Search

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.

Eleocharis vivipara Link is a unique amphibious leafless plant of the Cyperaceae. The terrestrial form develops culms with Kranz anatomy and C 4 -like traits, while the submerged form does culms with non-Kranz anatomy and C 3 traits. The submerged form develops new culms with C 4 -like mode when exposed to air or exogenous abscisic acid. In this study, we investigated whether salt stress (0.05-0.3 M NaCl) has a similar effect. When the submerged form was grown for one month in solutions of 0.1 M NaCl and more, culm growth was strongly suppressed. However, these plants slowly developed new culms that had Kranz anatomy with chloroplast-abundant Kranz bundle sheath cells. Although the culms of the submerged form had only few stomata, culms grown in the NaCl solution had many stomata. The NaCl-grown culms also accumulated large amounts of C 4 photosynthetic enzymes (phosphoenolpyruvate carboxylase and pyruvate Pi dikinase), and the cellular localization patterns of these enzymes and ribulose 1,5-bisphosphate carboxylase/oxygenase were similar to those in terrestrial culms. Accumulation of C 4 enzymes increased in mature culms of the submerged form (with non-Kranz anatomy) when exposed to 0.2 M NaCl solution for one week. These results suggest that salt stress induces development of Kranz anatomy and expression of C 4 photosynthetic enzymes in the submerged C 3 form of E. vivipara, whereas the anatomical and biochemical traits of C 4 photosynthesis appear to be regulated independently., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Maintaining energy production efficiency is of vital importance to plants growing under changing environments. Cardiolipin localized in the inner mitochondrial membrane plays various important roles in mitochondrial function and its activity, although the regulation of mitochondrial morphology to various stress conditions remains obscure, particularly in the context of changes in cellular water relations and metabolisms. By combining single-cell metabolomics with transmission electron microscopy, we have investigated the adaptation mechanism in tomato trichome stalk cells at moderate salt stress to determine the kinetics of cellular parameters and metabolisms. We have found that turgor loss occurred just after the stress conditions, followed by the contrasting volumetric changes in mitochondria and cells, the accumulation of TCA cycle-related metabolites at osmotic adjustment, and a temporal increase in cardiolipin concentration, resulting in a reversible topological modification in the tubulo-vesicular cristae. Because all of these cellular events were dynamically observed in the same single-cells without causing any disturbance for redox states and cytoplasmic streaming, we conclude that turgor pressure might play a regulatory role in the mitochondrial morphological switch throughout the temporal activation of cardiolipin biosynthesis, which sustains mitochondrial respiration and energy conversion even under the salt stress conditions., (© 2022. The Author(s).)

Malignant mesothelioma (MM) is a rare and highly lethal tumor that arises from mesothelial tissue on the surface of the chest and abdominal cavity. Cytological examination of body fluids, including pleural fluid and ascites, is essential for the differentiation of malignant mesothelioma from other carcinomas, such as lung and gastrointestinal carcinomas and metastatic tumors. To evaluate the effectiveness of cell block preparation procedures, which are used for immunocytochemical staining and genetic panel analysis of tumor-specific gene mutations, we used various fixatives. We also evaluated the effects of immunostaining, and the quality of nucleic acids for genetic analysis., Methods: Cell blocks were prepared using the malignant mesothelioma cell lines MESO4 and H226 and non-small cell lung carcinoma cell line HCC78. The cells were fixed using 10% neutral buffered formalin and four different fixatives for liquid cytology. Fixed cells were formed into cell clusters using sodium alginate or centrifugation, and paraffin-embedded cell blocks were prepared., Results: Cell blocks were morphologically evaluated by hematoxylin and eosin and immunocytological staining, and the nucleic acid quality was evaluated by DNA/RNA extraction, qPCR, and next-generation sequence analysis. D2-40 and WT1 staining differed depending on the fixation solution and the cell cluster formation method; however, the degree of nucleic acid degradation was not impaired by any method., Conclusion: Although the morphological evaluation of cytology specimens is affected by the method of cell block preparation, it is still useful for nucleic acid extraction and gene panel analysis, as long as there are sufficient amounts of tumor cells., (© 2022 Wiley Periodicals LLC.)

