation of neurogenic cells at ≥300 ppm, causing decreases in type-1 neural stem cells (NSCs) and type-2a neural progenitor cells. In addition, an increase of SST + GABAergic interneurons and decreasing trend for ARC + granule cells were observed at 1000 ppm. CNPase + mature OLs were decreased in number in the dentate gyrus hilus at ≥300 ppm. At PND 77, thyroid changes had disappeared; however, the decrease of type-1 NSCs and increase of SST + interneurons persisted, CCK + interneurons were increased, and white matter tissue area was decreased at 1000 ppm. Obtained results suggest an induction of hypothyroidism causing suppressed hippocampal neurogenesis (targeting early neurogenic processes and decreased synaptic plasticity of granule cells involving ameliorative interneuron responses) and suppressed OL maturation during the weaning period. In adulthood, suppression of neurogenesis continued, and white matter hypoplasia was evident. Observed brain changes were similar to those caused by developmental hypothyroidism, suggesting that AP-induced developmental neurotoxicity was due to hypothyroidism., (© 2024 The Author(s). Environmental Toxicology published by Wiley Periodicals LLC.)

Cobalt (Co) has been introduced to most of the practical Ni-rich layered positive electrode materials owing to its ability to stabilize the layered structure and lessen cation-mixing. However, it has been unclear whether a highly ordered structure is essential or Co addition itself has some effects. In this study, we synthesized Co-substituted LiNiO 2 (LNO) with and without the introduction of cation-mixing to investigate the detailed effects of Co on crystal/local structures and electrochemical properties. It was found that the charge-discharge reversibility of LNO was enhanced by Co substitution with an additional discharge capacity at around 3.5 V, showing that the reaction at the end of discharge was activated. This behavior was observed in Co-substituted LNO even if cation-mixing was largely introduced, implying the intrinsic effect of Co on reversibility. Solid-state NMR results showed that the local structure in LNO with cation-mixing significantly changed after charge-discharge, whereas that of Co-substituted LNO hardly changed even when cation-mixing was introduced, which seems to be responsible for better reversibility. Density functional theory calculation also supports the positive effect of Co on lithium transportation at the end of discharge.

Background: To elucidate the factors influencing auditory brainstem response (ABR) threshold improvement in infants., Methods: This retrospective study included 626 infants who underwent ABR at the our Health and Medical Center between 2016 and 2020. Preliminary assessment indicated that 352 infants had an ABR threshold ≥40 dBnHL in both ears. A second ABR examination was conducted 5 months after delivery. The participants were divided into the improved (improvement ≥20 dBnHL) and unchanged (improvement <20 dBnHL) groups. The associations between risk factors were evaluated. Furthermore, we measured and compared the latencies of waves I, III, and V between participants with normal hearing and those in the improved and unchanged groups., Results: The improved and unchanged groups consisted of 185 and 167 participants, respectively. ABR deterioration occurred in one infant with unilateral congenital cytomegalovirus-associated hearing loss. Binary logistic regression analysis revealed that the presence of otitis media with effusion and Down syndrome were factors contributing to ABR threshold improvement. In the ABR waveform analysis, patients in the improved group who had otitis media with effusion exhibited prolonged latencies of waves I, III, and V. Conversely, patients in the unchanged group who had Down syndrome showed shortened I-V interval., Conclusions: Half of the infants tested the second time showed improvement in ABR threshold. Children with congenital syndromes (such as Down syndrome) or otitis media with effusion should undergo a second ABR examination or other auditory assessments to ensure an accurate diagnosis of hearing loss., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Therapeutic oligonucleotides such as antisense oligonucleotide (ASO) and small interfering RNA (siRNA) are among the most remarkable modalities in modern medicine. ASOs and siRNA are composed of single- or double-stranded 15-25 mer synthesized oligonucleotides, which can be used to modulate gene expression. Liquid chromatography-mass spectrometry (LC/MS) is a necessary technique for the quality control of therapeutic oligonucleotides; it is used to evaluate the quantities of target oligonucleotides and their impurities. The widely applied oligonucleotide therapeutic quantitation method uses both ultraviolet (UV) absorbance and the MS signal intensity. Peaks separated from the main peak, which contains full-length product, are generally quantitated by UV. However, coeluting impurities, such as n - 1 shortmers, abasic oligonucleotides, and PS → PO (phosphorothiate to phosphodiester) oligonucleotides, are quantitated by MS. These coeluting impurities can also be comprised of various isomers with the same modification, thus increasing the difficulty in their separation and relative quantitation by LC/MS. It is possible that a specific isomer with a certain structural form induces toxicities. Therefore, characterization of each isomer separation is in high demand. In this study, we separated and characterized oligonucleotide isomers by employing a cyclic ion mobility mass spectrometry (cyclic IMS) system, which allows the separation of ions with the same m / z ratio based on their structural differences. Patisiran antisense and sense strands and their n - 1 and abasic isomers were used as sample sequences, and their ratio characterization was achieved by cyclic IMS. In addition, we evaluated the PS → PO conversion isomers of the antisense strand of givosiran, which originally contained four PS modification sites. The PS → PO isomers exhibited specific and distinguishable mobiligram patterns. We believe that cyclic IMS is a promising method for evaluating therapeutic oligonucleotide isomers.

Prurigo nodularis (PN) is a chronic inflammatory skin disease associated with intense pruritic nodules. The unclear patho-etiological mechanisms of PN cause difficulty in disease management; and there is a paucity of information on the current diagnosis and treatment options for PN in Japan. To describe the current management from a dermatologists' perspective we conducted a web-based survey (UMIN Clinical Trial Registry UMIN000047643) in 2022 among dermatologists from a Japanese commercially available physician panel, who had seen at least one patient with PN within the last 3 months. The survey included 117 dermatologists. The dermatologists diagnosed PN mainly by confirming clinical signs and patient interviews, while to assess the severity of PN, the number of pruritic nodules and the degree of itching were primarily utilized. Topical corticosteroids and antihistamines were the most used drugs, as recommended in the current guidelines on the diagnosis and treatment of prurigo. Dermatologists' treatment satisfaction decreased with increasing assumed severity of PN; almost 65% dermatologists were not satisfied with the treatment of severe PN. These results suggest the need of more effective medications and diagnostic tools for better management of PN in Japan., (© 2024 The Author(s). The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Given the continuous emergence of new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the development of new inhibitors is necessary to enhance clinical efficacy and increase the options for combination therapy for the coronavirus disease 2019. Because marine organisms have been a resource for the discovery of numerous bioactive molecules, we constructed an extract library of marine invertebrates collected from the Okinawa Islands. In this study, the extracts were used to identify antiviral molecules against SARS-CoV-2. Using a cytopathic effect (CPE) assay in VeroE6/TMPRSS2 cells, an extract from the marine sponge Theonella swinhoei was found to reduce virus-induced CPE. Eventually, onnamide A was identified as an antiviral compound in the extract using column chromatography and NMR analysis. Onnamide A inhibited several SARS-CoV-2 variant-induced CPEs in VeroE6/TMPRSS2 cells as well as virus production in the supernatant of infected cells. Moreover, this compound blocked the entry of SARS-CoV-2 pseudo-virions. Taken together, these results demonstrate that onnamide A suppresses SARS-CoV-2 infection, which may be partially related to entry inhibition, and is expected to be a candidate lead compound for the development of anti-SARS-CoV-2 drugs., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

Background: The cancer genome contains several driver mutations. However, in some cases, no known drivers have been identified; these remaining areas of unmet needs, leading to limited progress in cancer therapy. Whole-genome sequencing (WGS) can identify non-coding alterations associated with the disease. Consequently, exploration of non-coding regions using WGS and other omics data such as ChIP-sequencing (ChIP-seq) to discern novel alterations and mechanisms related to tumorigenesis have been attractive these days., Methods: Integrated multi-omics analyses, including WGS, ChIP-seq, DNA methylation, and RNA-sequencing (RNA-seq), were conducted on samples from patients with non-clinically actionable genetic alterations (non-CAGAs) in lung adenocarcinoma (LUAD). Second-level cluster analysis was performed to reinforce the correlations associated with patient survival, as identified by RNA-seq. Subsequent differential gene expression analysis was performed to identify potential druggable targets., Results: Differences in H3K27ac marks in non-CAGAs LUAD were found and confirmed by analyzing RNA-seq data, in which mastermind-like transcriptional coactivator 2 (MAML2) was suppressed. The down-regulated genes whose expression was correlated to MAML2 expression were associated with patient prognosis. WGS analysis revealed somatic mutations associated with the H3K27ac marks in the MAML2 region and high levels of DNA methylation in MAML2 were observed in tumor samples. The second-level cluster analysis enabled patient stratification and subsequent analyses identified potential therapeutic target genes and treatment options., Conclusions: We overcome the persistent challenges of identifying alterations or driver mutations in coding regions related to tumorigenesis through a novel approach combining multi-omics data with clinical information to reveal the molecular mechanisms underlying non-CAGAs LUAD, stratify patients to improve patient prognosis, and identify potential therapeutic targets. This approach may be applicable to studies of other cancers with unmet needs., (© 2024. The Author(s).)

