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[This corrects the article DOI: 10.1371/journal.pone.0277242.].

ObjectivesWe assessed the diagnostic advantage of dual-energy computed tomography (DECT) over single-energy computed tomography (SECT) to evaluate lipiodol accumulation in target lesions following transcatheter arterial chemoembolization (TACE).MethodsTACE was performed in 10 rabbits in whom the VX2 tumor was implanted in their left liver lobes. The miriplatin-lipiodol mixture was injected into the common hepatic artery. All rabbits were sacrificed 2 days after TACE, and the liver was harvested. CT was performed using both single-energy and dual-energy scan modes. The specimen was stained with Oil Red O to evaluate lipiodol accumulation; this was considered the reference standard. Mutual information (MI) was used to evaluate the significance of radiological-pathological correlation. Estimated iodine content values on iodine material density images were compared with actual values obtained using mass spectroscopy.ResultsMean MI values were 0.69, 0.32, 0.83, 0.72, 0.65, and 0.58 for single-energy scan; iodine density images; and virtual monoenergetic images for energy levels of 40, 60, 80, and 100 keV, respectively. The MI value of the monochromatic image (40 keV) was the highest among all sequences. However, this was not significant compared with the single-energy scan (p = 0.81). A significant correlation was observed between the estimated and actual values of iodine content (Pearson's product moment coefficient = 0.70, p = 0.023).ConclusionMore accurate and quantitative lipiodol evaluation in targeted tumors after TACE can be achieved by applying DECT rather than SECT.

Fabry disease, an X-linked lysosomal storage disorder caused by galactosidase α (GLA) gene mutations, exhibits diverse clinical manifestations, and poses significant diagnostic challenges. Early diagnosis and treatment are crucial for improved patient outcomes, pressing the need for reliable biomarkers. In this study, we aimed to identify miRNA candidates as potential biomarkers for Fabry disease using the KingFisher™ automated isolation method and NanoString nCounter® miRNA detection assay. Clinical serum samples were collected from both healthy subjects and Fabry disease patients. RNA extraction from the samples was performed using the KingFisher™ automated isolation method with the MagMAX mirVanaTM kit or manually using the Qiagen miRNeasy kit. The subsequent NanoString nCounter® miRNA detection assay showed consistent performance and no correlation between RNA input concentration and raw count, ensuring reliable and reproducible results. Interestingly, the detection range and highly differential miRNA between the control and disease groups were found to be distinct depending on the isolation method employed. Nevertheless, enrichment analysis of miRNA-targeting genes consistently revealed significant associations with angiogenesis pathways in both isolation methods. Additionally, our investigation into the impact of enzyme replacement therapy on miRNA expression indicated that some differential miRNAs may be sensitive to treatment. Our study provides valuable insights to identify miRNA biomarkers for Fabry disease. While different isolation methods yielded various detection ranges and highly differential miRNAs, the consistent association with angiogenesis pathways suggests their significance in disease progression. These findings lay the groundwork for further investigations and validation studies, ultimately leading to the development of non-invasive and reliable biomarkers to aid in early diagnosis and treatment monitoring for Fabry disease.

PurposeTo examine the hypothesis that an increase in response of postmenopausal bone to interval walking training (IWT) depends on baseline bone mineral densities (BMDs).MethodsTwo hundred and thirty-four postmenopausal women (64±5 (SD) yr) with no medication for osteoporosis performed 5-month IWT, repeating fast and slow walking at ≥70% and ~40% peak aerobic capacity, respectively, for 3 minutes each per set, ≥5 sets/day, ≥4 days/week. They were recruited from those who had performed IWT ≥6 months before participating in the study so that their physical fitness and lifestyle-related disease symptoms had almost reached a steady state at the time of their participation. We measured BMDs for the lumbar spine (LS), bilateral femoral neck (FN), and bilateral total hip (TH) by dual-energy X-ray absorptiometry (DXA) before and after the intervention. We used a multiple regression analysis to identify significant independent factors for increasing BMDs after the intervention as baseline physical characteristics, exercise intensity, and exercise time during IWT were the candidates. For any bone site where the independent factor identified was singular, we analyzed the relationship between the identified factor vs increases in BMD after the intervention (ΔBMD) by the locally weighted scatterplot smoothing (LOWESS) method.ResultsAlmost all subjects completed the designated protocol with minimal adverse events. We found that significant determinants for increasing BMDs were the baseline BMDs for all bone sites, as well as age and body mass index for TH (all, P0.3).ConclusionsIWT may be of benefit with minimal adverse events to postmenopausal women, although the effects were greater in those with lower baseline BMDs.Trial registrationUMIN000047428. https://rctportal.niph.go.jp/s/detail/um?trial_id=UMIN000047428#.