Background: Ischemic heart disease (IHD) is one of the leading causes of mortality worldwide and imposes a heavy burden on patients. Previous studies have indicated that the optimal care for IHD during hospitalisation may reduce the risk of in-hospital mortality. The standardised mortality ratio (SMR) is an indicator for assessing the risk-adjusted in-hospital mortality ratio based on case-mix. This indicator can crucially identify hospitals that can be changed to improve patient safety and the quality of care. This study aimed to determine the hospital-level characteristics of the SMR for IHD in Japan., 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 IHD (ICD-10, I20-I25) were used. Patients with complete variables data were included in this study. Hospitals with less than 200 IHD inpatients in each 2-year period were excluded. The SMR was defined as the ratio of the observed number of in-hospital deaths to the expected number of in-hospital deaths multiplied by 100.The observed number of in-hospital deaths was the sum of the actual number of in-hospital deaths at that hospital, and the expected number of in-hospital deaths was the sum of the probabilities of in-hospital deaths. Ratios of in-hospital mortality was risk-adjusted using multivariable logistic regression analyses. The c-statistic and Hosmer-Lemeshow test were used to evaluate the predictive accuracy of the logistic models. Changes in SMRs in each consecutive period were assessed using Spearman's correlation coefficient., Results: A total of 64,831 were admitted patients with IHD in 27 hospitals as complete submission data. The SMRs showed wide variation among hospitals, ranging from 35.4 to 197.6, and analysis models indicated good predictive ability with a c-statistic of 0.93 (95% CI [0.92-0.94]) and Hosmer-Lemeshow test of 0.30. The results of chi-square tests and t -tests for all variables to assess the association with in-hospital mortality were P  < 0.001. In the analysis of trends in each consecutive period, the SMRs showed positive correlations., Conclusions: This study denoted that the SMRs for IHD could be calculated using Japanese administrative claim data. The SMR for IHD might contribute to the development of more appropriate benchmarking systems for hospitals to improve quality of care., Competing Interests: The authors declare there are no competing interests., (©2022 Onishi et al.)

Background The biological mechanism of action for osteoprotegerin, a soluble decoy receptor for the receptor activator of nuclear factor-kappa B ligand in the vascular structure, has not been elucidated. The study aim was to determine if osteoprotegerin affects aortic structural integrity in angiotensin II (Ang II)-induced hypertension. Methods and Results Mortality was higher ( P <0.0001 by log-rank test) in 8-week-old male homozygotes of osteoprotegerin gene-knockout mice given subcutaneous administration of Ang II for 28 days, with an incidence of 21% fatal aortic rupture and 23% aortic dissection, than in age-matched wild-type mice. Ang II-infused aorta of wild-type mice showed that osteoprotegerin immunoreactivity was present with proteoglycan. The absence of osteoprotegerin was associated with decreased medial and adventitial thickness and increased numbers of elastin breaks as well as with increased periostin expression and soluble receptor activator of nuclear factor-kappa B ligand concentrations. PEGylated human recombinant osteoprotegerin administration decreased all-cause mortality ( P <0.001 by log-rank test), the incidence of fatal aortic rupture ( P =0.08), and aortic dissection ( P <0.001) with decreasing numbers of elastin breaks, periostin expressions, and soluble receptor activator of nuclear factor-kappa B ligand concentrations in Ang II-infused osteoprotegerin gene-knockout mice. Conclusions These data suggest that osteoprotegerin protects against aortic rupture and dissection in Ang II-induced hypertension by inhibiting receptor activator of nuclear factor-kappa B ligand activity and periostin expression.