We examined the relationship between inherited motor-related conformation and orientation of facial hair whorls in Japanese Kiso horses. Eleven horses were divided into clockwise, counterclockwise, and radial groups according to facial hair whorls. We placed six markers on anatomical landmarks of each lateral side in a horse and measured the height of the landmarks, the distance between adjacent landmarks, and the angle of the adjacent landmarks. In the counterclockwise group, the horses tended to exhibit higher values on the left side than on the right side, and the comparison of the height of landmarks revealed a significant difference between both sides. Therefore, the orientation of facial hair whorls may suggest the tendency of motor-related conformation, at least in counterclockwise group.

Purpose: The diploic veins have been suggested to be involved in the excretion of cerebrospinal fluid and intracranial waste products; however, to date, there have been no reports evaluating the space surrounding the diploic veins. Therefore, we aimed to visualize the distribution of gadolinium-based contrast agent (GBCA) in the space surrounding the diploic veins and to evaluate the spatial characteristics., Materials and Methods: Ninety-eight participants (aged 14-84 years) were scanned 4 h after intravenous GBCA injection at Nagoya University Hospital between April 2021 and December 2022. The volume of the space surrounding the diploic veins where the GBCA was distributed was measured using contrast-enhanced T1-weighted images with the application of three-axis motion-sensitized driven equilibrium. The parasagittal dura (PSD) volume adjacent to the superior sagittal sinus was also measured using the same images. Both volumes were corrected for intracranial volume. The correlation between age and the corrected volume was examined using Spearman's rank correlation coefficient; the relationship between the corrected volume and sex was assessed using the Mann-Whitney U test., Results: A significant weak negative correlation was observed between the volume of the space surrounding the diploic veins and age (r = -0.330, p < 0.001). Furthermore, there was a significant weak positive correlation between the PSD volume and age (r = 0.385, p < 0.001). Both volumes were significantly greater in men than in women. There was no correlation between the volume of the space surrounding the diploic veins and the volume of the PSD., Conclusion: The volume of the space surrounding the diploic veins was measurable and, in contrast to the volume of the PSD, was greater in younger participants. This space may be related to intracranial excretory mechanisms and immune responses during youth, requiring further research., (© 2024. The Author(s).)

Purpose: The aim of the study was to evaluate the safety/tolerability and pharmacokinetics of simlukafusp alfa (FAP-IL2v), an immunocytokine containing an anti-fibroblast activation protein-α (FAP) antibody and an IL2 variant, administered alone or with the PDL1 inhibitor atezolizumab, in Japanese patients with advanced solid tumors., Patients and Methods: In this phase 1, open-label, dose-escalation study, patients received i.v. FAP-IL2v at 10 or 15/20 mg alone or 10 mg when combined with i.v. atezolizumab. The primary objectives were identification of dose-limiting toxicities (DLT), recommended dose, and maximum tolerated dose, and evaluation of the safety/tolerability and pharmacokinetics of FAP-IL2v alone and combined with atezolizumab., Results: All 11 patients experienced adverse events (AE) during FAP-IL2v treatment. Although most AEs were of mild severity, four treatment-related AEs led to study treatment discontinuation in two patients: one with infusion-related reaction, hypotension, and capillary leak syndrome, and the other with increased aspartate aminotransferase. No AE-related deaths occurred. One DLT (grade 3 hypotension) occurred in a patient receiving FAP-IL2v 15/20 mg alone. The recommended dose and maximum tolerated dose could not be determined. The pharmacokinetics of FAP-IL2v remained similar with or without atezolizumab. The study was terminated early as FAP-IL2v development was discontinued because of portfolio prioritization (not for efficacy/safety reasons)., Conclusions: This study describes the safety/tolerability of FAP-IL2v 10 mg alone and in combination with atezolizumab in Japanese patients with advanced solid tumors; one DLT (hypotension) occurred with FAP-IL2v 15/20 mg. However, dose escalation of FAP-IL2v was not conducted because of early study termination., Significance: This phase I study assessed the safety/tolerability and PK of simlukafusp alfa alone or combined with atezolizumab in Japanese patients with advanced solid tumors. No notable differences in PK were noted with the combination versus simlukafusp alfa alone; however, high-dose simlukafusp alfa treatment was associated with recombinant IL2-related toxicity, despite the drug's FAP targeting and IL2Rβγ-biased IL2 variant design., (©2024 The Authors; Published by the American Association for Cancer Research.)

HIV disease remains prevalent in the United States and is particularly prevalent in sub-Saharan Africa. Recent investigations revealed that mitochondrial dysfunction in kidney contributes to HIV-associated nephropathy (HIVAN) in Tg26 transgenic mice. We hypothesized that nicotinamide adenine dinucleotide (NAD) deficiency contributes to energetic dysfunction and progressive tubular injury. We investigated metabolomic mechanisms of HIVAN tubulopathy. Tg26 and wild-type (WT) mice were treated with the farnesoid X receptor (FXR) agonist INT-747 or nicotinamide riboside (NR) from 6 to 12 wk of age. Multiomic approaches were used to characterize kidney tissue transcriptomes and metabolomes. Treatment with INT-747 or NR ameliorated kidney tubular injury, as shown by serum creatinine, the tubular injury marker urinary neutrophil-associated lipocalin, and tubular morphometry. Integrated analysis of metabolomic and transcriptomic measurements showed that NAD levels and production were globally downregulated in Tg26 mouse kidneys, especially nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD salvage pathway. Furthermore, NAD-dependent deacetylase sirtuin3 activity and mitochondrial oxidative phosphorylation activity were lower in ex vivo proximal tubules from Tg26 mouse kidneys compared with those of WT mice. Restoration of NAD levels in the kidney improved these abnormalities. These data suggest that NAD deficiency might be a treatable target for HIVAN. NEW & NOTEWORTHY The study describes a novel investigation that identified nicotinamide adenine dinucleotide (NAD) deficiency in a widely used HIV-associated nephropathy (HIVAN) transgenic mouse model. We show that INT-747, a farnesoid X receptor agonist, and nicotinamide riboside (NR), a precursor of nicotinamide, each ameliorated HIVAN tubulopathy. Multiomic analysis of mouse kidneys revealed that NAD deficiency was an upstream metabolomic mechanism contributing to HIVAN tubulopathy.

