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Naoko Katsurada,1 Motoko Tachihara,1 Yukihisa Hatakeyama,1 Kiyoko Koyama,1 Masako Yumura,1 Tatsunori Kiriu,1 Ryota Dokuni,1 Daisuke Hazama,1 Shuntaro Tokunaga,1 Daisuke Tamura,1 Kyosuke Nakata,1 Masatsugu Yamamoto,1 Hiroshi Kamiryo,1 Kazuyuki Kobayashi,1 Yugo Tanaka,2 Yoshimasa Maniwa,2 Yoshihiro Nishimura1 1Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan; 2Division of General Theocratic Surgery, Kobe University Graduate School of Medicine, Kobe, JapanCorrespondence: Motoko TachiharaDivision of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, JapanTel +81-78-382-5660Fax +81-78-382-5661Email mt0318@med.kobe-u.ac.jpPurpose: Adjuvant chemotherapy with cisplatin (CDDP) plus vinorelbine is the standard regimen for the treatment of non-small cell lung cancer (NSCLC). However, CDDP elicits severe toxic effects, including emesis, neurotoxicity, and renal damage; carboplatin (CBDCA) may be a feasible alternative for CDDP-unfit patients. CBDCA plus paclitaxel (PTX) adjuvant chemotherapy showed a survival benefit for patients with stage IB tumors > 4 cm in size, while CBDCA plus nanoparticle albumin-bound (nab)-PTX showed greater efficacy and lower neurotoxicity than CBDCA plus PTX in advanced NSCLC. Here, we investigated the feasibility of using CBDCA plus nab-PTX as adjuvant chemotherapy for NSCLC.Patients and Methods: Patients with completely resected stage II or III NSCLC, with an Eastern Cooperative Oncology Group performance status of 0– 1 and adequate kidney function, received four cycles of postoperative adjuvant chemotherapy with CBDCA (AUC=5 mg/mL/min, on day 1) and nab-PTX (100 mg/m2, on days 1, 8, and 15) administered every 4 weeks within 8 weeks after surgery. The study was designed as a prospective, single-center, Phase II study. The primary endpoint was the completion rate of chemotherapy; secondary endpoints were two-year relapse-free survival (RFS) and safety. The expected completion rate was 80%, with a 50% lower limit.Results: Of 21 enrolled patients, 18 (85.7%) were CDDP-unfit owing to age (≥ 75 years old [n=11, 52.4%]) or mild renal impairment (n=7, 33.3%). Nineteen of the 21 enrolled patients were assigned to the intervention. The most common grade 3 or 4 adverse events were neutropenia (n=15, 78.9%) and anemia (n=3, 15.8%). The completion rate for the four cycles was 63.2% (95% CI, 38.4– 83.7). Two-year RFS was 56.8% (95% CI, 29.7– 76.9).Conclusion: The completion rate for CBDCA plus nab-PTX as adjuvant chemotherapy for CDDP-unfit NSCLC patients did not reach treatment feasibility. Further dose modifications may be required in future studies.Keywords: nab-paclitaxel, carboplatin, adjuvant chemotherapy, non-small cell cancer

Motoko Tachihara,1 Tatsunori Kiriu,1 Akito Hata,2 Yukihisa Hatakeyama,3 Kyosuke Nakata,1 Tatsuya Nagano,1 Masatsugu Yamamoto,1 Kazuyuki Kobayashi,1 Hisashi Ohnishi,3 Nobuyuki Katakami,2 Yoshihiro Nishimura11Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan; 2Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Hyogo 650-0047, Japan; 3Department of Respiratory Medicine, Akashi Medical Center, Akashi, Hyogo 674-0063, JapanBackground: Nanoparticle albumin-bound paclitaxel (nab-PTX) plus gemcitabine (GEM) significantly improved overall survival in patients with metastatic pancreatic adenocarcinoma. Anti-tumor synergy between GEM and nab-PTX was recently demonstrated in a mouse model. We planned to assess the efficacy and safety of the combination of nab-PTX + GEM in patients with non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy.Methods: Patients with advanced NSCLC with progressive disease after platinum-based chemotherapy, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, and adequate kidney, liver and bone marrow function were eligible. Treatment consisted of nab-PTX (100 mg/m2) + GEM (1000 mg/m2) on days 1 and 8 of each 3-week cycle until progression disease or unacceptable toxicity occurred. The primary endpoint was progression-free survival (PFS).Results: Of the 28 patients enrolled, all were evaluable for response and toxicity. The median age was 68 years (range 47–79), and 23 were male and 5 female. The histologic subtypes were: adenocarcinoma in 19 patients, and squamous cell carcinoma in 9 patients. Seventeen patients had ECOG PS 1 and 11 patients had PS 0. Twenty-four patients were second line and 4 patients were third line. The median number of cycles administered was 4 (range 1–10). The overall response rate was 17.9%. The disease control rate was 67.9%. The median progression-free survival was 3.1 months (95% confidence interval [CI] =1.6–4.1). Adverse events were generally tolerable except grade 3 interstitial pneumonia with in 4 patients (14.3%).Conclusion: The efficacy of nab-PTX in combination with GEM in advanced second or third-line NSCLC patients was limited and the frequent occurrence of interstitial pneumonia was unacceptable.Keywords: nab-paclitaxel, gemcitabine, non-small-cell lung cancer

Objectives: When patients complete questionnaires during health checkups, many of their responses are subjective, making topic extraction difficult. Therefore, the purpose of this study was to develop a model capable of extracting appropriate topics from subjective data in questionnaires conducted during health checkups.Methods: We employed a latent topic model to group the lifestyle habits of the study participants and represented their responses to items on health checkup questionnaires as a probability model. For the probability model, we used latent Dirichlet allocation to extract 30 topics from the questionnaires. According to the model parameters, a total of 4381 study participants were then divided into groups based on these topics. Results from laboratory tests, including blood glucose level, triglycerides, and estimated glomerular filtration rate, were compared between each group, and these results were then compared with those obtained by hierarchical clustering.Results: If a significant (p < 0.05) difference was observed in any of the laboratory measurements between groups, it was considered to indicate a questionnaire response pattern corresponding to the value of the test result. A comparison between the latent topic model and hierarchical clustering grouping revealed that, in the latent topic model method, a small group of participants who reported having subjective signs of urinary disorder were allocated to a single group.Conclusions: The latent topic model is useful for extracting characteristics from a small number of groups from questionnaires with a large number of items. These results show that, in addition to chief complaints and history of past illness, questionnaire data obtained during medical checkups can serve as useful judgment criteria for assessing the conditions of patients. [ABSTRACT FROM AUTHOR]

