Search

Abstract Objective This study explored the predictors of abemaciclib discontinuation, a cyclin-dependent kinase 4 and 6 inhibitor, in patients with breast cancer. Material and Methods Between November 2018 and March 2023, 147 patients with breast cancer treated with abemaciclib at Osaka Medical and Pharmaceutical University Hospital and Kindai University Nara Hospital were included. The exclusion criteria were as follows: lack of blood testing within 2 weeks prior to starting abemaciclib therapy, transfer to another facility after the commencement of abemaciclib therapy, and discontinuation of abemaciclib therapy due to the diagnosis of another cancer. The duration from the initiation of abemaciclib to discontinuation for any reason and to temporary suspension or dose reduction due to adverse events were analyzed as outcome variables using multivariate Cox regression analysis. Results Baseline weight

Abstract During human embryonic development, early cleavage-stage embryos are more susceptible to errors. Studies have shown that many problems occur during the first mitosis, such as direct cleavage, chromosome segregation errors, and multinucleation. However, the mechanisms whereby these errors occur during the first mitosis in human embryos remain unknown. To clarify this aspect, in the present study, we image discarded living human two-pronuclear stage zygotes using fluorescent labeling and confocal microscopy without microinjection of DNA or mRNA and investigate the association between spindle shape and nuclear abnormality during the first mitosis. We observe that the first mitotic spindles vary, and low-aspect-ratio-shaped spindles tend to lead to the formation of multiple nuclei at the 2-cell stage. Moreover, we observe defocusing poles in many of the first mitotic spindles, which are strongly associated with multinucleation. Additionally, we show that differences in the positions of the centrosomes cause spindle abnormality in the first mitosis. Furthermore, many multinuclei are modified to form mononuclei after the second mitosis because the occurrence of pole defocusing is firmly reduced. Our study will contribute markedly to research on the occurrence of mitotic errors during the early cleavage of human embryos.

BackgroundDelirium frequently affects the consciousness of the elderly, particularly those in hospitals. Evidence increasingly associates linking delirium history to an increased risk of dementia. However, most studies are limited in scope, focusing mainly on postoperative or intensive care units with small patient samples, which affects the broader applicability of their findings.AimsTo elucidate the precise incidence of delirium and the subsequent onset of dementia within whole inpatients. Additionally, we aimed to explore the correlation between the emergence of delirium during hospitalization and the subsequent manifestation of dementia.Design, setting, and participantsWe conducted a retrospective cohort analysis employing a decade-long electronic medical record dataset consisted of 261,123 patients in Osaka Medical and Pharmaceutical University Hospital. Key analyses were performed October 2022 to January 2023.Main outcomes and measuresThe primary outcome, dementia onset, was determined by prescriptions for the anti-dementia drugs donepezil, galantamine, memantine, or rivastigmine, which are approved for use in Japan.Results10,781 patients met the inclusion criteria. The median interval between the onset of dementia was 972.5 days for individuals without a history of delirium, whereas for those with a history of delirium, it was notably shorter at 592.5 days. This disparity culminated in a hazard ratio of 5.29 (95% confidence interval: 1.35-20.75) for subsequent dementia onset.Conclusions and relevanceThis investigation underscores the imperative significance of directing attention toward preventive measures against delirium during hospitalization, alongside the necessity of diligent monitoring and intervention for cognitive decline in patients who encounter delirium.

IntroductionIn this study, we investigated the correlation between serum albumin levels and cognitive function, and examined the impact of including serum albumin values in the input layer on the prediction accuracy when forecasting cognitive function using deep learning and other machine learning models.MethodsWe analyzed the electronic health record data from Osaka Medical and Pharmaceutical University Hospital between 2014 and 2021. The study included patients who underwent cognitive function tests during this period; however, patients from whom blood test data was not obtained up to 30 days before the cognitive function tests and those with values due to measurement error in blood test results were excluded. The Mini-Mental State Examination (MMSE) was used as the cognitive function test, and albumin levels were examined as the explanatory variable. Furthermore, we estimated MMSE scores from blood test data using deep learning models (DLM), linear regression models, support vector machines (SVM), decision trees, random forests, extreme gradient boosting (XGBoost), and light gradient boosting machines (LightGBM).ResultsOut of 5,017 patients who underwent cognitive function tests, 3,663 patients from whom blood test data had not been obtained recently and two patients with values due to measurement error were excluded. The final study population included 1,352 patients, with 114 patients (8.4%) aged below 65 and 1,238 patients (91.6%) aged 65 and above. In patients aged 65 and above, the age and male sex showed significant associations with MMSE scores of less than 24, while albumin and potassium levels showed negative associations with MMSE scores of less than 24. Comparing MMSE estimation performance, in those aged below 65, the mean squared error (MSE) of DLM was improved with the inclusion of albumin. Similarly, the MSE improved when using SVM, random forest and XGBoost. In those aged 65 and above, the MSE improved in all models.DiscussionOur study results indicated a positive correlation between serum albumin levels and cognitive function, suggesting a positive correlation between nutritional status and cognitive function in the elderly. Serum albumin levels were shown to be an important explanatory variable in the estimation of cognitive function for individuals aged 65 and above.