Background: Some case reports have found that corticosteroid treatments shrunk thymoma lesions remarkably after the failure of chemotherapy or surgery. However, few studies have comprehensibly evaluated the antitumor effects of corticosteroids in patients with invasive thymomas., Methods: We reviewed the medical records of 13 consecutively enrolled patients with locally advanced or metastatic thymomas treated via corticosteroid monotherapies from January 2010 to March 2021 in our institute. A Cox's proportional hazard model and the Kaplan-Meier method were used to identify factors associated with survival., Results: The median follow-up time was 26 months (range, 13-115 months). The median initial dose of corticosteroid was 0.90 mg/kg/day prednisolone equivalent (range, 0.4-1.1 mg/kg/day). Of the 13 cases, 7 (53.8%, 95% CI: 0.25-0.81) exhibited a partial response and 5 (38.5%, 95% CI: 0.14-0.68) stable disease. The median progression-free survival was 5.7 months [95% confidence interval (CI): 1.5-9.6 months]. The median overall survival was 25.3 months (95% CI: 7.1-not attained). The median duration of corticosteroid use was 3 months (range, 1-64 months). Patients with WHO subtype B thymomas exhibited a better overall response rate to corticosteroids than did patients with other disease subtypes (75%, 95% CI: 0.19-0.99). Adverse events of Grade 3 or more were not observed., Conclusions: Corticosteroids are clinically valuable for patients with thymomas., Competing Interests: Declaration of competing interest Yasushi Goto received honoraria (lecture fees) from Chugai pharmaceutical Co. Ltd., Phizer, Daiichi-Sankyo, and received research funding from Phizer, Novartis, MSD, AbbVie, Daiichi-Sankyo, Preferred Networks, IQVIA, Chugai pharmaceutical Co Ltd.; Yuji Matsumoto received research funding from Hitachi, Ltd.; Yusuke Okuma received honoraria (lecture fees) from AstraZeneca, Eli Lilly Japan K.K, Chugai pharmaceutical Co. Ltd., Eisai Co. Ltd, and received research funding from Merk sharp and Dohm; Tatsuya Yoshida received honoraria (lecture fees) from AstraZeneca, Chugai pharmaceutical Co Ltd., and received research funding from Novartis, AbbVie, Amgen, Daiichi-Sankyo, AstraZeneca, MSD, Chugai pharmaceutical Co Ltd., Astellas Pharma Inc., Medpace, Boehringer Ingelheim, Bristol Myers Squibb, MSD, ONO pharmaceutical Co. Ltd., MERCK; Hidehito Horinouchi received honoraria (lecture fees) from AstraZeneca, Chugai pharmaceutical Co. Ltd./Roche, AbbVie, Daiichi-Sankyo, received research funding from AstraZeneca, Chugai pharmaceutical Co. Ltd./Roche, AbbVie, MSD, Janssen Pharmaceutical, Amgen, Daiichi-Sankyo; Noboru Yamamoto received honoraria (lecture fees) from Chugai pharmaceutical Co. Ltd. and received research funding from Astellas, Chugai pharmaceutical Co. Ltd., Eisai Co. Ltd., Taiho Pharmaceutical Co. Ltd., Bristol-Myers Squibb K.K., Pfizer, Novartis, Eli Lilly Japan K.K, AbbVie, Daiichi-Sankyo, Bayer, Boehringer Ingelheim, Kyowa Hakko Kirin Co. Ltd., Takeda Pharmaceutical Co. Ltd., ONO pharmaceutical Co. Ltd., Janssen Pharmaceutical, MSD, MERCK, GSK, Sumitomo Pharma, Chiome Bioscience, Otsuka, Carna Biosciences, Genmab, Shionogi, TORAY, KAKEN, AstraZeneca, Cmic, InventisBio, Rakuten Medical; Yuichiro Ohe received honoraria (lecture fees) from Chugai pharmaceutical Co. Ltd., Eisai and received research funding from AstraZeneca, Janssen, IQVIA, CIMIC, Syneos, MEDPACE; Tomohiro Tanaka, Ken Masuda, and Yuki Shinno have no conflict of interest., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Severe respiratory failure requires numerous interventions and its clinical implementation changes over time. We aimed to clarify the clinical practice and prognosis of severe respiratory failure and its changes over time., Methods: In a nationwide Japanese administrative database from 2016 to 2019, we identified nonoperative patients with severe respiratory failure without congestive heart failure as the main diagnosis who received mechanical ventilation (MV) for more than four days. We examined trends in patient characteristics, adjunctive interventions, and prognosis., Results: Among 66,905 patients included in this study, patients received antibiotics (90%), high-dose corticosteroids (14%), low-dose corticosteroids (18%), and 51% were admitted to the critical care unit. Hospital mortality was 35%. Median mechanical ventilation lasted 10 days. Tracheostomy occurred in 23% of cases. Median critical care and hospital stays were 10 and 25 days, respectively. Among survivors, 23% had mechanical ventilation dependency at hospital discharge. Large relative changes in adjunctive therapies included fentanyl (30%-38%), rocuronium (4.4%-6.7%), vasopressin (3.8%-6.0%), early rehabilitation (27%-38%), extracorporeal membrane oxygenation (0.7%-1.2%), dopamine (15%-10%), and sivelestat (8.6%-3.5%). No notable changes were seen in mechanical ventilation duration, tracheostomy, critical care unit stay, hospital stay, or ventilator dependency at discharge, except for a slight reduction in hospital mortality (36%-34%)., Conclusions: Several adjunctive therapies for severe respiratory failure changed from 2016 to 2019, with an increase in evidence-based practices and a slight decrease in hospital mortality., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

In cone-beam computed tomography (CBCT) for image-guided radiation therapy (IGRT) of the head, we evaluated the exposure dose reduction effect to the crystalline lens and position-matching accuracy by narrowing one side (X2) of the X-ray aperture (blade) in the X-direction. We defined the ocular surface dose of the head phantom as the crystalline lens exposure dose and measured using a radiophotoluminescence dosimeter (RPLD, GD-352 M) in the preset field (13.6 cm) and in each of the fields when blade X2 aperture was reduced in 0.5 cm increments from 10.0 to 5.0 cm. Auto-bone matching was performed on CBCT images acquired five times with blade X2 aperture set to 13.6 cm and 5.0 cm at each position when the head phantom was moved from - 5.0 to + 5.0 mm in 1.0 mm increment. The maximum reduction rate in the crystalline lens exposure dose was - 38.7% for the right lens and - 13.2% for the left lens when blade X2 aperture was 5.0 cm. The maximum difference in the amount of position correction between blade X2 aperture of 13.6 cm and 5.0 cm was 1 mm, and the accuracy of auto-bone matching was similar. In CBCT of the head, reduced blade X2 aperture is a useful technique for reducing the crystalline lens exposure dose while ensuring the accuracy of position matching., (© 2024. The Author(s), under exclusive licence to Japanese Society of Radiological Technology and Japan Society of Medical Physics.)

Objectives: To address the paucity of HIV-related lymphoma (HRL)-specific prognostic scores for the Japanese population by analyzing domestic cases of HRL and constructing a predictive model., Design: A single-center retrospective study coupled with a review of case reports of HRL., Methods: We reviewed all patients with HRL treated at our hospital between 2007 and 2023 and conducted a comprehensive search for case reports of HRL from Japan using public databases. A multivariate analysis for overall survival (OS) was performed using clinical parameters, leading to the formulation of the HIV-Japanese Prognostic Index (HIV-JPI)., Results: A total of 19 patients with HRL were identified in our institution, whereas the literature review yielded 44 cases. In the HIV-JPI, a weighted score of 1 was assigned to the following factors: age at least 45 years, HIV-RNA at least 8.0×10 4  copies/ml, Epstein-Barr virus-encoded small RNA positivity, and Ann Arbor classification stage IV. The overall score ranged from 0 to 4. We defined the low-risk group as scores ranging from 0 to 2 and the high-risk group as scores ranging from 3 to 4. The 3-year OS probability of the high-risk group [30.8%; 95% confidence interval (CI): 9.5-55.4%) was significantly poorer than that of the low-risk group (76.8%; 95% CI: 52.8-89.7%; P  < 0.01)., Conclusion: This retrospective analysis established pivotal prognostic factors for HRL in Japanese patients. The HIV-JPI, derived exclusively from Japanese patients, highlights the potential for stratified treatments and emphasizes the need for broader studies to further refine this clinical prediction model., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Conventional plant gene editing requires laborious tissue-culture-mediated transformation, which restricts the range of applicable plant species. In this study, we developed a heritable and tissue-culture-free gene editing method in Nicotiana benthamiana using tobacco ringspot virus (TRSV) as a vector for in planta delivery of Cas9 and single-guide RNA (sgRNA) to shoot apical meristems. Agrobacterium-mediated inoculation of the TRSV vector induced systemic and heritable gene editing in NbPDS. Transient downregulation of RNA silencing enhanced gene editing efficiency, resulting in an order of magnitude increase (0.8% to 13.2%) in the frequency of transgenerational gene editing. While the TRSV system had a preference for certain sgRNA sequences, co-inoculation of a TRSV vector carrying only Cas9 and a tobacco rattle virus vector carrying sgRNA successfully introduced systemic mutations with all five tested sgRNAs. Extensively gene-edited lateral shoots occasionally grew from plants inoculated with the virus vectors, of which the transgenerational gene editing frequency ranged up to 100%. This virus-mediated heritable gene editing method makes plant gene editing easy, requiring only the inoculation of non-transgenic plants with a virus vector(s) to obtain gene-edited individuals., (© The Author(s) 2024. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists.)