Background: The involvement of monoclonal immunoglobulin (MIg) in renal damage in patients with haematological disorders and renal biopsy-proven monoclonal gammopathy of renal significance is well established. However, no epidemiological studies have been conducted on the effects of MIg on renal function in other patients. We aimed to evaluate the renal prognosis of MIg-positive patients and the effects of MIg on renal function., Methods: This retrospective observational study was performed using clinical data from all outpatients and inpatients who underwent MIg measurements at the time of enrolment at Kochi Medical School Hospital between 1 January 2017 and 31 December 2021. The primary outcomes were the occurrence of acute kidney injury (AKI) and a decline of > 30% in the estimated glomerular filtration rate (eGFR)., Results: Among the 1362 patients, 750 were included in our cohort. The number of MIg-positive and MIg-negative patients was 119 (15.9%) and 631 (84.1%), respectively. In addition, the MIg-positive patients were significantly older than the MIg-negative patients. The survival probability of the MIg-positive group was significantly lower than that of the MIg-negative group during the 2 year observation period. The risk factors for the primary endpoint were positive MIg, female sex, lower eGFR, and lower albumin level., Conclusions: Our study showed that the presence of MIg was an independent risk factor for renal damage. Therefore, we suggest that MIg-positive patients require careful follow-up of their renal function, even in the absence of a clear underlying disease, such as multiple myeloma., Competing Interests: Declarations. Conflict of interest: The authors have declared that no conflict of interest exists. Informed consent: Informed consent was obtained from all the individual participants included in the study. Data were obtained from patients who completed a general consent form based on an opt-out policy at Kochi Medical School Hospital. Research involving human participants: All the procedures were performed in accordance with the ethical standards of the Institutional Research Committee of Kochi Medical School Hospital (IRB approval number: 23-15) and the 1964 Helsinki Declaration and its later amendments., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Background: The combination of urinary tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) ([TIMP-2]⋅[IGFBP7]) has emerged as a strong predictor of acute kidney injury (AKI), which is associated with poor outcomes. However, most studies have focused on non-Asian populations, and comparisons of [TIMP-2]⋅[IGFBP7] with other AKI biomarkers in Asian populations have not been performed. Furthermore, no study has examined the efficacy of [TIMP-2]⋅[IGFBP7] for predicting community-acquired AKI., Methods: We prospectively enrolled adult patients at Kochi Medical School Hospital in Kochi, Japan, and performed a receiver-operating characteristic (ROC) curve analysis to assess the ability of [TIMP-2]⋅[IGFBP7], neutrophil gelatinase-associated lipocalin (NGAL), and liver fatty acid-binding protein (L-FABP) measured at the time of admission to predict AKI., Results: Of the 170 enrolled patients, 40 (23.5%) developed AKI. Risk factors for AKI development were male sex, history of hypertension, low albumin levels, and high [TIMP-2]⋅[IGFBP7] and NGAL levels. The ROC curve analysis showed that the area under the ROC curve (AUC) of [TIMP-2]•[IGFBP7] for predicting AKI was 0.804 (95% confidence interval [CI], 0.728-0.880); however, the AUCs of L-FABP and NGAL were 0.688 (95% CI, 0.594-0.782) and 0.726 (95% CI, 0.639-0.813), respectively., Conclusion: Urinary [TIMP-2]⋅[IGFBP7] is a good predictor of community-acquired AKI., Competing Interests: Declarations. Conflicts of interest: The authors have declared that no conflict of interest exists. Research involving human participants and/or animals: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional at which the studies were conducted and/or the national research committee (Kochi Medical School Hospital IRB approval no.: 28–103) as well as with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent: Informed consent was obtained from all individual participants included in the study., (© 2025. The Author(s).)

Objectives: Routine clinical practice with extended anaerobic antibiotic coverage (EAC) has been recently reconsidered for several infections; however, its benefits remain unclear even in patients with anaerobic bacteremia (AB). Here, we aimed to elucidate the effects of EAC on AB prognosis., Methods: A multicenter retrospective observational study was conducted in patients with AB. Multivariate logistic regression analysis was performed to assess the effect of EAC on 30-day mortality. Inverse probability of treatment weighting analysis was performed to confirm the robustness of the findings., Results: In total, 483 patients were included, of whom 387 received EAC and 96 received limited anaerobic antibiotic coverage (LAC). Atypical foci of anaerobic infection, such as urinary tract infection and pneumonia, together with undetectable infection foci, comprised a larger proportion of infection foci in the LAC group than that in the EAC group (46.9% vs 30.5%). The 30-day mortality rates of the EAC and LAC groups were similar (12.5% and 14.2%, respectively; P = 0.664). Primary analysis revealed that EAC was not significantly associated with high mortality (odds ratio [OR], 1.42; 95% confidence interval [CI], 0.7-2.8), whereas source control significantly reduced this risk (OR, 0.28; 95% CI, 0.2-0.5). The sensitivity analysis results were consistent with those of the primary analyses., Conclusion: This study demonstrated a less significant effect of initial EAC on AB compared with source control, particularly on AB with atypical infection foci. These findings would prompt reconsideration of the necessity of an initial EAC in several infections., Competing Interests: Declarations of competing interest The authors declare that there is no conflict of interest. Mukae H received the payment for lectures and expert testimony from SHIONOGI Co., Ltd. and Meiji Seika Pharma Co., Ltd., regardless of this study., (Copyright © 2025 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aims: Itaconate (IA) is synthesized in the citric acid cycle via cis-aconitate decarboxylase (ACOD1); however, its biological significance in cancer remains incompletely understood. In previous studies, 4-octyl itaconate (OI) was used as a membrane-permeable form of IA, but little detailed verification of the difference in biological activities between IA and OI exists. Here, we investigated the direct effects of IA and OI on melanoma. Results: The proliferation of melanoma cells treated with OI was significantly suppressed in vitro , and our transcriptomic analysis revealed drastic changes in the expression of glutathione metabolism-related genes in OI-treated cells. Indeed, OI treatment decreased intracellular glutathione levels, followed by increased production of reactive oxygen species and expression of γH2AX, a marker of DNA damage, and β-galactosidase, a marker of cellular senescence. We further showed that the mitochondrial respiratory capacity in B16 cells was significantly decreased by OI treatment. OI administration also suppressed the growth of B16 tumor transplants in vivo , and the expression of γH2AX was increased in tumor tissues of OI-treated mice. In addition, minimal effects of OI treatment were observed in melanocytes and normal tissues. We also proved that not only exogenous IA, which enters intracellularly, but also endogenous IA has little effect on melanoma proliferation activity, via an investigation using Acod1 -overexpressing transfectants and Acod1 -deficient mice. Conclusion: This work revealed that OI disrupts the antioxidant system via the collapse of glutathione metabolism and inhibits cancer cell proliferation. Antioxid. Redox Signal. 00, 000-000.

Unicentric Castleman's disease (UCD) typically presents as an asymptomatic tumour in the anterior or middle mediastinum. Occurrence in the paravertebral region is comparatively rare and it requires differentiation from neurogenic tumours by imaging. In our patient, preoperative imaging findings were atypical of schwannoma. Contrast-enhanced MRI of the thoracic region showed a muscle-like mass in contact with the pleura on T1-weighted images. T2-weighted images showed high signal, especially at the margins. Diffusion-weighted images showed diffusion restriction around the limbus, and contrast-enhanced T1-weighted images displayed strong enhancement of the mass. Diagnosis could not be made preoperatively, although UCD was suspected. Thoracoscopic tumour resection was performed for definitive diagnosis and treatment and postoperative diagnosis was hyaline-vascular-type UCD. Diagnosis of neurogenic tumours can be difficult by imaging alone. When imaging findings are atypical, a definitive diagnosis is required, with consideration of the possibility of UCD., Competing Interests: The authors declare no conflicts of interest., (© 2025 The Author(s). Respirology Case Reports published by John Wiley & Sons Australia, Ltd on behalf of The Asian Pacific Society of Respirology.)