Background & Aims: Epithelial disruption in eosinophilic esophagitis (EoE) encompasses both impaired differentiation and diminished barrier integrity. We have shown that lysyl oxidase (LOX), a collagen cross-linking enzyme, is up-regulated in the esophageal epithelium in EoE. However, the functional roles of LOX in the esophageal epithelium remains unknown. Methods: We investigated roles for LOX in the human esophageal epithelium using 3-dimensional organoid and air–liquid interface cultures stimulated with interleukin (IL)13 to recapitulate the EoE inflammatory milieu, followed by single-cell RNA sequencing, quantitative reverse-transcription polymerase chain reaction, Western blot, histology, and functional analyses of barrier integrity. Results: Single-cell RNA sequencing analysis on patient-derived organoids revealed that LOX was induced by IL13 in differentiated cells. LOX-overexpressing organoids showed suppressed basal and up-regulated differentiation markers. In addition, LOX overexpression enhanced junctional protein genes and transepithelial electrical resistance. LOX overexpression restored the impaired differentiation and barrier function, including in the setting of IL13 stimulation. Transcriptome analyses on LOX-overexpressing organoids identified an enriched bone morphogenetic protein (BMP) signaling pathway compared with wild-type organoids. In particular, LOX overexpression increased BMP2 and decreased the BMP antagonist follistatin. Finally, we found that BMP2 treatment restored the balance of basal and differentiated cells. Conclusions: Our data support a model whereby LOX exhibits noncanonical roles as a signaling molecule important for epithelial homeostasis in the setting of inflammation via activation of the BMP pathway in the esophagus. The LOX/BMP axis may be integral in esophageal epithelial differentiation and a promising target for future therapies.

Bombus ignitus plays a vital role as a pollinator insect in greenhouse horticulture in Japan, China, and Korea. The activity of worker bees diminishes over time, prompting the replacement of the entire hive with new bees. However, considering the cost of hives, it is imperative to pinpoint the optimal replacement timing, balancing the decline in bee activity and the expenses associated with hive renewal. In pursuit of this goal, Calculating the ideal timing for replacement using activity data is preferable. Currently, Farmers often rely on visual monitoring and empirical judgments to decide when to replace hives due to the unavailability of activity data. Addressing this gap, Our study focuses on accurately quantifying the arrivals and departures of Bombus ignitus males and workers from hives, using these metrics as reliable indicators of bee activity. For this purpose, we propose a method for accurately tracking Bombus ignitus. Our proposed method combines specialized tracking techniques for honeybees, drawn from existing research, with commonly used tracking methods for pedestrians and automobiles. The evaluation of our method using test data showcases superior tracking precision with reduced errors, providing a more accurate tally of arrivals and departures compared to existing approaches. Furthermore, when applied on actual farms, our method revealed a significant decrease in worker bee arrivals and departures as the expected replacement time, based on farmers’ experience, drew nearer. This promising result suggests that our approach facilitates data-informed decision-making. As a result, our findings pave the way for significantly enhanced efficiency and precisely timed hive replacements, supported by compelling evidence, thus shaping the future landscape of beekeeping practices.

Abstract The training of multilayer spiking neural networks (SNNs) using the error backpropagation algorithm has made significant progress in recent years. Among the various training schemes, the error backpropagation method that directly uses the firing time of neurons has attracted considerable attention because it can realize ideal temporal coding. This method uses time-to-first-spike (TTFS) coding, in which each neuron fires at most once, and this restriction on the number of firings enables information to be processed at a very low firing frequency. This low firing frequency increases the energy efficiency of information processing in SNNs. However, only an upper limit has been provided for TTFS-coded SNNs, and the information-processing capability of SNNs at lower firing frequencies has not been fully investigated. In this paper, we propose two spike-timing-based sparse-firing (SSR) regularization methods to further reduce the firing frequency of TTFS-coded SNNs. Both methods are characterized by the fact that they only require information about the firing timing and associated weights. The effects of these regularization methods were investigated on the MNIST, Fashion-MNIST, and CIFAR-10 datasets using multilayer perceptron networks and convolutional neural network structures.

Immune checkpoint inhibitors (ICIs) are widely used in cancer treatment; however, they can lead to immune-related adverse events, including immune checkpoint inhibitor-induced type 1 diabetes mellitus (ICI-T1DM). While fulminant T1DM is common in East Asia, ICI-T1DM has predominantly been reported in Western countries. In this report, we present the case of a 66-year-old Japanese man with type 2 diabetes mellitus undergoing dialysis for diabetic nephropathy. The patient was diagnosed with left upper lobe lung cancer, and treatment with nivolumab and ipilimumab was initiated. After 48 days, the patient experienced impaired consciousness and difficulty moving. His blood glucose levels were 815 mg/dL, and metabolic acidosis was detected, leading to a diagnosis of diabetic ketoacidosis. The patient was subsequently treated with continuous intravenous insulin. However, his C-peptide levels rapidly depleted, and new-onset ICI-T1DM was diagnosed. Although most Japanese patients with ICI-T1DM test negative for glutamic acid decarboxylase (GAD) antibodies, this case exhibited a strong positivity. Thus, we reviewed the literature on 15 similar Japanese cases, revealing a mean HbA1c level at onset of 8.7% and a mean time from ICI administration to onset of 9.7 weeks, which was shorter than that in GAD-negative cases. Moreover, human leukocyte antigen typing revealed five cases of DRB1*04:05-DQB1*04:01, including the present case, and one case of DRB1*09:01-DQB1*03:03, both of which were susceptible to T1DM haplotypes. These findings suggest that GAD antibody positivity may be associated with acute onset and disease progression in some cases of Japanese patients with ICI-T1DM. Given that the prediction of new-onset ICI-T1DM is challenging, monitoring GAD antibody levels might be useful. However, further studies with large sample sizes and validation across different racial and ethnic populations are warranted.