Narratives posted on the internet by patients contain a vast amount of information about various concerns. This study aimed to extract multiple concerns from interviews with breast cancer patients using the natural language processing (NLP) model bidirectional encoder representations from transformers (BERT). A total of 508 interview transcriptions of breast cancer patients written in Japanese were labeled with five types of concern labels: "treatment," "physical," "psychological," "work/financial," and "family/friends." The labeled texts were used to create a multi-label classifier by fine-tuning a pre-trained BERT model. Prior to fine-tuning, we also created several classifiers with domain adaptation using (1) breast cancer patients' blog articles and (2) breast cancer patients' interview transcriptions. The performance of the classifiers was evaluated in terms of precision through 5-fold cross-validation. The multi-label classifiers with only fine-tuning had precision values of over 0.80 for "physical" and "work/financial" out of the five concerns. On the other hand, precision for "treatment" was low at approximately 0.25. However, for the classifiers using domain adaptation, the precision of this label took a range of 0.40-0.51, with some cases improving by more than 0.2. This study showed combining domain adaptation with a multi-label classifier on target data made it possible to efficiently extract multiple concerns from interviews.

Coccomyxa sp. KJ is a unicellular green microalga that accumulates abundant lipids when cultured under nitrogen-deficient conditions (KJ1) and high nitrogen levels when cultured under nitrogen-sufficient conditions (KJ2). Considering the different characteristics between KJ1 and KJ2, they are expected to have different effects on rumen fermentation. This study aimed to determine the effects of KJ1 and KJ2 on in vitro ruminal fermentation, digestibility, CH4 production, and the ruminal microbiome as corn silage substrate condition. Five treatments were evaluated: substrate only (CON) and CON + 0.5% dry matter (DM) KJ1 (KJ1_L), 1.0% DM KJ1 (KJ1_H), 0.5% DM KJ2 (KJ2_L), and 1.0% DM KJ2 (KJ2_H). DM degradability-adjusted CH4 production was inhibited by 48.4 and 40.8% in KJ2_L and KJ2_H, respectively, compared with CON. The proportion of propionate was higher in the KJ1 treatments than the CON treatment and showed further increases in the KJ2 treatments. The abundances of Megasphaera, Succiniclasticum, Selenomonas, and Ruminobacter, which are related to propionate production, were higher in KJ2_H than in CON. The results suggested that the rumen microbiome was modified by the addition of 0.5-1.0% DM KJ1 and KJ2, resulting in increased propionate and reduced CH4 production. In particular, the KJ2 treatments inhibited ruminal CH4 production more than the KJ1 treatments. These findings provide important information for inhibiting ruminal CH4 emissions, which is essential for increasing animal productivity and sustaining livestock production under future population growth.

Postoperative nausea and vomiting (PONV) is a common adverse effect of anesthesia. Identifying risk factors for PONV is crucial because it is associated with a longer stay in the post-anesthesia care unit, readmissions, and perioperative costs. This retrospective study used artificial intelligence to analyze data of 37,548 adult patients (aged ≥20 years) who underwent surgery under general anesthesia at Tohoku University Hospital from January 1, 2010 to December 31, 2019. To evaluate PONV, patients who experienced nausea and/or vomiting or used antiemetics within 24 hours after surgery were extracted from postoperative medical and nursing records. We create a model that predicts probability of PONV using the gradient tree boosting model, which is a widely used machine learning algorithm in many applications due to its efficiency and accuracy. The model implementation used the LightGBM framework. Data were available for 33,676 patients. Total blood loss was identified as the strongest contributor to PONV, followed by sex, total infusion volume, and patient's age. Other identified risk factors were duration of surgery (60-400 min), no blood transfusion, use of desflurane for maintenance of anesthesia, laparoscopic surgery, lateral positioning during surgery, propofol not used for maintenance of anesthesia, and epidural anesthesia at the lumbar level. The duration of anesthesia and the use of either sevoflurane or fentanyl were not identified as risk factors for PONV. We used artificial intelligence to evaluate the extent to which risk factors for PONV contribute to the development of PONV. Intraoperative total blood loss was identified as the potential risk factor most strongly associated with PONV, although it may correlate with duration of surgery, and insufficient circulating blood volume. The use of sevoflurane and fentanyl and the anesthesia time were not identified as risk factors for PONV in this study.