Human parvovirus B19 (B19V) causes fetal hydrops in pregnant women. Despite the significant impact of this virus, effective vaccines remain unclear. In this study, we successfully engineered B19V protein nanoparticles by fusing the N-terminal receptor-binding domain corresponding to 5-80 amino acids of VP1 with two distinct types of self-assembling protein nanoparticles. Gel filtration and electron microscopic analysis confirmed the spherical assembly of the antigen-fused nanoparticles. The purified nanoparticles are efficiently bound to the surface of UT7/Epo-S1 cells, which are semi-permissive hosts for B19V infection. Immunization of BALB/c mice with VP1u 5-80 nanoparticles elicited a robust production of B19V-specific IgG antibodies compared to single VP1u 5-80 peptides. Moreover, a neutralization assay using B19V derived from a blood donor sample revealed that antibodies from mice immunized with VP1u 5-80 nanoparticles exhibited stronger infection-neutralizing activity. These findings suggest that nanoparticle formation plays a crucial role in enhancing the immunogenicity of the B19V VP1u 5-80 amino acid peptide and that these nanoparticles could serve as promising vaccine candidates, effectively inducing immunity against B19V., (© 2024 The Author(s). Microbiology and Immunology published by The Societies and John Wiley & Sons Australia, Ltd.)

Background: Urinary creatinine levels are used to estimate the excretion rates of certain analytes from the respective analyte-to-creatinine ratios. We clarified the influence of age and sex on estimated daily urinary creatinine excretion (eUCrE) based on the urinary creatinine level and daily urine volume., Methods: All inpatients aged ≥ 18 years who attended the Kochi Medical School Hospital with serum and urinary creatinine measurement results were enrolled. Serum and urinary creatinine concentrations were extracted from the database and fluctuations with sex and age were investigated. The eUCrE was calculated for patients with early morning spot urine protein excretion (UPE), and daily urine volume was measured on the same day., Results: Overall, 643 participants (322 men, 321 women) were enrolled. The eUCrE levels of men and women aged 18 - 64 and 18 - 44 years, respectively, significantly exceeded 1 g/day. Those of women aged 65-74 and ≥ 75 years were significantly lower than 1 g/day. Each age group was further categorised into Groups A (patients with eGFR ≥ 30 mL/min/1.73 m 2 and UPE < 0.5 g/gCr), B (eGFR ≥ 30 mL/min/1.73 m 2 and UPE ≥ 0.5 g/gCr), and C (eGFR < 30 mL/min/1.73 m 2 and UPE ≥ 0.5 g/gCr). The eUCrE levels were the highest in Group A, followed by Groups B and C., Conclusion: This study revealed age-, sex-, and renal function-related biases in adjusted values using urinary biomarkers, including proteinuria and creatinine ratio., Competing Interests: Declarations. Conflict of interest: The authors have declared that no conflict of interest exists. Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee at which the studies were conducted (IRB approval number 23–15) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent: Informed consent was obtained from all individual participants included in the study., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Competing Interests: Declarations. Compliance with ethical standards: All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Conflict of interest: Hitoshi Shimada holds patents on compounds related to the present report (JP 5422782/EP 12 884 742.3/CA2894994/HK1208672), and received honoraria for lectures from Eizai Co., Ltd., consultant fee from Splink Co., Ltd., and research fundings from Splink Co., Ltd. and Novartis Pharmaceutical Co., Ltd. All other authors declare that they have no conflicts of interest regarding financial support or relationships. Ethical approval: The PET study conducted for the present report was approved by the Niigata University Certified Review Board (UMIN 000050731). Informed consent: Written informed consent was obtained from the patient.

Background: Delirium is a postoperative complication that may occur in older patients. This study aimed to investigate the incidence of postoperative delirium and its risk factors in patients who had undergone total hip arthroplasty (THA) or total knee arthroplasty (TKA). Few reports have addressed the occurrence of delirium when different methods of pain control are used following total joint arthroplasty, and, therefore, whether its incidence varied depending on differences in pain control was investigated., Methods: The study included 500 patients (250 cases of THA and 250 of TKA). They were divided into two groups according to the occurrence of postoperative delirium, and risk factors for delirium (patient factors and operative factors) were investigated. As pain control, all patients were given a Ranawat cocktail injection, with the concomitant use of one of epidural anesthesia, nerve block, or intravenous patient-controlled analgesia (IVPCA), and the occurrence of delirium in patients using each method was investigated., Results: On univariate analysis, advanced age, low serum albumin, nonbenzodiazepine use, and anti-parkinsonian drug use were identified as patient factors, and low postoperative minimum hemoglobin, non-use of epidural anesthesia, and non-use of nerve block were identified as operative factors associated with a significantly higher incidence of delirium. A receiver-operating characteristic curve was created for age and delirium, and the cutoff age was 77 years. On binomial logistic regression analysis for age ≥77 years, epidural anesthesia, IVPCA, and nerve block, the only factor associated with the occurrence of delirium was age, irrespective of the type of pain relief used, and the odds ratio for the occurrence of delirium at age ≥77 years was 4.64., Conclusions: To prevent delirium following total joint arthroplasty, it is important to improve anemia and nutritional status, check and manage regular medications, and provide appropriate pain control while avoiding opioid use., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: Few epidemiologic studies on acute kidney injury (AKI) have focused on the older adult population. This study aimed to clarify the characteristics and risk factors for AKI in this population., Methods: This retrospective observational study was performed with the clinical data of all outpatients and inpatients aged ≥ 65 years at the time of enrolment at Kochi Medical School Hospital between 1 January 1981 and 31 December 2021. The primary cohort was divided into those aged 65-74 and ≥ 75 years. The primary outcome was the occurrence of AKI., Results: Of 83,822 patients, 38,333 were included in the 65-74-year-old group, whereas 45,489 were included in the ≥ 75-year-old group. Prevalences of the first AKI event in the 65-74-year-old and ≥ 75-year-old groups were 11.9% and 12.4%, respectively. Overall, lower estimated glomerular filtration rate, lower albumin level, lower or higher level of serum uric acid, and histories of diabetes mellitus, chronic heart failure, ischaemic heart disease, non-ischaemic heart disease, cerebrovascular disease, cancer, and liver disease were independent risk factors for an AKI event. The risk factors for AKI unique to each cohort were using non-steroidal anti-inflammatory drugs (NSAIDs) and loop diuretics (L-DI), and histories of hypertension (HT) and vascular diseases (VD) in men aged 65-74 years; using NSAIDs, angiotensin-converting enzyme inhibitors (ACEIs), L-DI and other diuretics (O-DI), and histories of HT and VD in men aged ≥ 75 years; using NSAIDs and O-DI and not using angiotensin-receptor blockers (ARBs), and a history of HT in women aged 65-74 years; and use of L-DI and a history of VD in women aged ≥ 75 years. Presence of proteinuria was a risk factor for developing AKI., Conclusions: Many AKI risk factors reported thus far are associated with AKI development. However, there are differences in the effects of the renin-angiotensin system inhibitors, ACEIs, and ARBs (ARBs may be protective). Additionally, the U-shaped relationship between AKI onset and uric acid levels differs between sexes in the elderly population, similar to other age groups, but this sex difference disappears in the very elderly population. Pre-existing chronic kidney disease is a risk factor for the development of AKI., Competing Interests: Declarations Ethical approval All procedures were performed in accordance with the ethical standards of the institutional and/or national research committee at which the studies were conducted (institutional review board approval number 23–15) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent Informed consent to record and analyse data for research purposes was obtained from all study participants. Data were obtained from patients who completed a general consent form based on an opt-out policy at Kochi Medical School Hospital., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Pacific oysters were sampled from 22 human-impacted sites in northeastern Japan to measure Cr, Cu, Zn, Pb, Cd, and As. The hazard quotient was slightly >1 for Cu and/or As at two sites, but <1 for all metal species and As at the other sites, indicating low human health risks. Oysters' Cu, Zn, and Pb contents were positively related to their concentrations in the sediment, while Cr and As were not. Oysters' Cu and Zn were negatively related to the inorganic nitrogen in seawater, while oysters' Pb and As showed positive relationships with the particulate organic carbon. These findings suggest that marine trophic status affects oysters' metal uptake differently among the metal species. Furthermore, oysters' Cr, Cu, Zn, and Pb contents were negatively related to their eicosapentaenoic acid content and condition index. Therefore, the nutritional conditions of oysters may influence their elimination or accumulation of these metals., 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 Ltd.. All rights reserved.)