Background: Liquid-based cytology (LBC) is a widely used method for processing specimens obtained by endoscopic biopsy. This study evaluated next-generation sequencing (NGS) analysis of LBC specimens to improve the diagnostic accuracy of pancreatic lesions., Methods: Upon the diagnosis of a suspected pancreatic mass, LBC residues were used retrospectively. The quantity and quality of DNA extracted from residual LBC samples were evaluated, and an NGS analysis targeting 6 genes (KRAS, GNAS, TP53, CDKN2A, SMAD4, and PIK3CA) was performed., Results: The library was prepared from LBC specimens taken from 52 cases: 44 were successful, and 8 preparations failed. An analysis of DNA quantity and quality suggested that the success or failure of NGS implementation depended on both properties. The final diagnosis was achieved by a combination of the pathological analysis of the surgical excision or biopsy material with clinical information. Among the 33 cases of pancreatic ductal adenocarcinoma (PDAC), KRAS, TP53, CDKN2A, and SMAD4 mutations were identified in 31 (94%), 16 (48%), 3 (9%), and 2 (6%), respectively. Among the 11 benign cases, only a KRAS mutation was identified in 1 case. On the basis of NGS results, 18 of 33 PDACs (55%) were classified as highly dysplastic or more, and 10 of 11 benign lesions were evaluated as nonmalignant, which was consistent with the final diagnosis., Conclusions: NGS analysis using LBC specimens from which DNA of appropriate quantity and quality has been extracted could contribute to improving the assessment of pancreatic tumor malignancies and the application of molecular-targeted drugs., (© 2021 The Authors. Cancer Cytopathology published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Immobilization in external rotation (ER) after a first-time shoulder dislocation was introduced to reduce the risk of recurrence compared with immobilization in internal rotation (IR), but its efficacy remains controversial. The purpose of this study was to determine the long-term effect of immobilization in ER after a first-time shoulder dislocation., Methods: Between October 2000 and March 2004, 198 patients with a first-time anterior dislocation of the shoulder (average age 37) were randomly assigned to immobilization in ER (ER group = 104 shoulders) or IR (IR group = 94 shoulders) for 3 weeks. At an average 2-year follow-up, 159 patients (80.3%) were available for evaluation. In the current study, these 159 patients were further followed up and interviewed by telephone. The following items were evaluated: recurrent instability, apprehensive feeling, surgical intervention, limitation in the range of motion, return to sports, and the Single Assessment Numeric Evaluation (SANE) score., Results: The average follow-up period was 18.2 years (range, 16-20 years). Fifty-six patients were available for follow-up with the follow-up rate of 35%. The number of recurrent patients was 6 of 27 (22%) in the ER group and 6 of 29 (21%) in the IR group (P = .889). The number of surgically stabilized patients was 3 of 27 (11%) in the ER group and 10 of 29 (34%) in the IR group (P = .038). In total, the recurrence rate was 33% (9 of 27) in the ER group and 55% (16 of 29) in the IR group (P = .100). Adding the surgical cases and those with the SANE score ≤70% as failure cases, the failure rate in the ER group (26%) was significantly lower than that in the IR group (52%) (P = .048). Among those who survived without surgical intervention, there were no significant differences in apprehensive feeling, return to sports, limited range of motion, and the SANE score between the groups., Conclusions: Immobilization in ER reduced the risk of surgical intervention compared with IR in the long term., (Copyright © 2021 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Background: Patellar post impingement (PPI), which occurs when the post impinges on the patella, may reportedly cause poor total knee arthroplasty (TKA) outcomes. The causes of PPI and its effect on clinical outcomes and symptoms were investigated., Material and Methods: The study subjects were 100 patients who underwent TKA (65 posterior stabilized TKA, 35 bi-cruciate stabilized [BCS] TKA). Whether PPI occurred during surgery was investigated; the patients were then classified into a PPI+ group and a PPI- group, and whether the implant or patellar shape was related to the occurrence of PPI was examined. The measurement parameters included patellar shape, joint range of motion (ROM), and clinical outcome using the new Knee Society Score., Results: There were 38 knees in the PPI+ group and 62 knees in the PPI- group. There was no difference in patellar shape between the 2 groups, but PPI was more frequent in patients with short patellar tendon and those with low patellar height. In terms of implant type, the PPI+ group included 12 patients (18.5%) who underwent posterior stabilized TKA and 26 (74.3%) who underwent BCS TKA. There was no difference between the 2 groups in either joint ROM or new Knee Society Score. These results suggest that the position of the patella and implant shape that causes the post to be positioned anteriorly may contribute to PPI., Conclusion: PPI occurred more frequently in knees with low patellar height and in patients who had undergone BCS TKA. PPI had no effect on joint ROM or clinical outcome., (© 2021 The Authors.)