Objectives: Some studies reported a relationship between life-space mobility (LSM) and frailty assessed by physical aspects; however, a more comprehensive discussion of frailty is underdeveloped. In addition, previous studies have focused only on older Euro-American people. Therefore, we aimed to examine LSM-frailty relationships in community-dwelling older Japanese persons using physical and comprehensive frailty indices., Design: A cross-sectional study., Setting and Participants: We used the data of 8898 older adults from a baseline survey of the Kyoto-Kameoka Study in Japan., Methods: The validated life-space assessment (LSA) was used to evaluate LSM and categorized it into quartiles. Two validated indices were used to evaluate frailty: the Kihon Checklist (KCL) and the simple Frailty Screening Index (FSI). Multivariable logistic regression was used to determine the relationships between LSM scores and frailty., Results: The mean age (SD) of the participants was 73.4 (6.3) years, and 53.3% were women. The mean LSM score of the study participants was 53.0. The prevalence of frailty by KCL and FSI was 40.7% and 16.8%, respectively. Significant differences between LSM score and frailty prevalence were observed [KCL: Q1, reference; Q2, odds ratio (OR) 0.53, 95% CI 0.45-0.62; Q3, OR 0.30, 95% CI 0.25-0.35; Q4: OR 0.22, 95% CI 0.18-0.26, P for trend <.001; FSI: Q1, reference; Q2, OR 0.57, 95% CI 0.48-0.68; Q3: OR 0.38, 95% CI 0.31-0.46; Q4: OR 0.35, 95% CI 0.28-0.42, P for trend <.001]. Similar results were observed when LSM scores were examined at 10-point intervals, with LSM and frailty exhibiting an L-shaped relationship. The LSM score dose-response curve at which the OR for frailty plateaued among older individuals was approximately 81-90 score., Conclusions and Implications: LSM score and frailty prevalence exhibited L-shaped relationships in community-dwelling older persons. This study's findings provide useful data for setting LSM targets for preventing frailty in community-dwelling older persons., Competing Interests: Disclosure The authors declare no conflicts of interest., (Copyright © 2024 Post-Acute and Long-Term Care Medical Association. Published by Elsevier Inc. All rights reserved.)

Extranodal extension in metastatic lymph nodes (LNs) is a poor prognostic factor in bladder cancer (BC). Furthermore, cancer invasion levels in sentinel LNs are associated with prognosis in melanoma. The present study aimed to evaluate the LN invasion level, defined as the extent of cancer invasion in anatomical and immunological LN substructures, and compare it with the pathological node (pN) stage of the tumor-node-metastasis staging system in BC. A total of 98 patients with BC who underwent radical cystectomy and pelvic lymphadenectomy were retrospectively assessed. The LN invasion level was classified as follows: Level 0, no cancer cell within the resected LNs; Level 1, cancer cells confined to intracapsular lymph vessels and subcapsular or transverse sinuses; Level 2, cancer cells infiltrating the cortex, paracortex or medulla; and Level 3, cancer cells infiltrating or beyond the LN capsule. The proportion of patients with Levels 0, 1, 2 and 3 was 70.4% (69/98), 8.2% (8/98), 14.3% (14/98) and 7.1% (7/98), respectively. Kaplan-Meier survival curves of recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS) with LN invasion levels better stratified outcome patient when using Levels 1-3 compared with pN1-3. In addition, LN invasion levels better predicted RFS, CSS and OS, in comparison with the pN stage (c-index of 0.672 vs. 0.646, 0.688 vs. 0.665, and 0.702 vs. 0.661, respectively). Finally, multivariate analysis revealed that the predictive accuracy of the model integrating pathological tumor (pT) stage and LN invasion levels in RFS, CSS and OS was greater than that of the conventional model that included pT and pN stage (c-index of 0.723 vs. 0.703, 0.710 vs. 0.694, and 0.725 vs. 0.692, respectively). In conclusion, the model with LN invasion levels accurately predicted the prognosis of patients with BC after radical cystectomy and pelvic lymphadenectomy., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2024, Spandidos Publications.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported .Tarlatamab, a bispecific T-cell engager immunotherapy targeting delta-like ligand 3, has shown durable anticancer activity and manageable safety in previously treated small cell lung cancer (SCLC) in DeLLphi-300 phase I and DeLLphi-301 phase II trials. Here, we report extended follow-up of DeLLphi-300 (median follow-up, 12.1 months [range, 0.2-34.3]) in fully enrolled cohorts treated with tarlatamab ≥10 mg dose administered once every two weeks, once every three weeks, or once on day 1 and once on day 8 of a 21-day cycle (N = 152). Overall, the objective response rate (ORR) was 25.0%; the median duration of response (mDOR) was 11.2 months (95% CI, 6.6 to 22.3), and the median overall survival (mOS) was 17.5 months (95% CI, 11.4 to not estimable [NE]). Among 17 patients receiving 10 mg tarlatamab once every two weeks, the ORR was 35.3%, the mDOR was 14.9 months (95% CI, 3.0 to NE), the mOS was 20.3 months (95% CI, 5.1 to NE), and 29.4% had sustained disease control with time on treatment ≥52 weeks. No new safety signals were identified. In modified Response Assessment in Neuro-Oncology Brain Metastases analyses, CNS tumor shrinkage of ≥30% was observed in 62.5% of patients (10 of 16) who had a baseline CNS lesion of ≥10 mm, including in a subset of patients with tumor shrinkage long after previous brain radiotherapy. In DeLLphi-300 extended follow-up, tarlatamab demonstrated unprecedented survival and potential findings of intracranial activity in previously treated SCLC.

HIV disease remains prevalent in the USA and chronic kidney disease remains a major cause of morbidity in HIV-1-positive patients. Host double-stranded RNA (dsRNA)-activated protein kinase (PKR) is a sensor for viral dsRNA, including HIV-1. We show that PKR inhibition by compound C16 ameliorates the HIV-associated nephropathy (HIVAN) kidney phenotype in the Tg26 transgenic mouse model, with reversal of mitochondrial dysfunction. Combined analysis of single-nucleus RNA-seq and bulk RNA-seq data revealed that oxidative phosphorylation was one of the most downregulated pathways and identified signal transducer and activator of transcription (STAT3) as a potential mediating factor. We identified in Tg26 mice a novel proximal tubular cell cluster enriched in mitochondrial transcripts. Podocytes showed high levels of HIV-1 gene expression and dysregulation of cytoskeleton-related genes, and these cells dedifferentiated. In injured proximal tubules, cell-cell interaction analysis indicated activation of the pro-fibrogenic PKR-STAT3-platelet-derived growth factor (PDGF)-D pathway. These findings suggest that PKR inhibition and mitochondrial rescue are potential novel therapeutic approaches for HIVAN., Competing Interests: TY, KL, AR, BS, KM, YI, YZ, SS, BJ, XY, XW, VT, PS, ML, KO, CW, JK No competing interests declared

Aim: Severity, functional outcomes, and their secular changes in acute atrial fibrillation (AF)-associated stroke patients were determined., Methods: Acute ischemic stroke patients with AF in a hospital-based, multicenter, prospective registry from January-2000 through December-2020, were compared with those without AF. The co-primary outcomes were the initial severity assessed by the NIH Stroke Scale (NIHSS) score and favorable outcome assessed by the modified Rankin Scale scores 0-2 at hospital discharge., Results: Of the 142,351 patients studied, 33,870 had AF. AF patients had higher NIHSS scores (median 9 vs. 3, adjusted coefficient 5.468, 95% CI 5.354-5.582) than non-AF patients. Favorable outcome was less common in AF patients than in non-AF patients in the unadjusted analysis (48.4% vs. 70.4%), but it was more common with adjustment for the NIHSS score and other factors (adjusted OR 1.110, 95% CI 1.061-1.161). In AF patients, the NIHSS score decreased throughout the 21-year period (adjusted coefficient -0.088, 95% CI -0.115 - -0.061 per year), and the reduction was steeper than in non-AF patients (P＜0.001). In AF patients, favorable outcome became more common over the period (adjusted OR 1.018, 95% CI 1.010-1.026), and the increase was steeper than in non-AF patients (P＜0.001); the increase was no longer significant after further adjustment by reperfusion therapy., Conclusions: Initial stroke severity became milder and functional outcomes improved in AF patients over the 21-year period. These secular changes were steeper than in non-AF patients, suggesting that AF-associated stroke seemed to reap more benefit of recent development of stroke care than stroke without AF.