Deficit of oxygen and nutrients in the tumor microenvironment (TME) triggers abnormal angiogenesis that produces dysfunctional and leaky blood vessels, which fail to adequately perfuse tumor tissues. Resulting hypoxia, exacerbation of metabolic disturbances, and generation of an immunosuppressive TME undermine the efficacy of anticancer therapies. Use of carefully scheduled angiogenesis inhibitors has been suggested to overcome these problems and normalize the TME. Here, we propose an alternative agonist-based normalization approach using a derivative of the C-type natriuretic peptide (dCNP). Multiple gene expression signatures in tumor tissues were affected in mice treated with dCNP. In several mouse orthotopic and subcutaneous solid tumor models including colon and pancreatic adenocarcinomas, this well-tolerated agent stimulated formation of highly functional tumor blood vessels to reduce hypoxia. Administration of dCNP also inhibited stromagenesis and remodeling of the extracellular matrix and decreased tumor interstitial fluid pressure. In addition, treatment with dCNP reinvigorated the antitumor immune responses. Administration of dCNP decelerated growth of primary mouse tumors and suppressed their metastases. Moreover, inclusion of dCNP into the chemo-, radio-, or immune-therapeutic regimens increased their efficacy against solid tumors in immunocompetent mice. These results demonstrate the proof of principle for using vasculature normalizing agonists to improve therapies against solid tumors and characterize dCNP as the first in class among such agents.

Melanoma, a cancer arising from melanocytes, requires a novel treatment strategy because of the ineffectiveness of conventional therapies in certain patients. Fustin is a flavanonol found in young fustic (Cotinus coggygria). However, little is known about its antimelanoma effects. Our study demonstrates that fustin suppresses the growth of B16 melanoma cells. Phalloidin staining of cytoskeletal actin revealed that fustin induced a conformational change in the actin structure of melanoma cells, accompanied by suppressed phosphorylation of myosin regulatory light chain 2 (MLC2), a regulator of actin structure. Furthermore, the protein kinase A (cAMP-dependent protein kinase) inhibitor H89 completely attenuated fustin-induced downregulation of phosphorylated myosin phosphatase targeting subunit 1, which is involved in dephosphorylation of MLC2. In a mouse model, administration of fustin suppressed tumor growth in B16 melanoma cells without adverse effects. In conclusion, our findings suggest that fustin effectively suppresses melanoma cell growth both in vitro and in vivo., (© The Author(s) 2024. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Background: R-spondins (Rspos) are secreted proteins that modulate Wnt/β-catenin signaling. At the early stages of spinal cord development, Wnts (Wnt1, Wnt3a) and Rspos (Rspo1, Rspo3) are co-expressed in the roof plate, suggesting that Rspos are involved in development of dorsal spinal cord and neural crest cells in cooperation with Wnt ligands., Results: Here, we found that Rspo1 and Rspo3, as well as Wnt1 and Wnt3a, maintained roof-plate-specific expression until late embryonic stages. Rspo1- and Rspo3-double-knock-out (dKO) embryos partially exhibited the phenotype of Wnt1 and Wnt3a dKO embryos. While the number of Ngn2-positive sensory lineage neural crest cells is reduced in Rspo-dKO embryos, development of dorsal spinal cord, including its size and dorso-ventral patterning in early development, elongation of the roof plate, and proliferation of ependymal cells, proceeded normally. Consistent with these slight defects, Wnt/β-catenin signaling was not obviously changed in developing spinal cord of dKO embryos., Conclusions: Our results show that Rspo1 and Rspo3 are dispensable for most developmental processes involving roof plate-derived Wnt ligands, except for specification of a subtype of neural crest cells. Thus, Rspos may modulate Wnt/β-catenin signaling in a context-dependent manner., (© 2023 The Authors. Developmental Dynamics published by Wiley Periodicals LLC on behalf of American Association for Anatomy.)

Objectives: This study investigated the association between hyponatremia and falls in elderly hospitalized patients, focusing on mild hyponatremia as a potential risk factor., Materials and Methods: A retrospective analysis of 16,952 patients admitted to Kochi Medical School Hospital from 2012 to 2021 was performed. Serum sodium levels were categorized, and falls during a 30-day observation period were recorded. A Cox proportional hazards model and a machine learning model were used to estimate risk and explore interactions., Results: Mild hyponatremia (130-134 mEq/L) was identified as an independent risk factor for falls (hazard ratio: 1.42, 95 % confidence interval 1.16-1.74), especially in patients with higher activities of daily living. The fall prediction model showed an area under the curve (AUC) of 0.780 (95 % confidence interval 0.751-0.806)., Conclusion: A significant association between mild hyponatremia and falls in elderly hospitalized patients was found. The findings highlight the need for targeted fall prevention and further research into the underlying mechanisms. Mild hyponatremia may serve as a clinical marker for fall risk, especially in patients with independent activities of daily living., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2023. Published by Elsevier B.V.)

Background: The development of induced pluripotent stem cells (iPSCs) technology has enabled human cellular disease modeling for inaccessible cell types, such as neural cells in the brain. However, many of the iPSC-derived disease models established to date typically involve only a single cell type. These monoculture models are inadequate for accurately simulating the brain environment, where multiple cell types interact. The limited cell type diversity in monoculture models hinders the accurate recapitulation of disease phenotypes resulting from interactions between different cell types. Therefore, our goal was to create cell models that include multiple interacting cell types to better recapitulate disease phenotypes., Methods: To establish a co-culture model of neurons and astrocytes, we individually induced neurons and astrocytes from the same iPSCs using our novel differentiation methods, and then co-cultured them. We evaluated the effects of co-culture on neurons and astrocytes using immunocytochemistry, immuno-electron microscopy, and Ca 2+ imaging. We also developed a co-culture model using iPSCs from a patient with familial Alzheimer's disease (AD) patient (APP V717L mutation) to investigate whether this model would manifest disease phenotypes not seen in the monoculture models., Results: The co-culture of the neurons and astrocytes increased the branching of astrocyte processes, the number of GFAP-positive cells, neuronal activities, the number of synapses, and the density of presynaptic vesicles. In addition, immuno-electron microscopy confirmed the formation of a tripartite synaptic structure in the co-culture model, and inhibition of glutamate transporters increased neuronal activity. Compared to the co-culture model of the control iPSCs, the co-culture model of familial AD developed astrogliosis-like phenotype, which was not observed in the monoculture model of astrocytes., Conclusions: Co-culture of iPSC-derived neurons and astrocytes enhanced the morphological changes mimicking the in vivo condition of both cell types. The formation of the functional tripartite synaptic structures in the co-culture model suggested the mutual interaction between the cells. Furthermore, the co-culture model with the APP V717L  mutation expressed in neurons exhibited an astrocytic phenotype reminiscent of AD brain pathology. These results suggest that our co-culture model is a valuable tool for disease modeling of neurodegenerative diseases., (© 2024. The Author(s).)