KOJI AWARENESS is a newly developed self-rating whole-body movement assessment system that includes 11 domains and 22 tests. The primary aim of this study was to investigate the intersession reliability of KOJI AWARENESS, and the secondary aim was to determine whether a fixed bias existed between self-rating and external examiner rating. Fifty university students rated their movement ability in two separate sessions; an external examiner also rated the students' movement ability. Participants were blinded to their scores at the first session as well as the external examiner's rating scores. The primary analysis included examining the intersession reliability of the total score with intraclass correlation coefficients (ICCs). ICC values were interpreted as follows: insufficient, < .7 and sufficient, ≥ .7. To achieve the secondary aim, Bland-Altman analysis was performed. ICC for the intersession reliability was .86 with a 95% confidence interval (CI) of .77 to .92 and a minimum detectable change (MDC) of 5.15. Bland-Altman analysis revealed fixed bias as the 95% CIs of the mean difference between the two different rating scores (-3.49 to -2.43 and -3.94 to -2.98 in the first and second sessions, respectively) did not include 0 in the data of each session. However, no proportional bias was identified because no statistically significant Pearson's correlation (P > .05) was noted between the means of the two methods and the mean difference between the two different methods in each session. This study identified that KOJI AWARENESS has sufficient intersession reliability among relatively young and healthy participants. External examiner rating tended to have lower total scores than self-rating; however, the bias was below the MDC and seemed not to be clinically significant.

The generalization of deep neural network algorithms to a broader population is an important challenge in the medical field. We aimed to apply self-supervised learning using masked autoencoders (MAEs) to improve the performance of the 12-lead electrocardiography (ECG) analysis model using limited ECG data. We pretrained Vision Transformer (ViT) models by reconstructing the masked ECG data with MAE. We fine-tuned this MAE-based ECG pretrained model on ECG-echocardiography data from The University of Tokyo Hospital (UTokyo) for the detection of left ventricular systolic dysfunction (LVSD), and then evaluated it using multi-center external validation data from seven institutions, employing the area under the receiver operating characteristic curve (AUROC) for assessment. We included 38,245 ECG-echocardiography pairs from UTokyo and 229,439 pairs from all institutions. The performances of MAE-based ECG models pretrained using ECG data from UTokyo were significantly higher than that of other Deep Neural Network models across all external validation cohorts (AUROC, 0.913-0.962 for LVSD, p < 0.001). Moreover, we also found improvements for the MAE-based ECG analysis model depending on the model capacity and the amount of training data. Additionally, the MAE-based ECG analysis model maintained high performance even on the ECG benchmark dataset (PTB-XL). Our proposed method developed high performance MAE-based ECG analysis models using limited ECG data.

ObjectivePrior research has implied that promoting sustaining physical activity through nudges is challenging and boosting health literacy is important for the long-term establishment of behaviors. This study aimed to investigate the effects of commitment-based health application on step count and health literacy.MethodsA control experiment was conducted involving employees from companies located in Shizuoka Prefecture, Japan. Participants were divided into three groups: the commitment app group (utilizing a commitment-based application "Minchalle," where teams of around five members were randomly assigned to declare a target step count and report daily step count with pictures), the self-commitment group (individuals declaring a target step count and endeavoring on their own), and the control group (no intervention). Changes in step count and health literacy were examined over one month.ResultsA total of 109 employees from 7 companies participated. The changes in step count were an increase of 893 steps for the commitment app group, 243 steps for the self-commitment group, and 178 steps for the control group, with a significant increase in the commitment app group compared to the control group. Regarding health literacy measures, there was significant progress in four items out of five for the commitment app group compared to the control group, and significant progress in one item for the self-commitment group compared to the control group.ConclusionCommunication within the app teams, such as commitment, sharing photos of their goal achievements and provide encouraging comments to others, functioned as social nudges, suggesting the potential for an immediate increase in step count and long-term behavioral reinforcement through improved health literacy.