Abnormal neuronal morphological features, such as dendrite branching, axonal branching, and spine density, is thought to contribute to the symptoms of depression and anxiety. However, the role and molecular mechanisms of aberrant neuronal morphology in the regulation of mood disorders remain poorly characterized. Here, we show that Neuritin, an activity-dependent protein, regulates the axonal morphology of serotonin neurons. Male neuritin knockout mice harbored impaired axonal branches of serotonin neurons in the medial prefrontal cortex and basolateral region of the amygdala (BLA), and male neuritin knockout mice exhibited depressive and anxiety-like behaviors. We also observed that the expression of Neuritin was decreased by unpredictable chronic stress (UCS) in the male mouse brain and that decreased expression of neuritin was associated with reduced axonal branching of serotonin neurons in the brain and with depressive and anxiety behaviors in mice. Furthermore, the stress-mediated impairments in axonal branching and depressive behaviors were reversed by the overexpression of Neuritin in the BLA. The ability of neuritin to increase axonal branching in serotonin neurons involves FGF signaling, and neuritin contributes to FGF-2-mediated axonal branching regulation in vitro Finally, the oral administration of an FGF inhibitor reduced the axonal branching of serotonin neurons in the brain and caused depressive and anxiety behaviors in male mice. Our results support the involvement of neuritin in models of stress-induced depression and suggest that neuronal morphological plasticity may play a role in controlling animal behavior. Significance statement Axonal atrophy of serotonin neurons is one of the representative neuroanatomical features of depression. We found that the secreted/membrane-anchored neurotrophic factor Neuritin regulated axonal branch formation, which is involved in the development of depression and anxiety. In addition, Neuritin and the secreted signaling protein fibroblast growth factor 2 (FGF-2) cooperate to promote axonal branching in serotonin neurons. Furthermore, the inhibition of FGF signaling promoted axonal branching impairments and depressive behavior in mice. Taken together, these findings suggest that Neuritin regulates axonal branching in serotonin neurons and that the loss of neuritin is related to the development of depression. FGF signaling is involved in the neuritin-mediated axonal branching of serotonin neurons., (Copyright © 2024 the authors.)

Background: Generalized anxiety disorder (GAD) and social anxiety disorder (SAD) are distinguished by whether anxiety is limited to social situations. However, reports on the differences in brain functional networks between GAD and SAD are few. Our objective is to understand the pathogenesis of GAD and SAD by examining the differences in resting brain function between patients with GAD and SAD and healthy controls (HCs). Methods: This study included 21 patients with SAD, 17 patients with GAD, and 30 HCs. Participants underwent psychological assessments and resting-state functional magnetic resonance imaging. Whole-brain analyses were performed to compare resting-state functional connectivity (rsFC) among the groups. In addition, logistic regression analysis was conducted on the rsFC to identify significant differences between GAD and SAD. Results: Patients with SAD and GAD had significantly higher rsFC between the bilateral postcentral gyri and bilateral amygdalae/thalami than HCs. Compared with patients with SAD, those with GAD had significantly higher rsFC between the right nucleus accumbens and bilateral thalami and between the left nucleus accumbens and right thalamus. rsFC between the left nucleus accumbens and right thalamus positively correlated with state anxiety in patients with SAD and GAD, respectively. In addition, logistic regression analysis revealed that the right nucleus accumbens and the right thalamus connectivity could distinguish SAD from GAD. Conclusions: GAD and SAD were distinguished by the right nucleus accumbens and the right thalamus connectivity. Our findings offer insights into the disease-specific neural basis of SAD and GAD. Clinical Trial Registration Number: M10545. Impact Statement This study is the first to identify a resting state functional connectivity that distinguishes social anxiety disorder (SAD) from generalized anxiety disorder (GAD) and to clarify a common connectivity in both disorders. We found that the connectivity between the right nucleus accumbens and the right thalamus differentiated SAD from GAD. Furthermore, these rsFC differences suggest an underlying basis for fear overgeneralization. Our findings shed light on the pathophysiology of these conditions and could be used as a basis for further studies to improve outcomes for such patients.

Background: A comprehensive cardiac rehabilitation (CR) program is recommended for coronary artery disease (CAD). However, many facilities do not have established programs for dietary guidance and patient education, resulting in an exercise-based CR program and limited efficacy for secondary prevention., Methods and Results: A pilot study will be conducted to develop an online Japanese-style intensive cardiac rehabilitation (J-ICR) program for Japanese patients with CAD and will examine adherence, safety, and efficacy. Twenty-four patients diagnosed with stable CAD will be randomly assigned in a 1 : 1 ratio to either an early or late-phase group. The program will comprise the following four parts: exercise sessions; dietary education centered on "the Japan diet"; mindfulness; and group support, with a frequency of 3 h per session, once a week for 12 weeks (a total of 36 h). The primary endpoint will be program feasibility, determined by examining its adherence. Physical examination and function, stress-coping skills, risk of classic CAD (e.g., lipid profile, glucose tolerance, and blood pressure), and dietary changes will be assessed as secondary endpoints., Conclusions: The online J-ICR program is designed as a comprehensive CR program for Japanese patients with CAD. If this program shows high adherence and an improvement in CAD risk factors, its secondary prevention effect should be verified with appropriately powered randomized trials at multiple centers., Competing Interests: K.O. is a member of Circulation Reports’ Editorial Team. The authors declare that there are no conflicts of interest. Conflicts of interest were reviewed by the Kyoto University Clinical Research Conflict of Interest Review Committee in accordance with the Kyoto University Conflict of Interest Policy and Kyoto University Conflict of Interest Management Regulations., (Copyright © 2024, THE JAPANESE CIRCULATION SOCIETY.)

Imidacloprid (IMI) is a widely used neonicotinoid insecticide that poses risks for developmental neurotoxicity in mammals. The present study investigated the effects of maternal exposure to IMI on behaviors and adult neurogenesis in the hippocampal dentate gyrus (DG) of rat offspring. Dams were exposed to IMI via diet (83, 250, or 750 ppm in diet) from gestational day 6 until day 21 post-delivery on weaning, and offspring were maintained until adulthood on postnatal day 77. In the neurogenic niche, 750-ppm IMI decreased numbers of late-stage neural progenitor cells (NPCs) and post-mitotic immature granule cells by suppressing NPC proliferation and ERK1/2-FOS-mediated synaptic plasticity of granule cells on weaning. Suppressed reelin signaling might be responsible for the observed reductions of neurogenesis and synaptic plasticity. In adulthood, IMI at ≥ 250 ppm decreased neural stem cells by suppressing their proliferation and increasing apoptosis, and mature granule cells were reduced due to suppressed NPC differentiation. Behavioral tests revealed increased spontaneous activity in adulthood at 750 ppm. IMI decreased hippocampal acetylcholinesterase activity and Chrnb2 transcript levels in the DG on weaning and in adulthood. IMI increased numbers of astrocytes and M1-type microglia in the DG hilus, and upregulated neuroinflammation and oxidative stress-related genes on weaning. In adulthood, IMI increased malondialdehyde level and number of M1-type microglia, and downregulated neuroinflammation and oxidative stress-related genes. These results suggest that IMI persistently affected cholinergic signaling, induced neuroinflammation and oxidative stress during exposure, and increased sensitivity to oxidative stress after exposure in the hippocampus, causing hyperactivity and progressive suppression of neurogenesis in adulthood. The no-observed-adverse-effect level of IMI for offspring behaviors and hippocampal neurogenesis was determined to be 83 ppm (5.5-14.1 mg/kg body weight/day)., 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.)