The effects of Au addition on the acetone response of Cu2O-added porous SnO2 (pr-Cu2O-SnO2) powders, which were synthesized by ultrasonic spray pyrolysis employing polymethyl methacrylate microspheres as a template, were investigated in this study. The 3.0 wt% Au-added pr-Cu2O-SnO2 sensor showed the largest acetone response among all sensors. In addition, the magnitude of the acetone response was much larger than those of the ethanol and toluene responses. The catalytic activities of these gases over Au-added pr-Cu2O-SnO2 powders were also examined to clarify the key factors affecting their acetone-sensing properties. The Au addition increased the complete oxidation activity of all gases, and the complete oxidation activity of acetone was much higher than those of ethanol and toluene. These results indicate that the oxidation behavior during the gas-diffusion process in the sensitive Au-added pr-Cu2O-SnO2 layer of the sensors is quite important in enhancing the acetone-sensing properties.

Background: Patients with chronic heart failure often experience repeated acute exacerbations leading to high rates of rehospitalization. Therefore, the management of patients to prevent rehospitalization and retain their physical function is important. Brain natriuretic peptide (BNP) and N-terminal-pro BNP are used to estimate the conditions of patients with chronic heart failure, but some hospitals cannot measure these levels in real time. To overcome this, we used bioelectrical impedance analysis as an alternative. Methods and results: Between April 2017 and December 2019, we measured water balance in the outpatient department of Hirose Hospital in three groups: those who had been hospitalized for chronic heart failure (257 patients), those with chronic heart failure who had not been hospitalized (224 patients), and controls with other chronic diseases (275 patients). We found that water balance was significantly correlated to the history of hospitalization, and age was a confounding bias in this correlation, regardless of whether patients have been hospitalized with chronic heart failure. Moreover, patients who have high extracellular water content/total body water content ratios, even in a stable period, are at risk of becoming unstable and experiencing rehospitalization. Conclusion: Water balance monitoring could be a useful indicator to estimate patient condition in real time and predict improvement in chronic heart failure. This easy-to-use indicator may enable timely management of exacerbation of patient condition and reduce hospitalization events.

Rotational atherectomy is an effective procedure for heavily calcified lesions and those that cannot be crossed using conventional percutaneous coronary intervention (PCI) devices. Here, we report a rare case of intracoronary burr entrapment in the coronary artery due to burr disconnection from the driveshaft. A 67-year-old man undergoing hemodialysis for nephrosclerosis presented with exertional chest discomfort. Coronary angiography revealed stenotic lesions in the right coronary artery, and PCI was performed using a Rotawire Floppy. During the procedure, the disconnected burr was successfully removed without surgery using the child-in-mother technique with a guide extension catheter. Notably, the patient remained hemodynamically stable throughout the procedure and his recovery was uncomplicated. He was discharged on the second postprocedural day. At the 6-month follow-up, the patient remained asymptomatic with no evidence of myocardial ischemia. This report informs clinicians of the possibility of burr disconnection and the non-surgical intervention used for its removal.

Early operative fixation is widely recognized as essential for managing spinal fractures in patients with diffuse idiopathic skeletal hyperostosis (DISH). However, no report to date has addressed the occurrence of minimal vertebral fractures diagnosable only through magnetic resonance imaging (MRI) in these patients and the associated temporal changes in the fracture site. In this report, we describe a rare clinical case involving an 81-year-old man who developed progressive spinal destruction secondary to a minimal vertebral fracture. MRI showed minimum-intensity changes in the T12 vertebral body, whereas X-ray and computed tomography examinations showed DISH and no spinal fracture. Despite experiencing severe low back pain, the patient did not undergo operative therapy for 2 months, resulting in progressive spinal destruction. Spinal fusion with posterior instrumentation was performed, and the patient was followed for 1 year with no symptoms and good functional status. This case emphasizes the importance of clinicians being cautious to avoid overlooking and undervaluing minimal vertebral fractures diagnosable only through MRI in patients with DISH.

Cellulose nanofibers (CNFs) prepared via 2,2,6,6‐tetramethylpiperidine‐1‐oxyl (TEMPO)‐mediated oxidation of the C6 primary hydroxyls of native cellulose to carboxylates are used as pseudocatalysts for enhancing the aluminum powder/pure water reactions. The Al powder/pure water reaction is a stepwise reaction. It starts from hydration of the outmost native Al2O3 thin layer and then the reaction of the inner metallic Al with water. At lower temperatures ( 11) is dynamically generated, and as a result, the native Al2O3 thin layer dissolves rapidly via the reaction with OH− ions. The OH− ions function also as catalysts, accelerating the reaction of metallic Al with water. Al powders (2–200 μm) react promptly and a nearly 100% Al/H2 conversion is obtained at the reaction temperature below 50 °C.