Background: Clinical practice guidelines (CPGs) are representative methods for promoting healthcare standardization and improving its quality. Previous studies on the CPG (published by 2006) development process in Japan reported that the involvement of experts and patients, efficient evidence collection and appraisal, and paucity of evidence on Japanese patients should be improved for the efficient CPG development. This study aimed to clarify the trends of CPG development process in Japan, focusing on the involvement of experts and patients, efficient evidence collection and appraisal, and paucity of Japanese evidence., Methods: A cross-sectional questionnaire survey was conducted for CPG development groups to collect information on the development activities of the CPGs published from 2012 to 2019. These CPGs were identified from the Japanese guideline clearinghouse. The questionnaire included the questions on composing the group, securing funding sources, collecting and appraising the research evidence, and the difficulties in the CPG development process. The questionnaires were distributed to the chairpersons of the CPG development groups through postal mail from November 2020 to January 2021. Combining the data from the current survey with those of previous studies reporting the development process of CPGs published by 2011, we analyzed the trend in the CPG development process., Results: Of the total 265 CPGs included in the analysis, 164 (response rate: 41.4%) were from the current survey and 101 (response rate: 44.5%) were from previous studies. Among these, 40 (15.1%) were published by 2005, 47 (17.7%) in 2006-2010, 77 (29.1%) in 2011-2015, and 101 (38.1%) in 2016-2019. The proportion of CPGs involving methodologists did not increase through the publication periods. The proportion of CPGs involving patients almost doubled from the first period (15.9%) to the fourth period (32.4%). The yield rates of the articles did not change through the publication periods. The difficulty in "Coping with the paucity of Japanese evidence" has been improving consistently (69.2% in the first period to 37.4% in the fourth period)., Conclusions: Our results suggest the need for methodological improvement in the efficient collection and appraisal of evidence and in the system assigning experts to the CPG development groups., (© 2022. The Author(s).)

Proto-Kranz plants represent an initial phase in the evolution from C 3 to C 3 -C 4 intermediate to C 4 plants. The ecological and adaptive aspects of C 3 -C 4 plants would provide an important clue to understand the evolution of C 3 -C 4 plants. We investigated whether growth temperature and nitrogen (N) nutrition influence the expression of C 3 -C 4 traits in Chenopodium album (proto-Kranz) in comparison with Chenopodium quinoa (C 3 ). Plants were grown during 5 weeks at 20 or 30 °C under standard or low N supply levels (referred to as 20SN, 20LN, 30SN, and 30LN). Net photosynthetic rate and leaf N content were higher in 20SN and 30SN plants than in 20LN and 30LN plants of C. album but did not differ among growth conditions in C. quinoa. The CO 2 compensation point (Γ) of C. album was lowest in 30LN plants (36 µmol mol -1 ), highest in 20SN plants (51 µmol mol -1 ), and intermediate in 20LN and 30SN plants, whereas Γ of C. quinoa did not differ among the growth conditions (51-52 µmol mol -1 ). The anatomical structure of leaves was not considerably affected by growth conditions in either species. However, ultrastructural observations in C. album showed that the number of mitochondria per mesophyll or bundle sheath (BS) cell was lower in 20LN and 30LN plants than in 20SN and 30SN plants. Immunohistochemical observations revealed that lower accumulation level of P-protein of glycine decarboxylase (GDC-P) in mesophyll mitochondria than in BS mitochondria is the major factor causing the decrease in Γ values in C. album plants grown under low N supply and high temperature. These results suggest that high growth temperature and low N supply lead to the expression of C 3 -C 4 traits (the reduction of Γ) in the proto-Kranz plants of C. album through the regulation of GDC-P expression., (© 2021. The Botanical Society of Japan.)