The prompt initiation of stroke treatment significantly influences patient outcomes, highlighting the crucial role of prehospital triage. This study aimed to assess the implementation of the 7-Item Japan Urgent Stroke Triage (JUST-7) score by emergency medical services (EMS) in our region and its effect on emergency transportation for suspected stroke patients. Data were collected from patients suspected of having an acute stroke with a Cincinnati Prehospital Stroke Scale (CPSS) score of 1 or more who were transferred by ambulance within 24 h of symptom onset. Two prehospital stroke scales were employed during different periods: period 1 with CPSS alone (January to December 2020) and period 2 with both CPSS and JUST-7 (January 2021 to March 2023). On-scene time data were obtained from the EMS crews, and data regarding the final diagnosis of patients and their outcomes were obtained from the respective hospitals to which the patients were transferred. These data were compared between periods 1 and 2 and between the CPSS and JUST-7. The results revealed that additional evaluation with JUST-7 did not affect ambulance transport time. The CPSS+JUST-7 approach demonstrated higher specificity in identifying stroke and major artery occlusion than with the CPSS alone; however, an appropriate cut-off value needs to be considered. The JUST-7 achieved a diagnostic concordance rate of 35.9% for the most likely stroke type and 64.0% for the first two most likely types. This research emphasizes the potential of JUST-7 as a valuable addition to prehospital stroke diagnosis protocols. Its flexibility in adapting cut-off values based on regional factors and available medical resources optimizes its utility in diverse healthcare settings. The JUST-7 score is a promising tool for improving patient outcomes through prompt and accurate prehospital assessments., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Nishiwaki et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The cell signaling molecules nitric oxide (NO) and Ca 2+ regulate diverse biological processes through their closely coordinated activities directed by signaling protein complexes. However, it remains unclear how dynamically the multi-component protein assemblies behave within the signaling complexes upon the interplay between NO and Ca 2+ signals. Here we demonstrate that TRPC5 channels activated by stimulation of G-protein-coupled ATP receptors mediate Ca 2+ influx, that triggers NO production from endothelial NO synthase (eNOS), inducing secondary activation of TRPC5 via cysteine S-nitrosylation and eNOS in vascular endothelial cells. Mutations in the caveolin-1-binding domains of TRPC5 disrupt its association with caveolin-1 and impair Ca 2+ influx and NO production, suggesting that caveolin-1 serves primarily as the scaffold for TRPC5 and eNOS to assemble into the signal complex. Interestingly, during ATP receptor activation, eNOS is dissociated from caveolin-1 and in turn directly associates with TRPC5, which accumulates at the plasma membrane dependently on Ca 2+ influx and calmodulin (CaM). This protein reassembly likely results in a relief of eNOS from the inhibitory action of caveolin-1 and an enhanced TRPC5 S-nitrosylation by eNOS localized in the proximity, thereby facilitating the secondary activation of Ca 2+ influx and NO production. In isolated rat aorta, vasodilation induced by acetylcholine was significantly suppressed by the TRPC5 inhibitor AC1903. Thus, our study provides evidence that dynamic remodeling of the protein assemblies among TRPC5, eNOS, caveolin-1, and CaM determines the ensemble of Ca 2+ mobilization and NO production in vascular endothelial cells., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to compare the performances of photon-counting detector computed tomography (PCD-CT) and energy-integrating detector computed tomography (EID-CT) for visualizing nodules and airways in human cadaveric lungs., Materials and Methods: Previously obtained 20 cadaveric lungs were scanned, and images were prospectively acquired by EID-CT and PCD-CT at a radiation dose with a noise level equivalent to the diagnostic reference level. PCD-CT was scanned with ultra-high-resolution mode. The EID-CT images were reconstructed with a 512 matrix, 0.6-mm thickness, and a 350-mm field of view (FOV). The PCD-CT images were reconstructed at 3 settings: PCD-512: same as EID-CT; PCD-1024-FOV350: 1024 matrix, 0.2-mm thickness, 350-mm FOV; and PCD-1024-FOV50: 1024 matrix, 0.2-mm thickness, 50-mm FOV. Two specimens per lung were examined after hematoxylin and eosin staining. The CT images were evaluated for nodules on a 5-point scale and for airways on a 4-point scale to compare the histology. The Wilcoxon signed rank test with Bonferroni correction was performed for statistical analyses., Results: Sixty-seven nodules (1321 μm; interquartile range [IQR], 758-3105 μm) and 92 airways (851 μm; IQR, 514-1337 μm) were evaluated. For nodules and airways, scores decreased in order of PCD-1024-FOV50, PCD-1024-FOV350, PCD-512, and EID-CT. Significant differences were observed between series other than PCD-1024-FOV350 versus PCD-1024-FOV50 for nodules (PCD-1024-FOV350 vs PCD-1024-FOV50, P = 0.063; others P < 0.001) and between series other than EID-CT versus PCD-512 for airways (EID-CT vs PCD-512, P = 0.549; others P < 0.005). On PCD-1024-FOV50, the median size of barely detectable nodules was 604 μm (IQR, 469-756 μm) and that of barely detectable airways was 601 μm (IQR, 489-929 μm). On EID-CT, that of barely detectable nodules was 837 μm (IQR, 678-914 μm) and that of barely detectable airways was 1210 μm (IQR, 674-1435 μm)., Conclusions: PCD-CT visualized small nodules and airways better than EID-CT and improved with high spatial resolution and potentially can detect submillimeter nodules and airways., Competing Interests: Conflicts of interest and sources of funding: none declared. The study was supported by a grant from the Grants-in-Aid for Scientific Research–KAKENHI (JP21K07672)., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The introduction of combined antiretroviral therapy (cART) has greatly improved the quality of life of human immunodeficiency virus type 1 (HIV-1)-infected individuals. Nonetheless, the ever-present desire to seek out a full remedy for HIV-1 infections makes the discovery of novel antiviral medication compelling. Owing to this, a new late-stage inhibitor, Lenacapavir/Sunlenca, an HIV multi-phase suppressor, was clinically authorized in 2022. Besides unveiling cutting-edge antivirals inhibiting late-stage proteins or processes, newer therapeutics targeting host restriction factors hold promise for the curative care of HIV-1 infections. Notwithstanding, bone marrow stromal antigen 2 (BST2)/Tetherin/CD317/HM1.24, which entraps progeny virions is an appealing HIV-1 therapeutic candidate. In this study, a novel drug screening system was established, using the Jurkat/Vpr-HiBiT T cells, to identify drugs that could obstruct HIV-1 release; the candidate compounds were selected from the Ono Pharmaceutical compound library. Jurkat T cells expressing Vpr-HiBiT were infected with NL4-3, and the amount of virus release was quantified indirectly by the amount of Vpr-HiBiT incorporated into the progeny virions. Subsequently, the candidate compounds that suppressed viral release were used to synthesize the heterocyclic compound, HT-7, which reduces HIV-1 release with less cellular toxicity. Notably, HT-7 increased cell surface BST2 coupled with HIV-1 release reduction in Jurkat cells but not Jurkat/KO-BST2 cells. Seemingly, HT-7 impeded simian immunodeficiency virus (SIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) release. Concisely, these results suggest that the reduction in viral release, following HT-7 treatment, resulted from the modulation of cell surface expression of BST2 by HT-7., Competing Interests: Declaration of Interests The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Our objective was to investigate trends in the treatment of patients with late-onset rheumatoid arthritis (LORA) using data from the National Database of Rheumatic Diseases in Japan (NinJa)., Methods: Patients registered in the National Database of Rheumatic Diseases in Japan were classified according to the disease onset: at <65 years (young-onset rheumatoid arthritis); at 65-74 years (early LORA); and at ≥75 years (late LORA). Chronological changes in the treatment and disease activity were compared., Results: A total of 7178, 13,171, 15,295, and 15,943 patients were evaluated in 2010, 2013, 2016, and 2019, respectively. In all groups, the use of methotrexate gradually decreased, whereas that of biological/targeted synthetic disease-modifying antirheumatic drugs (DMARDs) increased; the use of tumor necrosis factor inhibitors decreased, whereas that of non-tumor necrosis factor inhibitors increased. LORA was characterized by more single DMARD use and less methotrexate and biological/targeted synthetic DMARD use. Tumor necrosis factor inhibitors and interleukin-6 inhibitors were used less frequently, whereas abatacept was utilized more frequently in late versus early LORA. Conventional synthetic DMARD (excluding methotrexate) and glucocorticoid use was higher in late versus early LORA., Conclusions: This analysis revealed chronological changes in the treatment of LORA in Japan. Differences between early and late LORA suggest that patients are not a homogeneous population., (© Japan College of Rheumatology 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Background: The incidence of esophageal adenocarcinoma has recently increased in Asia, including Japan. A system to identify individuals at high risk for Barrett's esophagus (BE), a pre-cancerous condition of esophageal adenocarcinoma, among the general population is needed to perform endoscopic surveillance appropriately. We therefore developed risk prediction scores for BE at health checkups in Japan., Methods: 4128 consecutive health checkup examinees were retrospectively enrolled from October 2021 to March 2022. A prediction score for BE was developed based on the linear transformation of β-regression coefficients in a multivariable regression model incorporating BE predictors. Internal validation was performed by evaluating discrimination and calibration of the prediction model., Results: Three prediction scores corresponding to BE based on its length were developed: all lengths, ≥ 1 cm, ≥ 2 cm. All scores were internally validated, and the model calibration was excellent. The performance of the prediction models was better for longer BE, with a c-statistic of 0.70 for BE ≥ 2 cm, than for shorter values. The prediction score for BE ≥ 2 cm yielded sensitivity and specificity of 52.9% and 78.6% in high-risk subjects and 91.2% and 29.3% in intermediate- or high-risk subjects, respectively., Conclusions: This prediction score can potentially increase the endoscopic detection of BE by identifying potentially high-risk individuals from the general population. This is the first report on developing a prediction score for BE that may suit the Japanese population., (© 2024. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Lymphoepithelial carcinoma of the submandibular gland is an extremely rare condition; therefore, no clear clinical features or established treatment is available for this. A 58-year-old Japanese man who came to our hospital with the complaint of swelling of the left submandibular region was diagnosed with stage IVa, T4aN2bM0 lymphoepithelial carcinoma of the submandibular gland. We also examined the relationship between the tumor and Epstein-Barr virus by Epstein-Barr virus encoded ribonucleoprotein in situ hybridization. The patient was treated by performing segmental mandibulectomy, neck dissection, mandibular reconstruction, and adjuvant chemoradiotherapy. After 2 years of treatment, good progress has been observed in the patient without any signs of recurrence. Here, we have reported the treatment of a patient with lymphoepithelial carcinoma of the submandibular gland using literature review., (© 2024 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)