Background: It is still unclear whether optimal medical therapy (OMT) after percutaneous coronary intervention (PCI) has beneficial effects on long-term clinical outcomes in patients aged ≥80 years with coronary artery disease (CAD). Methods: This study analyzed the time to the first major adverse clinical event including death or nonfatal myocardial infarction (MI), for up to 3 years after PCI using multicenter registry data. Data for 1056 patients aged > 80 years successfully treated with PCI were included in the analysis. OMT was defined as a combination of antiplatelet drug, statin, beta-blocker, and angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker. Results: In total, 204 (19%) patients in this study received OMT and 852 (81%) received sub-OMT. During a median follow-up of 725 days, adverse clinical events occurred in 183 patients (death, n=177; nonfatal MI, n=6). Kaplan-Meier analysis showed that patients who received OMT had a lower probability of adverse clinical events than those who received sub-OMT (p

Background & Aims: Although basal cell hyperplasia is a histologic hallmark of eosinophilic esophagitis (EoE), little is known about the capabilities of epithelial renewal and differentiation in the EoE inflammatory milieu. In murine esophageal epithelium, there are self-renewing and slowly proliferating basal stem-like cells characterized by concurrent expression of CD73 (5'-nucleotidase ecto) and CD104 (integrin β4). Here, we investigated CD73+CD104+ cells within the basal population of human esophageal epithelium and clarified the biological significance of these cells in the EoE epithelium. Methods: We performed flow cytometry on esophageal biopsy samples from EoE and non-EoE patients to determine the quantity of CD73+CD104+ cells in the epithelium. Simulating the EoE milieu we stimulated primary patient-derived and immortalized cell line–derived esophageal organoids with interleukin (IL)4 and IL13 and analyzed by flow cytometry, immunohistochemistry, and quantitative reverse-transcription polymerase chain reaction. We performed single-cell RNA sequencing on primary organoids in the setting of IL13 stimulation and evaluated the CD73+CD104+ population. We performed fluorescent-activated cell sorting to purify CD73+CD104+ and CD73- CD104+ populations and seeded these groups in organoid culture to evaluate the organoid formation rate and organoid size. We used RNA interference to knock down CD73 in esophageal organoids to evaluate organoid formation rates and size. We evaluated the effects of signal transducer and activator of transcription 6 (STAT6) signaling inhibition by RNA interference, a STAT6 inhibitor, AS1517499, as well as the proton pump inhibitor omeprazole. Results: EoE patients showed decreased epithelial CD73+CD104+ cell content. IL4 and IL13 stimulation depleted this population in 3-dimensional organoids with a recapitulation of basal cell hyperplasia as corroborated by single-cell RNA sequencing of the organoids, which suggests depletion of CD73+CD104+ cells. The CD73+CD104+ population had enhanced organoid formation compared with the CD73-CD104+ population. Similarly, knock-down of CD73 resulted in decreased organoid formation rate. Genetic and pharmacologic inhibition of STAT6 prevented T helper 2 cytokine-induced depletion of CD73+CD104+ cells. Lastly, omeprazole treatment prevented the effects of IL4 and IL13 on the CD73+CD104+ population. Conclusions: This study addressed the role of CD73+CD104+ cells in epithelial renewal and homeostasis in the context of EoE. The depletion of the CD73+CD104+ self-renewal population by helper T cell 2 cytokines in EoE milieu may be perpetuating epithelial injury. Future therapies targeting epithelial restitution in EoE could decrease the need for immune modulation and steroid therapy.

Abstract Purpose This study investigated the consistency between results of preimplantation genetic testing for aneuploidy performed on trophectoderm (TE) cells and remaining blastocyst cells. Methods TE biopsy was performed on 29 surplus cryopreserved human blastocysts. Biopsy samples and remaining blastocysts were processed using the VeriSeq PGS kit, and chromosomal statuses were compared by next‐generation sequencing. Results Discordance was observed in the chromosomal status of 11 out of 29 blastocysts between the biopsied TE and remaining blastocysts. Concordance was observed in 11 of 12 blastocysts classified as euploid by TE biopsy and in 7 of 17 blastocysts classified as aneuploid. There was 100% concordance (7/7) in cases diagnosed as aneuploid with no mosaicism by TE biopsy. However, discordance was observed in all 10 cases showing mosaicism or partial chromosomal abnormality. Conclusion Chromosomal status analysis based on TE biopsy does not accurately reflect the chromosomal status of the whole blastocyst. The chromosomal status is usually the same between the TE and remaining blastocyst cells in cases diagnosed as euploid or aneuploid with no mosaicism. However, mosaic blastocysts and those with other types of structural rearrangements have a higher risk of inconsistency, warranting caution during embryo selection.

A 71-year-old man visited our hospital with dyspnea and left pleural effusion. Left pleural effusion was diagnosed as chylothorax by thoracentesis. He had no history of trauma or surgery, and there were no findings of malignant lymphoma or thrombosis. Furthermore, he was diagnosed with liver cirrhosis and hepatocellular carcinoma by computed tomography and hematological examinations, and the chylothorax was considered to be caused by liver cirrhosis. We report a review of the literature with this case since it is relatively rare for cirrhosis and hepatocellular carcinoma diagnosed from chylothorax.

Abstract Echinoderm microtubule‐associated protein‐like 4‐anaplastic lymphoma kinase (EML4‐ALK) rearrangements are found in ~ 5% of patients with non‐small cell lung cancer (NSCLC). Several tyrosine kinase inhibitors (TKIs) have been developed for treatment of so‐called ALK‐positive NSCLC. In cases of tumor progression during treatment with second‐generation ALK‐TKIs, such as alectinib, brigatinib, or ceritinib, National Comprehensive Cancer Network guidelines propose a switch to lorlatinib, a third‐generation ALK‐TKI, or to cytotoxic chemotherapy. However, they do not mention switching to other second‐generation ALK‐TKIs. Here, we present a rare case of a 53‐year‐old Japanese woman, who had never smoked, with ALK‐positive lung adenocarcinoma who survived alectinib‐resistant postoperative recurrence for 4 years by switching to ceritinib. She underwent curative resection for lung adenocarcinoma, but the cancer recurred at the bronchial stump and mediastinal lymph nodes. After platinum‐doublet chemotherapy, the patient still had a single growing liver metastasis, but the tumor was found to harbor EML4‐ALK rearrangement. Therefore, the patient started to take ALK‐TKIs. Alectinib was the second ALK‐TKI used to treat this patient. Alectinib shrank the liver metastasis, which was surgically resected. The tumor relapsed again during continued treatment with alectinib, which was switched to ceritinib. Ceritinib was effective for the relapsed tumor and treatment continued well for 4 years. This case report suggests that, in case of tumor progression during treatment with a second‐generation ALK‐TKI, switching to another second‐generation ALK‐TKI may be one of the treatment options. Further analyses are warranted to find robust markers to determine which ALK‐TKI is best for each patient.