Objective: Accumulating evidence indicates that an adverse perinatal environment contributes to a higher risk of metabolic disorders in the later life of the offspring. However, the underlying molecular mechanisms remain largely unknown. Thus, we investigated the contribution of maternal high-calorie diet and osteocalcin to metabolic homeostasis in the offspring., Methods: Eight-week-old C57Bl/6N female mice were mated with age-matched males and allocated randomly to three groups: a normal-diet (ND) or a high-fat, high-sucrose diet group, which was administered either saline (control) or GluOC (10 ng/g body mass) from the day of mating to that of delivery, and the dams were fed a ND after the delivery. Pups weaned at 24 days after birth were analyzed., Results: A maternal high-fat, high-sucrose diet during pregnancy causes metabolic disorders in the liver of the offspring via hypermethylation of the Pygl gene, encoding glycogen phosphorylase L, which mediates hepatic glycogenolysis. The reduced expression of Pygl induced by the maternal diet causes the hepatic accumulation of glycogen and triglyceride in the offspring, which remains in adulthood. In addition, the administration of uncarboxylated osteocalcin during pregnancy upregulates Pygl expression via both direct CREBH and ATF4 and indirect epigenomic pathways, mitigating the maternal diet-induced obesity and abnormal glucose and lipid metabolism in adulthood., Conclusions: We propose that maternal energy status is reflected in the hepatic glycogenolysis capacity of the offspring via epigenetic modification of Pygl and uncarboxylated osteocalcin regulates glycogenolysis., (Copyright © 2021 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: To investigate risk factors for orally administered 5-aminolevulinic acid (ALA)-induced hypotension for bladder cancer patients receiving photodynamic diagnosis (PDD)-assisted transurethral resection of bladder tumor (TURBT)., Methods: Patients were categorized into two groups intraoperatively: a hypotensive group (minimum systolic blood pressure (SBP) ≤80 mmHg) and a non-hypotensive group (minimum SBP > 80 mmHg). We examined differences between the hypotensive group and non-hypotensive groups to identify clinical risk of ALA-induced hypotension using multivariate logistic regression analysis and decision tree analysis., Results: Among 282 cases with ALA-PDD-assisted TURBT from three institutions who were screened, 245 patients were included in the final analysis. In total, 156 patients (63.7%) showed any grade of hypotension during ALA-PDD-assisted TURBT. General anesthesia and spinal anesthesia were induced intraoperatively in 113 patients (46.1%) and 132 patients (53.9%), respectively. Median SBP at baseline (before taking ALA) and at the beginning of anesthesia was 127 mmHg (range, 69-186 mmHg) and 124 mmHg (range, 69-186 mmHg), respectively. Median minimum SBP during ALA-PDD-assisted TURBT was 75 mmHg (range, 43-140 mmHg). Multivariate logistic regression analysis revealed that history of hypertension (odds ratio (OR) 7.568, p < 0.05) and general anesthesia (OR 14.435, p < 0.05) as significantly associated with an increased risk of hypotension incidence. Use of calcium antagonist showed significant negative associations with hypotension (OR 0.183, p < 0.05). Decision tree analysis showed presence of general anesthesia, age ≥ 74 years and American Society of Anesthesiologists physical status (ASA-PS) ≥2 as the most important discriminators., Conclusions: General anesthesia and hypertension were independent risk factors related to ALA-induced hypotension. In contrast, use of calcium antagonists was identified as a factor associated with reduced risk of ALA-induced hypotension., (© 2021. The Author(s).)

Background: In conventional total knee arthroplasty (TKA), the anterior cruciate ligament (ACL) is resected. ACL dysfunction causes knee instability and is regarded as one factor in poor TKA outcomes. In bi-cruciate stabilized (BCS) TKA, the implant reproduces ACL function and provides anterior stability. The objective of this study was to evaluate preoperative and postoperative X-rays and accelerometer gait measurements in patients who underwent BCS TKA and posterior-stabilized (PS) TKA to assess the postoperative acceleration changes of knees after these procedures and to compare them in terms of joint range of motion (ROM) and the New Knee Society Score (New KSS)., Methods: The subjects were 60 patients, 30 of whom underwent BCS TKA and 30 PS TKA. Joint ROM, New KSS, lateral X-rays of the standing extended knee, and accelerometer data were evaluated 12 months postoperatively., Results: There was no significant difference in joint ROM between the groups. Both had good New KSS results, but the functional activity score was significantly higher after BCS TKA than after PS TKA. X-rays showed a lower posterior offset ratio after BCS TKA than after PS TKA, with anteroposterior positioning closer to that of the normal knee. Accelerometer data showed that postoperative anteroposterior acceleration on the femoral side in the stance phase and swing phase was lower after BCS TKA than after PS TKA., Conclusion: Compared with PS TKA, BCS TKA resulted in a higher functional activity score, closer positioning to that of the normal knee on lateral X-ray, and lower anteroposterior acceleration on the femoral side., 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 © 2021 Elsevier B.V. All rights reserved.)