PurposeThyrotoxic periodic paralysis (TPP) is characterized by muscle paralysis and significant intracellular potassium movement resulting in hypokalemia. Since TPP is a rare condition, only a few studies have explicated the clinical characteristics of patients with this disease. This study aimed to elucidate the clinical characteristics of patients with TPP by comparing them with those with thyrotoxicosis without paralysis (non-TPP) and sporadic periodic paralysis (SPP).MethodsThis was a single-center retrospective cohort study. Clinical data of patients with hyperthyroidism (n = 62) or periodic paralysis (n = 92) who were emergently admitted to our hospital was extracted from the electronic medical records and analyzed.ResultsAll patients in the TPP group (15 males and 2 females) had Graves' disease, with 14 being newly diagnosed. The average serum potassium level on admission was 2.3±0.75 mEq/L. No significant correlation was observed among serum potassium level, amount of potassium required for normalization, and thyroid hormone levels. The TPP group showed significantly younger age, higher male ratio and body mass index (BMI), and lower serum potassium and phosphorus levels than the non-TPP group, which comprised 36 patients with Graves' disease. No significant differences were observed between the TPP and SPP (n = 11) groups in terms of age, sex, BMI, serum electrolyte levels, potassium requirement for normalization, and recovery time.Main conclusionsConsidering that most patients with TPP have undiagnosed Graves' disease, distinguishing TPP from SPP based on clinical information and course alone is difficult in emergency settings. Therefore, for early detection and launch of specific treatment of Graves' disease, screening for thyroid hormone and anti-thyroid stimulating hormone receptor antibody levels is necessary when treating patients with periodic paralysis.

BackgroundThe International Committee of Medical Journal Editors (ICMJE) has published Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals. These provide a global standard for writing and editing medical articles, including research integrity. However, no study has examined the research integrity-related content of Japanese medical journals' Instructions for Authors. We therefore compared research integrity content in ICMJE member journals with those in the English- and Japanese-language journals of the Japanese Association of Medical Sciences (JAMS).Materials and methodsThis was a descriptive literature study. We obtained Instructions for Authors from English- and Japanese-language journals listed on the JAMS website and the ICMJE member journals listed on the ICMJE website as of September 1, 2021. We compared the presence of 20 topics (19 in the ICMJE Recommendations plus compliance with ICMJE) in the Instructions for Authors, and analyzed the content of the conflict of interest disclosure.ResultsWe evaluated 12 ICMJE member journals, and 82 English-language and 99 Japanese-language subcommittee journals. The median number of topics covered was 10.5 for ICMJE member journals, 10 for English-language journals, and three for Japanese-language journals. Compliance with ICMJE was mentioned by 10 (83%) ICMJE member journals, 75 (91%) English-language journals, and 29 (29%) Japanese-language journals. The ICMJE Conflicts of Interest Disclosure Form was requested by seven (64%) ICMJE member journals, 15 (18%) English-language journals, and one (1%) Japanese-language journal.ConclusionsAlthough the topics in the JAMS English-language journals resembled those in the ICMJE member journals, the median value of ICMJE-related topic inclusion was approximately one-third lower in JAMS Japanese-language journals than in ICMJE member journals. It is hoped that Japanese-language journals whose conflict of interest disclosure policies differ from ICMJE standards will adopt international standards to deter misconduct and ensure publication quality.

This study examines whether the experience of being bullied at school has a long-term impact on three health outcomes in adulthood in Japan: subjective health, mental health, and activity restriction due to health conditions. We employed a random effects model and the Karlson-Holm-Breen method to decompose the total effect of being bullied at school on health inequality into a direct effect and an indirect effect working through intervening factors including education, marriage, economic well-being, and social networks. We used the Japanese Life Course Panel Surveys 2007-2020 (waves 1-14), a nationally representative panel data set that includes 2,260 male and 2,608 female respondents. The results demonstrate that for both men and women, the direct effect of being bullied at school was strong and significant. Bullying experiences in childhood had a long-term impact on health outcomes in adulthood, regardless of social background and mediating factors of education, marriage, economic well-being, and social networks. Bullying victimization increased the risk of poor subjective health, low mental health scores, and activity restriction due to health conditions. Intervening factors (especially economic well-being and friendship) mediated the association between bullying experiences and all health outcomes, but their contributions were modest. Policy measures not only to prevent bullying during childhood but also to alleviate its negative consequences in adulthood should be considered to help people who have encountered adverse childhood experiences.