Abstract Pharmacogenetics/pharmacogenomics have enabled the detection of risk of human leukocyte antigen (HLA) variants for clozapine-induced agranulocytosis/granulocytopenia (CIAG). To apply this evidence to the clinical setting, we compared the cost-effectiveness of the proposed “HLA-guided treatment schedule” and the “current schedule” being used in Japan and the United Kingdom (UK) (absolute neutrophil count (ANC) cutoff at 1500/mm3); in the “HLA-guided treatment schedules,” we considered a situation wherein the HLA test performed before clozapine initiation could provide “a priori information” by detecting patients harboring risk of HLA variants (HLA-B*59:01 and “HLA-B 158T/HLA-DQB1 126Q” for Japanese and Caucasian populations, respectively), a part of whom can then avoid CIAG onset (assumed 30% “prevention rate”). For the primary analysis, we estimated the incremental cost-effectiveness ratio (ICER) of “HLA-guided treatment schedule” and “current schedule” used in Japan and the UK, using a Markov model to calculate the cost and quality-adjusted life years (QALYs) over a 10-year time period. Furthermore, as an explorative analysis, we simulated several situations with various ANC cutoffs (1000/mm3 and 500/mm3) and plotted the cost/QALYs for each option to identify the best, or estimate the next best candidate option applicable in actual clinical settings. The primary probabilistic analysis showed that the “HLA-guided treatment schedule” was more cost effective than the “current schedule”; the ICER was £20,995 and £21,373 for the Japanese and the UK populations, respectively. Additional simulation revealed that the treatment option of ANC cutoff at 500/mm3 without HLA screening was the most cost-effective option; however, several options may be candidates to break away from the “current schedule” of ANC cutoff at 1500/mm3. Owing to its cost-effectiveness, we propose such pharmacogenetic-guided/pharmacogenomic-guided clozapine treatment for use in the real-world setting, which provides key information for optimization of clinical guidelines for high-risk patients for gradual change of clozapine treatment schedule under the safety consideration.

Adsorption/combustion-type gas sensors, subspecies of catalytic combustion-type gas sensors, show large dynamic responses to volatile organic compounds (VOCs) under the operation with a mode of pulsed temperature heating, because of the flash catalytic combustion of target VOCs adsorbed on the gas-sensing films. Catalytic combustion behavior of ethanol over γ-Al2O3 powders loaded with and without 1 wt% Pt and/or 10 wt% metal oxide (MO: CeO2 or Bi2O3) and their adsorption/desorption properties of ethanol (adsorption temperature: 150°C) were investigated, and then the ethanol-sensing characteristics of the sensors utilizing the gas-sensing materials (low and high temperatures under dynamic operation: 150°C and 450°C, respectively) have been discussed on the basis of the findings on both their catalytic combustion behavior and adsorption/desorption properties. Especially, the co-loading of Pt with CeO2 onto γ-Al2O3 was the most effective in enhancing the dynamic response, because the relatively small amounts of various compounds that were adsorbed on the surface at 150°C efficiently oxidized at the initial stage of the pulse-driven heating to form CO2. The effects of low and high temperatures under the pulse-heating operation on the ethanol-sensing properties of the sensor utilizing γ-Al2O3 co-loaded with Pt and CeO2 were also clarified on the basis of the above findings.

Abstract Aims The aim of this study was to analyze the sensitivity and specificity of a shortened Hasegawa Dementia Scale Revised (shortened HDS‐R) questionnaire and explore its utility for the rapid screening and diagnosis of Alzheimer’s disease (AD). Methods We included 113 patients over the age of 60 years who visited our hospital from June 2018 to January 2021 including 70 subjects with AD and 43 healthy subjects. AD was diagnosed in accordance with the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, and the standard HDS‐R questionnaire was used as a neuropsychological examination. The shortened HDS‐R questionnaire was composed of the first seven subdomains (1 to 7) of the HDS‐R questionnaire and excluded subdomains 8 and 9. Magnetic resonance imaging (MRI) was performed to calculate the degree of atrophy of the whole brain, hippocampus, and parahippocampal gyrus. Results The cumulative contribution ratio of subdomains 1 to 7 of the HDS‐R questionnaire was as high as 94%, indicating that the construct validity of the shortened HDS‐R was very good. The correlation coefficient of the total scores of the shortened HDS‐R and the HDS‐R was 0.96, indicating that the criterion‐related validity was also very good. Furthermore, the shortened HDS‐R was significantly negatively correlated with the degree of atrophy in the whole brain, hippocampus, and parahippocampal gyrus, indicating that its concurrent validity was very good in relation to imaging parameters. Cronbach’s α coefficient of the shortened HDS‐R was 0.76, and the correlation coefficient of the item‐total correlation analysis was between 0.68 and 0.76, indicating that this questionnaire has high internal consistency and reliability. The total shortened HDS‐R score of the normal group (17.0 ± 1.9) was significantly higher than that of the AD group (8.6 ± 3.8), demonstrating that the total shortened HDS‐R score can be used to identify healthy individuals and patients with AD. When the cutoff score was 14 of 15, the sensitivity was 92.9% and the specificity was 88.4%. The diagnostic ability of the shortened HDS‐R was 91.2%, which indicates that it is similar to the full HDS‐R questionnaire as an AD screening tool. Conclusion As a neuropsychological examination questionnaire for the screening and diagnosis of AD, the shortened HDS‐R had very high validity and reliability. Its sensitivity, specificity, and diagnostic ability were similar to those of the gold standard HDS‐R; therefore, it can be considered a concise and useful questionnaire for AD screening and diagnosis in the older population.