We propose a novel type of skin effects in non-Hermitian quantum many-body systems that we dub a "non-Hermitian Mott skin effect." This phenomenon is induced by the interplay between strong correlations and the non-Hermitian point-gap topology. The Mott skin effect induces extreme sensitivity to the boundary conditions only in the spin degree of freedom (i.e., the charge distribution is not sensitive to boundary conditions), which is in sharp contrast to the ordinary non-Hermitian skin effect in noninteracting systems. Concretely, we elucidate that a bosonic non-Hermitian chain exhibits the Mott skin effect in the strongly correlated regime by closely examining an effective Hamiltonian. The emergence of the Mott skin effect is also supported by numerical diagonalization of the bosonic chain. The difference between the ordinary non-Hermitian skin effect and the Mott skin effect is also reflected in the time evolution of physical quantities; under the time evolution spin accumulation is observed while the charge distribution remains spatially uniform.

Background: The cancer risk for each length of Barrett's esophagus (BE) in Japanese is unknown. This nationwide, multi-institutional study aims to clarify the cancer risk by length of BE in the general Japanese population., Methods: Consecutive subjects who underwent upper endoscopic screening at 17 centers between 2013 and 2017 and had at least one follow-up endoscopy by December 2022 were included. The presence/absence of BE and, if present, its length were retrospectively assessed using the retrieved endoscopic images recorded at baseline. Information on the subsequent occurrence of esophageal adenocarcinoma and other upper gastrointestinal cancers was also collected. Cancer incidence was calculated and expressed as %/year., Results: A total of 33,478 subjects were enrolled, and 17,884 (53.4%), 10,641 (31.8%), 4889 (14.6%), and 64 (0.2%) were diagnosed as absent BE, BE < 1 cm, 1-3 cm, and ≥ 3 cm, respectively. During a median follow-up of 80 months, 11 cases of esophageal adenocarcinoma developed. The annual incidence of esophageal adenocarcinoma is 0%/year for absent BE, 0.0032 (0.00066-0.013)%/year for BE < 1 cm, 0.026 (0.011-0.054)%/year for 1-3 cm, and 0.58 (0.042-2.11)%/year for ≥ 3 cm, respectively. Meanwhile, the incidence of esophageal squamous cell carcinoma and gastric cancer were 0.039 (0.031-0.049)%/year and 0.16 (0.14-0.18)%/year, respectively., Conclusions: By enrolling a large number of subjects with long-term follow-up, this study demonstrated that the risk of cancer increased steadily with increasing length of BE in the Japanese population. Therefore, it is important to consider the length of BE when determining the management strategy for BE., (© 2024. Japanese Society of Gastroenterology.)

There are four genogroups and 18 genotypes of human sapoviruses (HuSaVs) responsible for acute gastroenteritis. To comprehend their antigenic and virological differences, it is crucial to obtain viral stocks of the different strains. Previously, we utilized the human duodenum-derived cell line HuTu80, and glycocholate, a conjugated bile acid, to replicate and propagate GI.1, GI.2, and GII.3 HuSaVs (H. Takagi et al., Proc Natl Acad Sci U S A 117:32078-32085, 2020, https://10.1073/pnas.2007310117). First, we investigated the impact of HuTu80 passage number on HuSaV propagation. Second, we demonstrated that taurocholate improved the initial replication success rate and viral RNA levels in fecal specimens relative to glycocholate. By propagating 15 HuSaV genotypes (GI.1-7, GII.1-5, -8, and GV.1-2) and accomplishing preparation of viral stocks containing 1.0 × 10 9 to 3.4 × 10 11 viral genomic copies/mL, we found that all strains required bile acids for replication, with GII.4 showing strict requirements for taurocholate. The deduced VP1 sequences of the viruses during the scale-up of serial passaged virus cultures were either identical or differed by only two amino acids from the original sequences in feces. In addition, we purified virions from nine strains of different genotypes and used them as immunogens for antiserum production. Enzyme-linked immunosorbent assays (ELISAs) using rabbit and guinea pig antisera for each of the 15 strains of different genotypes revealed distinct antigenicity among the propagating viruses across genogroups and differences between genotypes. Acquisition of biobanked viral resources and determination of key culture conditions will be valuable to gain insights into the common mechanisms of HuSaV infection., Importance: The control of human sapovirus, which causes acute gastroenteritis in individuals of all ages, is challenging because of its association with outbreaks similar to those caused by human norovirus. The establishment of conditions for efficient viral propagation of various viral strains is essential for understanding the infection mechanism and identifying potential control methods. In this study, two critical factors for human sapovirus propagation in a conventional human duodenal cell line were identified, and 15 strains of different genotypes that differed at the genetic and antigenic levels were isolated and used to prepare virus stocks. The preparation of virus stocks has not been successful for noroviruses, which belong to the same family as sapoviruses. Securing virus stocks of multiple human sapovirus strains represents a significant advance toward establishing a reliable experimental system that does not depend on limited virus-positive fecal material.

Lissencephaly is a rare brain malformation characterized by abnormal neuronal migration during cortical development. In this study, we performed a comprehensive genetic analysis using next-generation sequencing in 12 unsolved Japanese lissencephaly patients, in whom PAFAH1B1, DCX, TUBA1A, and ARX variants were excluded using the Sanger method. Exome sequencing (ES) was conducted on these 12 patients, identifying pathogenic variants in CEP85L, DYNC1H1, LAMC3, and DCX in four patients. Next, we performed genome sequencing (GS) on eight unsolved patients, and structural variants in PAFAH1B1, including an inversion and microdeletions involving several exons, were detected in three patients. Notably, these microdeletions in PAFAH1B1 could not to be detected by copy number variation (CNV) detection tools based on the depth of coverage methods using ES data. The density of repeat sequences, including Alu sequences or segmental duplications, which increase the susceptibility to structural variations, is very high in some lissencephaly spectrum genes (PAFAH1B1, TUBA1A, DYNC1H1). These missing CNVs were due to the limitations of detecting repeat sequences in ES-based CNV detection tools. Our study suggests that a combined approach integrating ES with GS can contribute to a higher diagnostic yield and a better understanding of the genetic landscape of the lissencephaly spectrum., (© 2024. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Purpose: The technical difficulties of laparoscopic liver resection (LLR) are greatly associated with the location of liver tumors. Since segment 8 (S8) contains a wide area, the difficulty of LLR for S8 tumors may vary depending on the location within the segment, such as the ventral (S8v) and dorsal (S8d) area, but the difference is unclear., Methods: We retrospectively investigated 30 patients who underwent primary laparoscopic partial liver resection for liver tumors in S8 at Kobe University Hospital between January 2018 and June 2023., Results: Thirteen and 17 patients underwent LLR for S8v and S8d, respectively. The operation time was significantly longer (S8v 203[135-259] vs. S8d 261[186-415] min, P = 0.002) and the amount of blood loss was significantly higher (10[10-150] vs. 10[10-200] mL, P = 0.034) in the S8d group than in the S8v group. No significant differences were observed in postoperative complications or postoperative length of hospital stay. Additionally, intraoperative findings revealed that the rate at which the case performed partial liver mobilization in the S8d group was higher (2[15.4%] vs. 8[47.1%], P = 0.060) and the median parenchymal transection time of the S8d group was longer (102[27-148] vs. 129[37-175] min, P = 0.097) than those in the S8v group, but there were no significant differences., Conclusion: The safety of LLR for the S8d was comparable to that of LLR for S8v, although LLR for S8d resulted in longer operative time and more blood loss., The Trial Registration Number: B230165 (approved at December 26, 2023)., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Appendiceal goblet cell adenocarcinoma (GCA) is a rare subtype of primary appendiceal adenocarcinoma with an incidence of 1-5 per 10,000,000 people per year. Appendiceal tumors are often diagnosed after appendectomy for acute appendicitis. Notably, however, there is currently no standard treatment strategy for GCA, including additional resection. We report a case of appendiceal GCA with perineural extension into the cecum, in which ileal resection was considered effective., Case Presentation: A 41-year-old man was diagnosed with acute appendicitis and underwent appendectomy. Histopathological findings revealed GCA (T3, Pn1). He was referred to our hospital for additional resection. Preoperative examination indicated a diagnosis of GCA cT3N0M0. Laparoscopic ileocecal resection and D3 lymph node dissection were performed 2 months after initial appendectomy. The patient had a good postoperative course and was discharged 8 days after surgery. Histopathological findings showed a GCA invading the cecum, despite an intact appendiceal stump, no lymph node metastasis, no vascular invasion, and no horizontal extension into the submucosa. Direct invasion of the tumor through the serosa was not observed, but perineural extension was conspicuous in the cecum, suggesting that the GCA extended into the cecum via perineural invasion. The resection margins were negative. The patient has survived free of recurrence for a year after ileocecal resection., Conclusions: The current patient was diagnosed with appendiceal GCA following appendectomy for acute appendicitis. Despite intact of appendiceal stump and no evidence of lymph node or distant metastasis, he underwent laparoscopic ileocecal resection and D3 lymph node dissection 2 months after initial appendectomy, with a favorable outcome. Despite the detection of perineural invasion, the patient declined adjuvant therapy. This case suggests that extensive resection may be required in patients with appendiceal GCA, but the role of adjuvant therapy remains unclear., (© 2024. The Author(s).)