Pneumonia is a major cause of morbidity and mortality in older adults. In the aging society, screening methods for predicting aspiration pneumonia are crucial for its prevention. Changes in the oropharyngeal morphology and hyoid bone position may increase the risk of aspiration pneumonia. This multicenter study aimed to investigate a simple and effective screening method for predicting dysphagia and aspiration pneumonia. Overall, 191 older adults (aged 65 years or older) were randomly sampled using the simple random sampling technique. Oropharyngeal morphology was assessed using the modified Mallampati classification, which reflects the size of the tongue in the oropharyngeal cavity. The hyoid position was measured as the distance between the menton and laryngeal prominence to evaluate aging-related changes in the muscles of the laryngopharynx. Dysphagia was assessed using the repetitive saliva swallowing test (RSST), which measures the number of swallowing movements in 30 seconds; dysphasia is defined as less than 3 swallowing movements in 30 seconds. The aspiration signs were assessed based on history of choking or coughing reflex during eating or drinking and medical history of pneumonia. The study findings revealed that the modified Mallampati classification was significantly correlated with a medical history of pneumonia. A higher incidence of pneumonia was evident in the lower Mallampati classification, which shows the smaller size of the tongue base in the oropharyngeal cavity. The results of this study suggest that the modified Mallampati classification may be a possible screening method to predict the occurrence of pneumonia.

IntroductionBrain positron emission tomography/computed tomography (PET/CT) scans are useful for identifying the cause of dementia by evaluating glucose metabolism in the brain with F-18-fluorodeoxyglucose or Aβ deposition with F-18-florbetaben. However, since imaging time ranges from 10 to 30 minutes, movements during the examination might result in image artifacts, which interfere with diagnosis. To solve this problem, data-driven brain motion correction (DDBMC) techniques are capable of performing motion corrected reconstruction using highly accurate motion estimates with high temporal resolution. In this study, we investigated the effectiveness of DDBMC techniques on PET/CT images using a Hoffman phantom, involving continuous rotational and tilting motion, each expanded up to approximately 20 degrees.Materials and methodsListmode imaging was performed using a Hoffman phantom that reproduced rotational and tilting motions of the head. Brain motion correction processing was performed on the obtained data. Reconstructed images with and without brain motion correction processing were compared. Visual evaluations by a nuclear medicine specialist and quantitative parameters of images with correction and reference still images were compared.ResultsNormalized Mean Squared Error (NMSE) results demonstrated the effectiveness of DDBMC in compensating for rotational and tilting motions during PET imaging. In Cases 1 and 2 involving rotational motion, NMSE decreased from 0.15-0.2 to approximately 0.01 with DDBMC, indicating a substantial reduction in differences from the reference image across various brain regions. In the Structural Similarity Index (SSIM), DDBMC improved it to above 0.96 Contrast assessment revealed notable improvements with DDBMC. In continuous rotational motion, % contrast increased from 42.4% to 73.5%, In tilting motion, % contrast increased from 52.3% to 64.5%, eliminating significant differences from the static reference image. These findings underscore the efficacy of DDBMC in enhancing image contrast and minimizing motion induced variations across different motion scenarios.ConclusionsDDBMC processing can effectively compensate for continuous rotational and tilting motion of the head during PET, with motion angles of approximately 20 degrees. However, a significant limitation of this study is the exclusive validation of the proposed method using a Hoffman phantom; its applicability to the human brain has not been investigated. Further research involving human subjects is necessary to assess the generalizability and reliability of the presented motion correction technique in real clinical scenarios.

AimThis study aimed to determine whether excessive maternal weight gain during pregnancy was associated with a higher risk of prolonged labor.MethodsWe analyzed the data regarding maternal weight gain during pregnancy for the participants of Japan Environment and Children's Study (JECS), which is an ongoing nationwide prospective birth cohort study in Japan. After excluding participants with multiple pregnancies, with deliveries before 37 or beyond 42 weeks of gestation, or who had undergone cesarean section, 71,154 (nulliparous, n = 28,442) Japanese women were included. Prolonged labor was defined by a cutoff ranking at the 95th percentile and consequently defined as labor duration exceeding 12.7 h in multiparous women and exceeding 23.2 h in nulliparous women. These classifications were made according to labor curves established by the Japanese Society of Obstetrics and Gynecology Perinatal Committee developed in June 2021. Considering that no studies have conducted an investigation based on this new guideline, we analyzed the association between excessive maternal weight gain during pregnancy and prolonged labor by parity.ResultsThe overall incidence of prolonged labor was 10.2% (2,907/28,442) in nulliparous women and 6.1% (2,597/42,712) in multiparous women. Multivariable analysis indicated that excessive maternal weight gain was significantly associated with prolonged labor in nulliparous (adjusted odds ratio, 1.21; 95% confidence interval, 1.10-1.32) and multiparous women (adjusted odds ratio, 1.15; 95% confidence interval, 1.05-1.27). Kaplan-Meier survival analysis showed that as labor progressed, the percentage of women who had not yet delivered was higher among those with excessive maternal weight gain than among those with normal maternal weight gain in both the nulliparous (median labor duration 12.9 h vs 12.2 h, pConclusionExcessive maternal weight gain was significantly associated with prolonged labor in Japanese women.