Abstract Malignant mesothelioma is a cancer with a poor survival rate. It is difficult to diagnose mesotheliomas because they show a variety of histological patterns similar to those of various other cancers. However, since currently used positive markers for mesotheliomas may show false positives or false negatives, a novel mesothelial positive marker is required. In the present study, we screened 25 claudins and found that claudin-15 is expressed in the mesothelial cells. We made new rat anti-human claudin-15 (CLDN15) monoclonal antibodies that selectively recognize CLDN15, and investigated whether CLDN15 is a good positive marker for malignant pleural mesotheliomas (MPMs) using MPM tissue samples by immunohistochemistry and semi-quantification of the expression level using an immunoreactive score (IRS) method. Of 42 MPM samples, 83% were positive for CLDN15. The positive ratio was equal to or greater than other positive markers for MPMs including calretinin (81%), WT-1 (50%), and D2-40 (81%). In 50 lung adenocarcinoma sections, four cases were positive for CLDN15 and the specificity (92%) was comparable with other markers (90–100%). Notably, CLDN15 was rarely detected in 24 non-mesothelial tumors in the tissue microarray (12/327 cases). In conclusion, CLDN15 can be used in the clinical setting as a positive marker for MPM diagnosis.

Although diffuse cysts in the lung can be found in many diseases, they are uncommon in metastatic lung adenocarcinoma. They are even more unusual after the administration of immune checkpoint inhibitors. A case of lung adenocarcinoma that developed diffuse cysts in the lungs during treatment with nivolumab is reported. The patient was a 60-year-old woman with postoperative recurrent lung adenocarcinoma in mediastinal lymph nodes and pleural dissemination. After first-line treatment with cisplatin, pemetrexed, and bevacizumab, computed tomography (CT) showed disease progression. Treatment was then switched to nivolumab. After 5 courses of nivolumab, CT showed multiple ground-glass nodules in her lungs. After 4 more courses of nivolumab, the ground-glass nodules increased in size, and cystic air spaces appeared in their centers. The patient did not have any symptoms. Laboratory tests showed no evidence of infection or nivolumab-induced pneumonitis. Sialyl Lewis X-i antigen increased, and positron emission tomography showed abnormal uptake of 18F-fluorodeoxyglucose in these lesions. Considering this evidence, the cystic lesions were diagnosed as multiple lung metastases. Various differential diagnoses should be considered when diffuse cystic lesions are found in the lungs after the administration of immune checkpoint inhibitors.

Large cell neuroendocrine carcinoma (LCNEC) of the lung with epidermal growth factor receptor (EGFR) mutation is rare, and few cases have been treated with EGFR tyrosine kinase inhibitors (TKIs). We report the treatment of combined LCNEC with adenocarcinoma harboring an EGFR mutation with EGFR-TKIs and bevacizumab. Our patient was a 70-year-old asymptomatic woman who underwent surgical resection of the lung for combined LCNEC with adenocarcinoma harboring an activating EGFR mutation 11 months previously. Magnetic resonance imaging (MRI) and positron emission tomography revealed metastatic lesions in the brain and lung. The patient was diagnosed with recurrence of combined LCNEC with adenocarcinoma. The brain lesion was irradiated, followed by administration of afatinib. Eight months after irradiation, brain MRI revealed ringed enhancement and perilesional edema after radiotherapy without new metastatic lesions. We switched treatment to erlotinib and bevacizumab, resulting in maintenance of stable disease for 10 months. Overall, the disease was controlled for 18 months with EGFR-TKIs and bevacizumab. Combination treatment with EGFR-TKIs and bevacizumab could be a treatment option for LCNEC of the lung harboring EGFR mutations, especially with brain metastasis.

Abstract Background The evidence regarding the safety and efficacy of nonoperative management is growing. However, the best treatment strategy for acute complicated appendicitis remains controversial. We aimed to evaluate the cost-effectiveness of treatment strategies for complicated appendicitis patients. This study sought to determine the most cost-effective strategy from the health care-payer’s perspective. Methods The primary outcome was an incremental cost effectiveness ratio (ICER) using nonoperative management with or without interval laparoscopic appendectomy (ILA) as the intervention compared with operative management with emergency laparoscopic appendectomy (ELA) alone as the control. Model variables were abstracted from a literature review, and from data obtained from the hospital records of Tochigi Medical Center. Cost-effectiveness was evaluated using an ICER. We constructed a Markov model to compare treatment strategies for complicated appendicitis in otherwise-healthy adults, over a time horizon of a single year. Uncertainty surrounding model parameters was assessed via one-way- and probabilistic-sensitivity analyses. Threshold analysis was performed using the willingness-to-pay threshold set at the World Health Organization’s criterion of $107,690. Results Three meta-analysis were included in our analysis. Operative management cost $6075 per patient. Nonoperative management with interval laparoscopic appendectomy (ILA) cost $984 more than operative management and produced only 0.005 more QALYs, resulting in an ICER of $182,587. Nonoperative management without ILA cost $235 more than operative management, and also yielded only 0.005 additional QALYs resulting in an ICER of $45,123 per QALY. Probabilistic sensitivity analysis with 1000 draws resulted in average ICER of $172,992 in nonoperative management with ILA and $462,843 in Nonoperative management without ILA. The threshold analysis demonstrated that regardless of willingness-to-pay, nonoperative management without ILA would not be most cost-effective strategy. Conclusions Nonoperative management with ILA and Nonoperative management without ILA were not cost-effective strategies compared with operative management to treat complicated appendicitis. Based on our findings, operative management remains the standard of care and nonoperative management would be reconsidered as a treatment option in complicated appendicitis from economic perspective.