Introduction: 17β-Estradiol (E2) is a sex hormone that has been previously demonstrated to have neurotherapeutic effects on animal models of Alzheimer's disease (AD). However, clinical trials on E2 replacement therapy for preventing AD onset yielded inconsistent results. Therefore, it is imperative to clarify the therapeutic effects of E2 on human cells. In this study, we utilized induced pluripotent stem cells (iPSCs) derived from multiple AD donors to explore the therapeutic effects of E2 on the in vitro model of human cells., Methods: We conducted a systematic review and meta-analysis using a random-effects model of the previously reported AD clinical trials to summarize the effects of E2 replacement therapy on AD prevention. Subsequently, we induced iPSCs from the donors of the healthy control (1210B2 line (female) and 201B7 line (female)), the familial AD (APP V717L line (female) and APP KM670/671NL line (female)), and the sporadic AD (UCSD-SAD3.7 line (APOE ε3/ε3) (male), UCSD-SAD7D line (APOE ε3/ε4) (male), and TMGH-1 line (APOE ε3/ε3) (female)), then differentiated to neurons. In addition to the mono-culture model of the neurons, we also examined the effects of E2 on the co-culture model of neurons and astrocytes., Results: The meta-analysis of the clinical trials concluded that E2 replacement therapy reduced the risk of AD onset (OR, 0.69; 95 % confidence interval [CI], 0.53-0.91; I 2  = 82 %). Neural models from the iPSCs of AD donors showed an increase in secreted amyloid-beta (Aβ) levels in the mono-culture model and an astrogliosis-like phenotype in the co-culture model. E2 treatment to the neuronal models derived from the iPSCs enhanced neuronal activity and increased neurite complexity. Furthermore, E2 treatment of the co-culture model ameliorated the astrogliosis-like phenotype. However, in contrast to the previous reports using mouse models, E2 treatment did not change AD pathogenesis, including Aβ secretion and phosphorylated tau (pTau) accumulation., Conclusion: E2 treatment of the human cellular model did not impact Aβ secretion and pTau accumulation, but promoted neuronal plasticity and alleviated the astrogliosis-like phenotype. The limited effects of E2 may give a clue for the mixed results of E2 clinical trials., Competing Interests: Hideyuki Okano is a founder scientist and a Scientific Advisory Board Member for SanBio Co., Ltd., and K Pharma Inc. The remaining authors declare no conflicts of interest., (© 2024 The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V.)

Patient participation is considered important for the safety and quality of care. The patient's perception of actually being able to participate in healthcare, namely, the sense of participation, may influence patient satisfaction (PS). This study aimed to quantitatively determine the relationship between sense of participation to healthcare and PS. A questionnaire survey was conducted among 100 inpatients from each of the 5 target hospitals. The questionnaire included 6 PS items and 4 patient achievement goals, which were indicators of whether the patients had a sense of participation. The response rate was 60.6% (303/500). Patients who perceived that they could choose a treatment that reflected their values and wishes had significantly higher scores on all PS items. Patients who achieved the goal of "I want to be a member of the medical team and participate actively in treatment and safety activities" showed significantly higher PS related to coping to reduce pain and symptoms. Additionally, patients who achieved the goal of "I believe I am able to voluntarily learn about the disease/treatment and use it to make decisions" had significantly higher PS related to psychological support. Sense of participation may improve PS in a wide range of areas. Hospitals and healthcare workers are expected to empower patients to develop a sense of participation., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background and Aims: The introduction of crassulacean acid metabolism (CAM) into C3 crops has been considered as a means of improving water-use efficiency. In this study, we investigated photosynthetic and leaf structural traits in F1 hybrids between Cymbidium ensifolium (female C3 parent) and C. bicolor subsp. pubescens (male CAM parent) of the Orchidaceae., Methods: Seven F1 hybrids produced through artificial pollination and in vitro culture were grown in a greenhouse with the parent plants. Structural, biochemical and physiological traits involved in CAM in their leaves were investigated., Key Results: Cymbidium ensifolium accumulated very low levels of malate without diel fluctuation, whereas C. bicolor subsp. pubescens showed nocturnal accumulation and diurnal consumption of malate. The F1s also accumulated malate at night, but much less than C. bicolor subsp. pubescens. This feature was consistent with low nocturnal fixation of atmospheric CO2 in the F1s. The δ13C values of the F1s were intermediate between those of the parents. Leaf thickness was thicker in C. bicolor subsp. pubescens than in C. ensifolium, and those of the F1s were more similar to that of C. ensifolium. This was due to the difference in mesophyll cell size. The chloroplast coverage of mesophyll cell perimeter adjacent to intercellular air spaces of C. bicolor subsp. pubescens was lower than that of C. ensifolium, and that of the F1s was intermediate between them. Interestingly, one F1 had structural and physiological traits more similar to those of C. bicolor subsp. pubescens than the other F1s. Nevertheless, all F1s contained intermediate levels of phosphoenolpyruvate carboxylase but as much pyruvate, Pi dikinase as C. bicolor subsp. pubescens., Conclusions: CAM traits were intricately inherited in the F1 hybrids, the level of CAM expression varied widely among F1 plants, and the CAM traits examined were not necessarily co-ordinately transmitted to the F1s., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Human neural cell models derived from induced pluripotent stem cells (iPSCs) have been widely accepted to model various neurodegenerative diseases such as Alzheimer's disease (AD) in vitro . Although the most common sources of iPSCs are fibroblasts and peripheral blood mononuclear cells, the collection of these cells is invasive. To reduce the donor's burden, we propose the use of urine-derived cells (UDCs), which can be obtained non-invasively from a urine sample. However, the collection of UDCs from elderly donors suffering from age-related diseases such as AD has not been reported, and it is unknown whether these UDCs from the donor aged over 80 years old can be converted into iPSCs and differentiated into neural cells. In this study, we reported a case of using the UDCs from the urine sample of an 89-year-old AD patient, and the UDCs were successfully reprogrammed into iPSCs and differentiated into neural cells in four different ways: (i) the dual SMAD inhibition with small-molecules via the neural progenitor precursor stage, (ii) the rapid induction method using transient expression of Ngn2 and microRNAs without going through the neural progenitor stage, (iii) the cortical brain organoids for 3D culture, and (iv) the human astrocytes. The accumulation of phosphorylated Tau proteins, which is a pathological hallmark of AD, was examined in the neuronal models generated from the UDCs of the aged donor. The application of this cell source will broaden the target population for disease modeling using iPS technology., 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., (© 2023 The Authors.)