Background: Proton-pump inhibitors (PPIs) are widely used to treat gastroesophageal reflex disease, peptic ulcer disease, and stress ulcer prophylaxis. This study estimated the progress rate of renal dysfunction in patients taking PPIs in clinical settings and compared the results with those of patients taking histamine-2 receptor antagonists (H2RAs)., Methods: We retrospectively reviewed patients' data collected from Kochi Medical School Hospital's information system between 2001 and 2019. Patients were classified into PPI and H2RA groups, and survival time was defined as the period between initial drug administration and a 30% decrease in estimated glomerular filtration rate (eGFR)., Results: On survival analysis, the PPI group was associated with higher event incidence rates compared to that in the H2RA group. The rate of underlying disease was significantly higher in the PPI group than in the H2RA group, with no significant differences in age and sex between the groups. Comparing the PPI group to the H2RA group, the use of aspirin, clopidogrel, statin, and angiotensin II receptor blocker was significantly higher, whereas the use of non-steroidal anti-inflammatory drugs and steroids was significantly less. Regarding survival rate and 30% decrease in eGFR, the PPI group had a significantly higher survival rate compared to that in the H2RA group at 730 days, but not earlier. PPI use, older age, and eGFR ≥ 90 mL/min/1.73 m 2 exhibited high hazard ratios., Conclusions: PPI use was significantly associated with an increased risk of chronic kidney disease development compared to that with H2RA use., (© 2021. Japanese Society of Nephrology.)

Background: Parvovirus B19 (B19) is a well-known cause of fifth disease in children, but infection during pregnancy may cause hydrops fetalis and stillbirth. The receptor-binding domain (RBD) of the VP1 unique capsid plays a pivotal role in infection. Here, we aimed to improve the immunogenicity of an RBD-based vaccine by genetically fusing it with Streptococcus pneumoniae surface protein A (PspA)., Methods: Mice were intramuscularly injected with RBD-based vaccines. Antigen-specific antibodies and neutralizing activity against B19 were measured. Protective immunity against S. pneumoniae was evaluated by monitoring the survival of mice nasally challenged with bacteria and determining antigen-specific T cell activation in splenic cells., Results: RBD alone failed to generate neutralizing antibodies against B19, but fusion with PspA induced higher levels of neutralizing IgG compared to B19 virus-like particles. Furthermore, a comparable level of PspA-specific IgG was induced by RBD-PspA and PspA alone, which was sufficient to protect mice against pneumococcal infection. Stimulation with PspA, but not RBD, induced cytokine production in splenic cells from mice immunized with RBD-PspA, suggesting that PspA-specific T cells supported immunoglobulin class switching of both RBD- and PspA-specific B cells., Conclusions: RBD-PspA should be an effective bivalent vaccine against B19 and S. pneumoniae infections., 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 © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Watercore is a physiological disorder in apple (Malus × domestica Borkh.) fruits that appears as water-soaked tissues adjacent to the vascular core, although there is little information on what exactly occurs at cell level in the watercored apples, particularly from the viewpoint of cell water relations. By combining picolitre pressure-probe electrospray-ionization mass spectrometry (picoPPESI-MS) with freezing point osmometry and vapor pressure osmometry, changes in cell water status and metabolisms were spatially assayed in the same fruit. In the watercored fruit, total soluble solid was lower in the watercore region than the normal outer parenchyma region, but there was no spatial difference in the osmotic potentials determined with freezing point osmometry. Importantly, a disagreement between the osmotic potentials determined with two methods has been observed in the watercore region, indicating the presence of significant volatile compounds in the cellular fluids collected. In the watercored fruit, cell turgor varied across flesh, and a steeper water potential gradient has been established from the normal outer parenchyma region to the watercore region, retaining the potential to transport water to the watercore region. Site-specific analysis using picoPPESI-MS revealed that together with a reduction in turgor, remarkable metabolic modifications through fermentation have occurred at the border, inducing greater production of watercore-related volatile compounds, such as alcohols and esters, compared with other regions. Because alcohols including ethanol have low reflection coefficients, it is very likely that these molecules would have rapidly penetrated membranes to accumulate in apoplast to fill. In addition to the water potential gradient detected here, this would physically contribute to the appearance with high tissue transparency and changes in colour differences. Therefore, it is concluded that these spatial changes in cell water relations are closely associated with watercore symptoms as well as with metabolic alterations., (© 2021. The Author(s).)