Elevator functioning as a vertical transport facility remains stand-alone and incapable of accessing the fine-grained traffic information. It significantly restricts the flexibility and efficiency of vertical transporting. In particular, while in peak-time, the limited elevator physical capacity with the momentary traffic increment gives rise to the vertical traffic bottleneck problem in large-scale buildings. The problem further results in the long waiting, dissatisfaction, frustration of passengers. In this paper, we present our proposal named Intellevator: an intelligent elevator system that enables the passively functioning elevator system be proactive and intelligent in traffic control for optimizing the transport efficiency. The proposal is an end-to-end architecture that composed of three aspects: Internet of things (IoT)-enabling technology on a conventional elevator; an agent server to enhance elevator computational capability and a novel user interface for delivering system intelligence to end-users. The proposal was experimented on a conventional elevator in a built smart-building environment. Numerical simulation results have demonstrated the system efficiency improvement. In addition, the system usability and user experience have been evaluated by a user study as well.

Three-dimensional elastoplastic finite element (FE) analysis models considering a damage zone and cleavage were developed, including plastic behavior of embedment tests parallel and perpendicular to the grain at ambient and high temperatures, in order to study the embedment behavior of timber. In a numerical analysis of compression tests to define material properties of timber, the post-yield behavior of the X-axis in the axial direction was larger than the test values when the post-yield slope of the test result were set to the plastic modulus. The reason was that the stress on the Y-axis and Z-axis increased after the yield point; thus, the equivalent yield stress decreased. In the numerical analysis of the embedment tests, the effect of the damage zone must be considered in the analytical models because the initial stiffness of the numerical results in compression parallel to the grain was considerably higher than that of the test results when the damage zone was not considered. In the numerical analysis of the embedment tests in compression perpendicular to the grain, the two models reproduced the stiffness and behavior after the yield point of the test results. The model that considered cleaving showed the stress distribution after cleavage.

Lung cancer is the leading cause of cancer-related deaths worldwide. The standard of care for advanced non-small-cell lung cancer (NSCLC) without driver-gene mutations is a combination of an anti-PD-1/PD-L1 antibody and chemotherapy, or an anti-PD-1/PD-L1 antibody and an anti-CTLA-4 antibody with or without chemotherapy. Although there were fewer cases of disease progression in the early stages of combination treatment than with anti-PD-1/PD-L1 antibodies alone, only approximately half of the patients had a long-term response. Therefore, it is necessary to elucidate the mechanisms of resistance to immune checkpoint inhibitors. Recent reports of such mechanisms include reduced cancer-cell immunogenicity, loss of major histocompatibility complex, dysfunctional tumor-intrinsic interferon-γ signaling, and oncogenic signaling leading to immunoediting. Among these, the Wnt/β-catenin pathway is a notable potential mechanism of immune escape and resistance to immune checkpoint inhibitors. In this review, we will summarize findings on these resistance mechanisms in NSCLC and other cancers, focusing on Wnt/β-catenin signaling. First, we will review the molecular biology of Wnt/β-catenin signaling, then discuss how it can induce immunoediting and resistance to immune checkpoint inhibitors. We will also describe other various mechanisms of immune-checkpoint-inhibitor resistance. Finally, we will propose therapeutic approaches to overcome these mechanisms.

Porous (pr-)SnO2-based powders were synthesized by ultrasonic spray pyrolysis employing home-made polymethylmethacrylate (PMMA) microspheres (typical particle size: 70 nm in diameter), and effects of the CuxO addition to the pr-SnO2 powder on the acetone and toluene sensing properties were investigated. Well-developed spherical pores reflecting the morphology of the PMMA microsphere templates were formed in the SnO2-based powders, which were quite effective in enhancing the acetone and toluene responses. The 0.8 wt% Cu-added pr-SnO2 sensor showed the largest acetone response at 350 °C among all the sensors. Furthermore, we clarified that the addition of CuxO onto the pr-SnO2 decreased the concentration of carrier electrons and the acetone-oxidation activity, leading to the improvement of the acetone-sensing properties of the pr-SnO2 sensor.