This study aimed to clarify neurological differences among the epiconus, conus medullaris, and cauda equina syndromes. Eighty-seven patients who underwent surgery for acute thoracolumbar spinal injuries were assessed. We defined the epiconus as the region from the terminal end of the spinal cord to the proximal 1.0 to 2.25 vertebral bodies, the conus medullaris as the region proximal to < 1.0 vertebral bodies, and the cauda equina as the distal part of the nerve roots originating from the spinal cord. On the basis of the distance from the terminal end of the spinal cord to the narrowest level of the spinal canal, the narrowest levels were ordered as follows: the epiconus followed by the conus medullaris and cauda equina. The narrowest levels were the epiconus in 22 patients, conus medullaris in 37 patients, and cauda equina in 25 patients. On admission, significantly more patients had a narrowed epiconus of Frankel grades A-C than a narrowed cauda equina. At the final follow-up, there were no significant differences in neurological recovery among those with epiconus, conus medullaris, or cauda equina syndrome. Anatomically classifying the narrowest lesion is useful for clarifying the differences and similarities among these three syndromes., Competing Interests: No potential conflict of interest relevant to this article was reported.

Objectives: The combination of chemotherapy and immune checkpoint inhibitors (chemo-ICI) has become the new standard of treatment for extensive-stage small cell lung cancer (ES-SCLC). Recently, slight changes in interstitial shadows, defined as interstitial lung abnormalities (ILA), have been identified. In patients with ES-SCLC who received chemo-ICI, there are limited data on the incidence of drug-induced interstitial lung disease (D-ILD) in daily practice and the association between the development of D-ILD and ILA in the baseline computed tomography (CT)., Materials and Methods: A multicenter, retrospective study was conducted to investigate the incidence of D-ILD, the risk factors for developing D-ILD, progression-free survival (PFS), and overall survival (OS) in patients with ES-SCLC who received chemo-ICI between August 2019 and November 2021., Results: This study enrolled 70 patients (median age, 71 years; including 58 men) from nine institutions in Japan. There were 62 patients (89%) treated with carboplatin/etoposide/atezolizumab and 8 patients treated with carboplatin or cisplatin/etoposide/durvalumab. Twenty-nine patients (41.4%) were found to have ILA at baseline CT. Eleven patients (15.7%) developed D-ILD. The proportion of patients with ILA was significantly higher in the group who developed D-ILD than in the group who did not (9/11 (81.8%) vs. 20/59 (33.9%), respectively, P = 0.0057). In addition, the frequency of ground glass attenuation (GGA) and reticulation was higher in patients who developed D-ILD. There was no significant difference in PFS and OS between patients who developed D-ILD and those who did not (median PFS, 8.0 (95% confidence interval (CI), 5.5-9.5) months vs. 5.0 (95% CI, 4.5-5.6) months, respectively, P = 0.11 and median OS, not reached (NR) (95% CI, 8.7-NR) vs. 18.2 (95% CI, 13.2-NR) months, respectively, P = 0.20)., Conclusion: The incidence of D-ILD in patients with ES-SCLC who received chemo-ICI in clinical practice was higher than that in clinical trials. Patients with pre-existing ILA were more likely to develop D-ILD., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Matters requiring disclosure of COI with regard to our presentation are lecture fee by Chugai Pharmaceutical Co Ltd and research expenses from company by AstraZeneca., (© 2023 The Authors. Published by Elsevier Ltd.)

Background: In Japan, the crude mortality rate of colorectal cancer is the second highest among men and highest among women by site. We aimed to calculate the social burden of colorectal cancer using the cost of illness (COI) method and identify the main factors that drove changes in the COI., Methods: From 1996 to 2020, the COI was estimated by summing direct, morbidity, and mortality costs. In addition, the COI by 2035 was projected by fitting approximate curves obtained from historical data to health-related indicators by sex and age. Future projections of the number of patients by the stage of disease were also made to explore the factors that changed the COI., Results: The number of deaths and incidence from colorectal cancer was expected to continue increasing due to population aging. However, the COI was projected to rise from 850.3 billion yen in 1996 to 1.451 trillion yen in 2020, and peaked at 1.478 trillion yen in 2023 before it declined., Conclusion: Although the increased number of deaths associated with population aging increased COI, it was expected that the COI would decrease around 2023 due to a decrease in the human capital value of the deceased. In addition, the mortality rate was expected to decrease in the future due to an increase in the percentage of early detection of colorectal cancer via widespread screening and advances in medical technology., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objective: To evaluate whether the involvement of methodological experts improves the quality of clinical practice guidelines (CPGs) after adjusting for other factors., Setting: The quality of Japanese CPGs published in 2011-2019 was assessed using the Appraisal of Guidelines, Research, and Evaluation (AGREE) II instrument. A questionnaire survey targeting CPG development groups was conducted through postal mail., Participants: 405 CPGs were retrieved from a Japanese CPG clearinghouse. Questionnaires were distributed to the 405 CPG development groups. Of the 178 respondents, 22 were excluded because of missing values. Finally, 156 participants representing their CPG development groups were included in the analysis., Primary and Secondary Outcome Measures: CPG quality was assessed using the AGREE II tool. The characteristics of CPGs, including publication year, development organisation, versions, number of members in the development group and involvement of methodological experts, were corrected from the description in the CPGs and the questionnaire survey. We performed multiple logistic regressions using the quality of CPGs as the dependent variable and the involvement of experts as the independent variable, adjusting for other possible factors., Results: A total of 156 CPGs were included. Expert involvement was significantly associated with the AGREE II instrument scores in domains 1 (β=0.207), 2 (β=0.370), 3 (β=0.413), 4 (β=0.289), 5 (β=0.375), 6 (β=0.240) and overall (β=0.344)., Conclusion: This study revealed that the involvement of methodological experts in the CPG development process improves the quality of CPGs. The results suggest the importance of establishing a training and certification programme for experts and constructing expert referral systems that meet CPG developers' needs to improve the quality of CPGs., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We studied the spatiotemporal variations in 134 Cs, 137 Cs, and 228 Ra concentrations at the sea surface off southeastern Hokkaido, Japan (off-Doto region) from 2018 to 2022 using low-background γ-spectrometry. The 134 Cs concentrations in the off-Doto region, decay-corrected to the date of the Fukushima Dai-ichi Nuclear Power Plant (FDNPP) accident, exhibited wide lateral variation each year (e.g., 0.7-1.1 mBq/L in 2020). By studying the 228 Ra concentrations and salinity, this variation was explained based on the current mixing patterns. Furthermore, the 134 Cs concentrations in the waters highly affected by the Oyashio Current (OYC) gradually increased from 2018 to 2020, and subsequently decreased in 2022. This implies that the water mass maximally contaminated with 134 Cs was transported back to the side of the Japanese islands 10 years after the FDNPP accident along with counter-clockwise currents (e.g., the OYC) in the northern North Pacific Ocean. The 134 Cs concentrations in the OYC-affected waters in the off-Doto region in 2020 were ~ 1/6 times those in the 134 Cs-enriched core of waters off the western American Coast in 2015, which can be ascribed to dilution via spatial dispersion during subarctic current circulation. Overall, we elucidated the ocean-scale subarctic current systems in the northwestern North Pacific Ocean, including water circulation timespans., (© 2023. The Author(s).)