Both voluntary in-hospital reporting and mandatory national-level reporting systems for patient safety issues need to work well to develop a patient safety learning system that is effective in preventing the recurrence of adverse events. Some of the hospital systems and activities may increase voluntary in-hospital reporting and mandatory national-level reporting. This study aimed to identify the hospital systems and activities that increase voluntary in-hospital reporting and mandatory national-level reporting for patient safety issues. An anonymous mail survey of hospitals in Japan was conducted in 2017. The hospitals were selected by stratified random sampling according to number of beds. The survey examined the annual number of reported events in the voluntary in-hospital reporting system for patient safety and experience of reporting unexpected patient deaths possibly due to medical interventions to the mandatory national-level reporting system in the last 2 years. The relationship of the answer to the questions with the patient safety management systems and activities at each hospital was analyzed. The response rate was 18.8% (603/3,215). The number of in-hospital reports per bed was positively related to identifying events by referring complaints or questions of patients or family members, using root cause analysis for analyzing reported events, and developing manuals or case studies based on reported events, and negatively related to the unification and standardization of medical devices and equipment. The experience with mandatory national-level reporting of serious adverse events was positively related to identifying problematic cases by a person in charge of patient safety management from the in-hospital reporting system of complications and accidental symptoms. Enhanced feedback for reporters may promote voluntary in-hospital reporting of minor cases with low litigation risks. Developing an in-hospital mechanism that examines all serious complications and accidental symptoms may promote mandatory national-level reporting of serious adverse events with high litigation risks., Competing Interests: The authors have declared that no competing interests exist.

Previous studies indicated that optimal care for pneumonia during hospitalization might reduce the risk of in-hospital mortality and subsequent readmission. This study was a retrospective observational study using Japanese administrative claims data from April 2010 to March 2019. We analyzed data from 167,120 inpatients with pneumonia ≥15 years old in the benchmarking project managed by All Japan Hospital Association. Hospital-level risk-adjusted ratios of 30-day readmission for pneumonia were calculated using multivariable logistic regression analyses. The Spearman's correlation coefficient was used to assess the correlation in each consecutive period. In the analysis using complete 9-year data including 54,756 inpatients, the hospital standardized readmission ratios (HSRRs) showed wide variation among hospitals and improvement trend (r = -0.18, p = 0.03). In the analyses of trends in each consecutive period, the HSRRS were positively correlated between '2010-2012' and '2013-2015' (r = 0.255, p = 0.010), and '2013-2015' and '2016-2018' (r = 0.603, p < 0.001). This study denoted the HSRRs for pneumonia could be calculated using Japanese administrative claims data. The HSRRs significantly varied among hospitals with comparable case-mix, and could relatively evaluate the quality of preventing readmission including long-term trends. The HSRRs can be used as yet another measure to help improve quality of care over time if other indicators are examined in parallel.

Background: Pediatric spinal infections are rare and often accompanied by abscesses. Delayed diagnosis commonly leads to a poor neurological prognosis, emphasizing the need for early diagnosis and treatment., Case Description: We report on two cases of spinal infection; one in a 5-year-old boy with a T8-11 epidural abscess and one in a 10-year-old boy with an L5-S1 epidural abscess. Both cases improved with conservative therapy., Conclusion: Early magnetic resonance imaging diagnosis and systemic treatment in collaboration with pediatricians are key factors in the successful management of children with spinal infections., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Surgical Neurology International.)

Aim: To clarify the effects of the duration of acute damage and/or loss of renal function following an acute kidney injury event on the renal prognosis after recovery., Methods: We retrospectively reviewed data collected between 1995 and 2016 from the Kochi Medical School Hospital. Patients were stratified according to the time required for recovery with fluid therapy (expected to reflect the presence of renal dysfunction): ≤2 days after onset, transient injury group (n = 491); 3 to 7 days after onset, persistent injury group (n = 1076); and ≥ 8 days after onset, acute kidney disease group (n = 1046). The healthy group comprised 1000 randomly selected adult patients without acute kidney injury with at least two creatinine measurement results during the study. Survival time was defined as the time from recovery to a 30% decrease in the estimated glomerular filtration rate (primary endpoint). Kaplan-Meier and Cox proportional hazards analyses were conducted., Results: Event incidence rates were higher for the transient injury, persistent injury and acute kidney disease groups than for the healthy group. Persistent injury and acute kidney disease presented a higher risk of renal function decline than transient injury following recovery., Conclusion: Transient acute kidney injury, persistent acute kidney injury and acute kidney disease resulted in functional decline and rapid chronic kidney disease progression risks despite recovery. Transient acute kidney injury recovery within 2 days could be associated with better long-term prognoses than persistent acute kidney injury and acute kidney disease persisting beyond 2 days., (© 2020 Asian Pacific Society of Nephrology.)