In vertebrate embryos, dorsal midline tissues, including the notochord, the prechordal plate, and the floor plate, play important roles in patterning of the central nervous system, somites, and endodermal tissues by producing extracellular signaling molecules, such as Sonic hedgehog (Shh). In Ciona, hedgehog.b, one of the two hedgehog genes, is expressed in the floor plate of the embryonic neural tube, while none of the hedgehog genes are expressed in the notochord. We have identified a cis-regulatory region of hedgehog.b that was sufficient to drive a reporter gene expression in the floor plate. The hedgehog.b cis-regulatory region also drove ectopic expression of the reporter gene in the endodermal strand, suggesting that the floor plate and the endodermal strand share a part of their gene regulatory programs. The endodermal strand occupies the same topographic position of the embryo as does the vertebrate hypochord, which consists of a row of single cells lined up immediately ventral to the notochord. The hypochord shares expression of several genes with the floor plate, including Shh and FoxA, and play a role in dorsal aorta development. Whole-embryo single-cell transcriptome analysis identified a number of genes specifically expressed in both the floor plate and the endodermal strand in Ciona tailbud embryos. A Ciona FoxA ortholog FoxA.a is shown to be a candidate transcriptional activator for the midline gene battery. The present findings suggest an ancient evolutionary origin of a common developmental program for the midline structures in Olfactores.

Abstract Background Immune checkpoint inhibitor therapy has changed the standard drug therapy for relapsed or advanced non-small cell lung cancer; its efficacy is well-recognized by pulmonary physicians, oncologists, and thoracic surgeons. Nivolumab, one of the anti-programmed cell death 1 antibodies, was the first immune checkpoint inhibitor to be approved and is used as a standard second-line regimen for patients with non-small cell lung cancer irrespective of the expression of programmed cell death ligand 1. Programmed cell death 1 antibodies have been generally confirmed to be less toxic than conventional cytotoxic chemotherapy, although unusual immune-related adverse events such as type I diabetes mellitus, adrenal failure, and myasthenia gravis may occur with a very low incidence. A case of severe grade V immune-related thrombocytopenia after two courses of nivolumab as second-line therapy for relapsed non-small cell lung cancer is reported. Case presentation An 82-year-old Japanese woman with relapsed lung adenocarcinoma was treated with nivolumab as second-line systemic therapy at our institute. Her laboratory data indicated thrombocytopenia suspected to be an immune-related adverse event following two courses of nivolumab. Subsequently, she developed a massive pulmonary hemorrhage and left cerebral infarction despite intensive treatment including systemic steroid therapy. Although there have been a few reports of thrombocytopenia caused by nivolumab, this is the first report of grade V thrombocytopenia following administration of nivolumab for relapsed non-small cell lung cancer. Conclusion A very difficult case of grade V immune-related thrombocytopenia after the administration of nivolumab as second-line therapy for relapsed lung adenocarcinoma was described. Immune-related thrombocytopenia is a rare adverse event, but it must be considered a possible complication because it may become critical once it has occurred.

Background & Aims: Oropharyngeal and esophageal squamous cell carcinomas, especially the latter, are a lethal disease, featuring intratumoral cancer cell heterogeneity and therapy resistance. To facilitate cancer therapy in personalized medicine, three-dimensional (3D) organoids may be useful for functional characterization of cancer cells ex vivo. We investigated the feasibility and the utility of patient-derived 3D organoids of esophageal and oropharyngeal squamous cell carcinomas. Methods: We generated 3D organoids from paired biopsies representing tumors and adjacent normal mucosa from therapy-naïve patients and cell lines. We evaluated growth and structures of 3D organoids treated with 5-fluorouracil ex vivo. Results: Tumor-derived 3D organoids were grown successfully from 15 out of 21 patients (71.4%) and passaged with recapitulation of the histopathology of the original tumors. Successful formation of tumor-derived 3D organoids was associated significantly with poor response to presurgical neoadjuvant chemotherapy or chemoradiation therapy in informative patients (P = 0.0357, progressive and stable diseases, n = 10 vs. partial response, n = 6). The 3D organoid formation capability and 5-fluorouracil resistance were accounted for by cancer cells with high CD44 expression and autophagy, respectively. Such cancer cells were found to be enriched in patient-derived 3D organoids surviving 5-fluorouracil treatment. Conclusions: The single cell-based 3D organoid system may serve as a highly efficient platform to explore cancer therapeutics and therapy resistance mechanisms in conjunction with morphological and functional assays with implications for translation in personalized medicine. Keywords: 3D Organoids, Autophagy, CD44, 5-Fluorouracil

Oxytocin (OT) and vasopressin (VP) superfamily neuropeptides are distributed in not only vertebrates but also diverse invertebrates. However, no VPergic innervation of invertebrates has ever been documented. In the ascidian, Ciona intestinalis Type A (Ciona robusta), an OT/VP superfamily peptide was identified, and the Ciona vasopressin (CiVP) induces oocyte maturation and ovulation. In the present study, we characterize the innervation and phenotypes of genetically modified Ciona: CiVP promoter-Venus transgenic and CiVP mutants. CiVP promoter-Venus transgenic Ciona demonstrated that CiVP gene was highly expressed in the cerebral ganglion and several nerves. Fluorescence was also detected in the ovary of young CiVP promoter-Venus transgenic ascidians, suggesting that the CiVP gene is also expressed temporarily in the ovary of young ascidians. Furthermore, a marked decrease of post-vitellogenic (stage III) follicles was observed in the ovary of CiVP mutants, whereas pre-vitellogenic (stage I) and vitellogenic (stage II) follicles were increased in the mutant ovary, compared with that of wildtype Ciona. Gene expression profiles showed that the expression of various genes, including genes related to ovarian follicle growth, was altered in the ovary of CiVP mutants. Altogether, these results indicated that CiVP, mainly as a neuropeptide, plays pivotal roles in diverse biological functions, including growth of early-stage ovarian follicles via regulation of the expression of a wide variety of genes. This is the first report describing a VP gene promoter-transgenic and VP gene-edited invertebrate and also on its gene expression profiles and phenotypes.