Background: Maintenance of activities of daily living (ADL) during acute hospitalization is an important treatment goal, especially for elderly inpatients with diseases that often leave disabilities, such as cerebral infarction. However, studies assessing risk-adjusted ADL changes are limited. In this study, we developed and calculated a hospital standardized ADL ratio (HSAR) using Japanese administrative claims data to measure the quality of hospitalization care for patients with cerebral infarction., Methods: This study was designed as a retrospective observational study using the Japanese administrative claim data from 2012 to 2019. The data of all hospital admissions with a primary diagnosis of cerebral infarction (ICD-10, I63) were used. The HSAR was defined as the ratio of the observed number of ADL maintenance patients to the expected number of ADL maintenance patients multiplied by 100, and ratio of ADL maintenance patients was risk-adjusted using multivariable logistic regression analyses. The c-statistic was used to evaluate the predictive accuracy of the logistic models. Changes in HSARs in each consecutive period were assessed using Spearman's correlation coefficient., Results: A total of 36,401 patients from 22 hospitals were included in this study. All variables used in the analyses were associated with ADL maintenance, and evaluations using the HSAR model showed predictive ability with c-statistics (area under the curve, 0.89; 95% confidence interval, 0.88-0.89)., Conclusions: The findings indicated a need to support hospitals with a low HSAR because hospitals with high/low HSAR were likely to produce the same results in the subsequent periods. HSAR can be used as a new quality indicator of in-hospital care and may contribute to the assessment and improvement of the quality of care., (© 2023. The Author(s).)

Wnt signaling is required to maintain bipotent progenitors for neural and paraxial mesoderm cells, the neuromesodermal progenitor (NMP) cells that reside in the epiblast and tailbud. Since epiblast/tailbud cells receive Wnt ligands produced by one another, this exchange may average out the heterogeneity of Wnt signaling levels among these cells. Here, we examined this possibility by replacing endogenous Wnt3a with a receptor-fused form that activates signaling in producing cells, but not in neighboring cells. Mutant mouse embryos show a unique phenotype in which maintenance of many NMP cells is impaired, although some cells persist for long periods. The epiblast cell population of these embryos increases heterogeneity in Wnt signaling levels as embryogenesis progresses and are sensitive to retinoic acid, an endogenous antagonist of NMP maintenance. Thus, mutual intercellular exchange of Wnt ligands in the epiblast cell population reduces heterogeneity and achieves robustness to environmental stress., (© 2023. The Author(s).)

Background: The epidemiology of renal impairment in patients with cancer remains unclear. We aimed to clarify associations between various cancer sites and renal impairment., Methods: We reviewed data from 5674 patients aged ≥ 18 years receiving cancer treatment at a single hospital facility. The primary endpoints were the occurrence of acute kidney injury (AKI), a 30% decrease in the estimated glomerular filtration rate (eGFR), or death. Survival time was defined as the time from study enrolment to AKI occurrence. Kaplan-Meier and Cox proportional hazard analyses were performed., Results: Hazard ratios (HRs) for AKI occurrence and a ≥ 30% decline in eGFR were significantly higher for kidney, urinary tract, pancreatic, liver, and gallbladder cancers than for colon cancer. Compared with colon cancer, digestive tract cancer showed a significantly higher HR for AKI occurrence alone. The HRs for a ≥ 30% decline in eGFR were significantly higher for patients aged 71‒77 years or ≥ 78 years than for those aged < 68 years, and for patients with eGFR ≥ 90 mL/min/1.73 m 2 or 30-44 mL/min/1.73 m 2 than for those with eGFR = 45‒59 mL/min/1.73 m 2 ., Conclusions: Kidney, urinary, hepatobiliary, or pancreatic cancer are associated with a higher risk of AKI development and eGFR decrease than other cancers. Renal function changes should be more closely monitored in patients with these cancers., (© 2022. The Author(s), under exclusive licence to The Japanese Society of Nephrology.)

Although a variety of patient safety interventions have been implemented, prioritizing them in a limited resource environment is important. The intervention priorities of patient safety managers may differ from those of patient safety experts. This study aimed to clarify the difference in prioritization of interventions between experts and safety managers to better identify interventions that should be promoted in Japan. We performed a secondary data analysis of two surveys: the Delphi survey for Japanese experts and a nationwide questionnaire survey for safety managers in hospitals. Regarding the 32 interventions constituting 14 organizational-level and 18 clinical-level interventions examined in the previous studies, we assessed three correlations to examine the difference in prioritization between experts and safety managers: correlations between experts and safety managers in the three perspectives (contribution, dissemination, and priority), those between priorities of experts and safety managers at the clinical and organizational level, and those among the three perspectives in experts and safety managers. Contribution (r = 0.768) and dissemination (r = 0.689) of patient safety interventions evaluated by experts and safety managers were positively correlated, but priorities were not. Interventions with priorities that differed between experts and safety managers were identified. In experts, there was no significant correlation between contribution and priority or between dissemination and priority. For safety managers, contributions (r = 0.812) and dissemination (r = 0.691) were positively correlated with priority. Our results suggest that patient safety managers evaluated future priority based on past contributions and current dissemination, whereas experts evaluated future priority based on other factors, such as expected impacts in the future, as mentioned in the previous study. In health policymaking, promotion of patient safety interventions that were given high priority by experts, but low priority by safety managers, should be considered with possible incentives., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Hayashi 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 germination of a microsporidian polar tube generally occurs under alkaline conditions. Typically, microsporidian spores can be stored in physiological salt solution for short periods. However, because of differences in the lodging area, the requirements may not always be uniform. In fact, Trachipleistophora sp. OSL-2012-10 ( nomen nudum Trachipleistophora haruka ) germinated when preserved in physiological salt solution. In this study, the germination characteristics of the large-spore microsporidia Trachipleistophora sp. FOA-2014-10 and Vavraia sp. YGSL-2015-13 were compared with those of Trachipleistophora sp. OSL-2012-10; moreover, we investigated whether these characteristics are specific to these microsporidia. We found that both microsporidia germinated in physiological salt solution. These differences in germination rates were affected by the preservation solution and temperature.