Evidence suggests that positive pacing strategy improves exercise performance and fatigue tolerance in athletic events lasting 1-5 min. This study investigated muscle metabolic responses to positive and negative pacing strategies in Thoroughbred horses. Eight Thoroughbred horses performed 2 min treadmill running using positive (1 min at 110% maximal O 2 uptake [V̇O 2 max], followed by 1 min at 90% V̇O 2 max) and negative (1 min at 90% V̇O 2 max, followed by 1 min at 110% V̇O 2 max) pacing strategies. The arterial-mixed venous O 2 difference did not significantly differ between the two strategies. Plasma lactate levels increased toward 2 min, with significantly higher concentrations during positive pacing than during negative pacing. Muscle glycogen level was significantly lower at 1 and 2 min of positive pacing than those of negative pacing. Metabolomic analysis showed that the sum of glycolytic intermediates increased during the first half of positive pacing and the second half of negative pacing. Regardless of pacing strategy, the sum of tricarboxylic acid cycle metabolites increased during the first half but remained unchanged thereafter. Our data suggest that positive pacing strategy is likely to activate glycolytic metabolism to a greater extent compared to negative pacing, even though the total workload is identical., (© 2024. The Author(s).)

Background: This study aimed to compare the efficacy of robot-assisted partial nephrectomy for completely endophytic renal tumors with the reported outcomes of conventional laparoscopic partial nephrectomy and investigate the transition of renal function after robot-assisted partial nephrectomy., Methods: We conducted a prospective, multicenter, single-arm, open-label trial across 17 academic centers in Japan. Patients with endophytic renal tumors classified as cT1, cN0, cM0 were included and underwent robot-assisted partial nephrectomy. We defined two primary outcomes to assess functional and oncological aspects of the procedure, which were represented by the warm ischemic time and positive surgical margin, respectively. Comparisons were made using control values previously reported in laparoscopic partial nephrectomy studies. In the historical control group, the warm ischemia time was 25.2, and the positive surgical margin was 13%., Results: Our per-protocol analysis included 98 participants. The mean warm ischemic time was 20.3 min (99% confidence interval 18.3-22.3; p < 0.0001 vs. 25.2). None of the 98 participants had a positive surgical margin (99% confidence interval 0-5.3%; p < 0.0001 vs. 13.0%). The renal function ratio of eGFR before and after protocol treatment multiplied by splits was 0.70 (95% confidence interval: 0.66-0.75). Factors such as preoperative eGFR, resected weight, and warm ischemic time influenced the functional loss of the partially nephrectomized kidney after robot-assisted partial nephrectomy., Conclusions: Robot-assisted partial nephrectomy for completely endophytic renal tumors offers a shorter warm ischemia time and comparable positive surgical margin rate compared with conventional laparoscopic partial nephrectomy., (© 2024. The Author(s).)

This study explored postoperative outcomes for patients with lower rectal cancer who underwent low anterior resection (LAR) or intersphincteric resection (ISR). A total of 49 patients (33 LAR, 16 ISR) were followed using anorectal manometry and quality of life (QOL) questionnaires over a year, pre- and post surgery. The primary aim of this study is to clarify differences in anal manometry, sphincter function, fecal incontinence, and QOL between the two surgical arms. The secondary aim was to identify indicators suitable for assessing relationships between anorectal manometry measurements, fecal incontinence, and QOL. Anorectal manometry elements (AMEs), such as atmospheric maximum mean squeeze pressure (aMSP), maximum tolerable volume (MTV), and incremental maximum mean squeeze pressure (iMSP), showed no significant differences during the observation period. However, maximum resting pressure (MRP), high-pressure zone length (HPZ), and threshold volume (TV) were significantly worse in the ISR group. Fecal incontinence, measured by Wexner and Kirwan scores, was significantly better in the LAR group. We observed no differences in SF36 between the two groups. Multi-correlation analysis revealed positive and negative correlations among these factors, with inverse correlations between anorectal manometry measurements and incontinence assessments decreasing post-surgery. We found no correlation between SF36 and anorectal manometry at any time. The findings indicate that surgical technique affects postoperative anal function, fecal incontinence, and SF36. However, combined assessment methods should be used with caution when deriving relationships between anal function and SF36.

Background: A new diagnostic criterion for malnutrition, the Global Leadership Initiative on Malnutrition (GLIM) criteria, has been proposed. Despite a recognized link between malnutrition and oral health, further clarification is needed regarding this association when using the GLIM criteria. This study examined the association between malnutrition and oral health in community-dwelling older adults aged ≥ 85., Methods: This study was conducted using data from the Tokyo Oldest Old Survey on Total Health study, and altogether 519 participants ≥ 85 years were enrolled. Malnutrition was assessed using the GLIM criteria. Oral health information, on the number of teeth, maximum occlusal force (MOF), saliva production, denture-related questions (dissatisfaction and frequency of use), dental visit history in the past year, whether participants enjoyed meals, and oral-related quality of life was assessed using the Geriatric Oral Health Assessment Index (GOHAI) were collected. MOF was assessed the average values of three measurements and lower tertile by sex as decline in MOF. For GOHAI, the score for each items (Q1-Q12) was also evaluated, and further, the decline in each item (score: 1-2 points on a 5-point scale) was assessed as a "problem with each items." Oral health factors differing between those with and without malnutrition were analyzed. For differing items, malnutrition risk was evaluated using Cox regression., Results: Eighty-nine (17.1%) participants experienced malnutrition. Significant differences were observed in the decline in MOF, enjoyment of meals, individual scores for Q2, Q4, and Q6, and the problem with Q3, Q6, Q7, and Q11. Cox regression analysis showed that decline in MOF (odds ratio [OR]: 1.728, 95% confidence interval [CI]: 1.010-2.959), enjoyment of meals (OR: 0.502, 95% CI: 0.289-0.873), problem with Q3 (OR: 5.474, 95% CI: 1.301-23.028), Q6 (OR: 5.325, 95% CI: 1.026-27.636), and Q7 (OR: 2.867, 95% CI: 1.397-5.882) were associated with ORs of malnutrition., Conclusion: Decline in MOF, enjoyment of meals, swallowing problem (problem with Q3), limit contact due to oral condition (problem with Q6), and esthetics problem (problem with Q7) were associated with malnutrition as assessed using the GLIM criteria., (© 2024. The Author(s).)