Background: Osimertinib is associated with a relatively high frequency of drug-induced interstitial lung disease (D-ILD), and transient asymptomatic pulmonary opacities (TAPO) have been reported to occur during osimertinib administration. The frequency of TAPO during first-line treatment and the pros and cons of osimertinib continuation is unknown., Methods: This was a multicenter, retrospective study. The purpose of this study was to research the frequency of TAPO and to evaluate osimertinib continuation in first-line therapy. We also evaluated progression-free survival (PFS) including subgroup analysis., Results: From August 2018 to December 2020, 133 patients were enrolled into the study. The median observation period was 23.2 months (0.3-48.3 months). Thirty patients (22.6%) experienced D-ILD events, including 16 patients (12.1%) with CTCAE grade 1, five patients (3.8%) with grade 2, and nine patients (6.7%) with grade 3 and above D-ILD. Among the patients with grade 1 D-ILD, 11 cases (8.3%) of TAPO were observed, and all patients succeeded in osimertinib continuation. The TAPO images were characterized by localized patchy opacities (73%). The median PFS was 22.6 months (95% confidence interval [CI]: 17.8-28.7 months). Patients with TAPO had a significantly longer PFS than patients with non-TAPO D-ILD in the multivariate analysis., Conclusions: This study showed that grade 1 D-ILD might include TAPO and that patients with TAPO might have good PFS. We need to consider the possibility of osimertinib continuation when lung opacities appear., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Salivary glands are physiologically orchestrated by the coordinated balance between cell differentiation, proliferation, apoptosis, and interactions between epithelial, mesenchymal endothelial, and neuronal cells, and they are frequent sites of manifestations of Sjögren's syndrome (SS) or IgG4-related disease (IgG4-RD). However, little is known about salivary gland homeostasis and its involvement in those diseases. Inhibitor of DNA binding/differentiation 4 (Id4) is an Id protein involved in the transcriptional control of many biological events, including differentiation. Studies of Id4-deficient mice revealed that Id4-deficient submandibular glands were smaller and exhibited accelerated differentiation, compared with those from wild-type littermates. In addition, dry mouth symptoms and Th17 expansion in splenocytes were also observed in the absence of Id4. Furthermore, Id4 levels in the salivary glands of patients with IgG4-RD, but not SS, were significantly decreased compared with those of healthy controls. miRNA-mRNA integrated analysis demonstrated that miR-486-5p was upregulated in IgG4-RD patients and that it might regulate Id4 in the lesion sites. Together, these results provide evidence for the inhibitory role of Id4 in salivary differentiation, and a critical association between Id4 downregulation and IgG4-RD., 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 © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Three major diseases in Japan, cancer, heart disease, and cerebrovascular disease (CVD) are the leading causes of death in Japan. This study aimed to clarify the social burden of these diseases, including long-term care (LTC), and to predict future trends., Methods: The comprehensive cost of illness (C-COI), a modification of the cost of illness (COI), was used to estimate the social burden of the three major diseases in Japan. The C-COI can macroscopically estimate both direct and indirect costs, including the LTC. A new method for future projections of the C-COI was developed according to the method for future projections of the COI. All data sources were government statistics., Results: The C-COI of cancer, heart diseases, and CVD in 2017 amounted to 11.0 trillion JPY, 5.3 trillion JPY, and 6.5 trillion JPY, respectively. The projected future C-COI in 2029 was 10.3 trillion JPY, 5.3 trillion JPY, and 4.4 trillion JPY, respectively. In 2029, the LTC costs accounted for 4.4%, 12.8%, and 44.1% of the total C-COI, respectively. Informal care costs are projected to be approximately 1.7 times higher, assuming that all family caregivers will be replaced by professional caregivers in 2029., Conclusion: Indirect costs for all three diseases were projected to decrease owing to aging of the patient. In contrast to the other two diseases, the LTC cost of CVD accounted for a large proportion of the burden. The burden of CVD is expected to decrease in the future, but informal care by older family caregivers is suggested to reach its limits. In the future, the focus of resource allocation should shift from medical care to LTC, especially support for family caregivers. A method of future projections for the social burden based on the C-COI was considered effective for identifying issues for healthcare policy in the context of the times., Competing Interests: There were no competing interests., (Copyright: © 2023 Hirata 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.)

Background: Aging increases the disease burden because of an increase in disease prevalence and mortality among older individuals. This could influence the perception of the social burden of different diseases and treatment prioritization within national healthcare services. Cancer is a disease with a high disease burden in Japan; however, the age-specific frequency and age-specific mortality rates differ according to site. In this study, we evaluated the relationship between the aging of the Japanese society and the disease burden by comparing the features of three cancers with different age-specific frequency rates in Japan. Furthermore, we made projections for the future to determine how the social burden of these cancers will change., Methods: We calculated the social burden of breast, lung, and prostate cancers by adding the direct, morbidity, and mortality costs. Estimates were made using the cost of illness (COI) method. For future projections, approximate curves were fitted for mortality rate, number of hospital admissions per population, number of outpatient visits per population, and average length of hospital stay according to sex and age., Results: The COI of breast, lung, and prostate cancers in 2017 was 903.7, 1,547.6, and 390.8 billion yen, respectively. Although the COI of breast and prostate cancers was projected to increase, that of lung cancer COI was expected to decrease. In 2017, the average age at death was 68.8, 76.8, and 80.7 years for breast, lung, and prostate cancers, respectively., Conclusions: Patients with breast cancer die earlier than those with other types of cancer. The COI of breast cancer ("young cancer") was projected to increase slightly because of an increase in mortality costs, whereas that of prostate cancer ("aged cancer") was projected to increase because of an increase in direct costs. The COI of lung cancer ("aging cancer") was expected to decrease in 2020, despite the increase in deaths, as the impact of the decrease in human capital value outweighed that of the increase in deaths. Our findings will help prioritize future policymaking, such as cancer control research grants., (© 2022. The Author(s).)

Background: Listeria monocytogenes is a causative agent of food poisoning and is also known to cause invasive diseases, such as bacteremia, meningitis, and encephalitis, in neonates, elderly and immunocompromised patients. However, the clinical course of a multi-organ disseminated disease secondary to bacteremia has been rarely reported., Case Presentation: A 76-year-old woman undergoing immunosuppressive therapy for rheumatoid arthritis presented to our outpatient clinic with a chief complaint of weight loss. Computed tomography showed a left adrenal mass, enlarged lymph nodes, and multiple intrahepatic nodules. Positron emission tomography demonstrated accumulation of fluorodeoxyglucose F18 in the adrenal mass, lymph nodes, hepatic nodules, and bones, leading to the suspicion of systemic metastasis of adrenal cancer. She subsequently developed a fever. Blood culture results led to the diagnosis of Listeria monocytogenes bacteremia. Percutaneous needle biopsy of the adrenal lesion revealed no malignant findings. After extended treatment with antimicrobial agents, the fever resolved, along with the disappearance of the systemic lesions., Conclusions: This case shows that listeriosis can lead to lesions in the adrenal gland, which can exhibit clinical presentation that is difficult to differentiate from malignancy on imaging studies., (© 2022. The Author(s).)

Discharge to home is considered appropriate as a treatment goal for diseases that often leave disabilities such as cerebral infarction. Previous studies showed differences in risk-adjusted in-hospital mortality and readmission rates; however, studies assessing the rate of hospital-to-home transition are limited. We developed and calculated the hospital standardized home-transition ratio (HSHR) using Japanese administrative claims data from 2016-2020 to measure the quality of in-hospital care for cerebral infarction. Overall, 24,529 inpatients at 35 hospitals were included. All variables used in the analyses were associated with transition to another hospital or facility for inpatients, and evaluation of the HSHR model showed good predictive ability with c-statistics (area under curve, 0.73 standard deviation; 95% confidence interval, 0.72-0.73). All HSHRs of each consecutive year were significantly correlated. HSHRs for cerebral infarction can be calculated using Japanese administrative claims data. It was found that there is a need for support for low HSHR hospitals because hospitals with high/low HSHR were likely to produce the same results in the following year. HSHRs can be used as a new quality indicator of in-hospital care and may contribute to assessing and improving the quality of care.