This study developed and validated a surgical instrument motion measurement system for skill evaluation during practical laparoscopic surgery training. Owing to the various advantages of laparoscopic surgery including minimal invasiveness, this technique has been widely used. However, expert surgeons have insufficient time for providing training to beginners due to the shortage of surgeons and limited working hours. Skill transfer efficiency has to be improved for which there is an urgent need to develop objective surgical skill evaluation methods. Therefore, a simple motion capture-based surgical instrument motion measurement system that could be easily installed in an operating room for skill assessment during practical surgical training was developed. The tip positions and orientations of the instruments were calculated based on the marker positions attached to the root of the instrument. Because the patterns of these markers are individual, this system can track multiple instruments simultaneously and detect exchanges. However due to the many obstacles in the operating room, the measurement data included noise and outliers. In this study, the effect of this decrease in measurement accuracy on feature calculation was determined. Accuracy verification experiments were conducted during wet-lab training to demonstrate the capability of this system to measure the motion of surgical instruments with practical accuracy. A surgical training experiment on a cadaver was conducted, and the motions of six surgical instruments were measured in 36 cases of laparoscopic radical nephrectomy. Outlier removal and smoothing methods were also developed and applied to remove the noise and outliers in the obtained data. The questionnaire survey conducted during the experiment confirmed that the measurement system did not interfere with the surgical operation. Thus, the proposed system was capable of making reliable measurements with minimal impact on surgery. The system will facilitate surgical education by enabling the evaluation of skill transfer of surgical skills.

The aim of this study was to examine the association of insulin resistance (evaluated by the short insulin tolerance test [SITT]) with parameters related to obesity and insulin resistance. We prospectively recruited controls and patients with type 2 diabetes mellitus (T2DM), subjected them to the SITT, and calculated the K indices of the intravenous insulin tolerance test (KITT(iv)) and the subcutaneous insulin tolerance test (KITT(sc)). We compared KITT(iv) results between the volunteers and patients and examined its correlation with KITT(sc). We also examined the association of KITT(iv) with obesity, insulin resistance-related parameters, and the insulin dose required for glycemic control. A total of 24 participants (seven controls and 17 patients with T2DM) were studied. The mean KITT(iv) was significantly lower in patients with T2DM than in the controls (2.5%±2.1% vs. 4.5%±1.8%). In all participants, KITT(iv) was significantly correlated with the homeostasis model assessment for insulin resistance (HOMA-IR) values (r = -0.601, p

ObjectiveTo determine the long-term survival of patients receiving home hemodialysis (HHD) through self-punctured arteriovenous access.MethodsWe conducted an observational study of all patients receiving HHD at our facility between 2001 and 2020. The primary outcome was treatment survival, and it was defined as the duration from HHD initiation to the first event of death or technique failure. The secondary outcomes were the cumulative incidence of technique failure and mortality. Cox proportional hazard models were used to identify the predictive factors for treatment survival.ResultsA total of 77 patients (mean age, 50.7 years; 84.4% male; 23.4% with diabetes) were included. The median dialysis duration was 18 hours per week, and all patients self-punctured their arteriovenous fistula. During a median follow-up of 116 months, 30 treatment failures (11 deaths and 19 technique failures) were observed. The treatment survival was 100% at 1 year, 83.5% at 5 years, 67.2% at 10 years, and 34.6% at 15 years. Age (adjusted hazard ratio [aHR], 1.07) and diabetes (aHR, 2.45) were significantly associated with treatment survival. Cardiovascular disease was the leading cause of death, and vascular access-related issues were the primary causes of technique failure, which occurred predominantly after 100 months from HHD initiation.ConclusionThis study showed a favorable long-term prognosis of patients receiving HHD. HHD can be a sustainable form of long-term kidney replacement therapy. However, access-related technique failures occur more frequently in patients receiving it over the long term. Therefore, careful management of vascular access is crucial to enhance technique survival.

BackgroundPheochromocytoma, or paraganglioma (PPGL), is a tumor that arises from catecholamine-producing chromaffin cells of the adrenal medulla or paraganglion. Systemic therapy, such as the combination of cyclophosphamide, vincristine, and dacarbazine or therapeutic radiopharmaceuticals such as [131I] meta-iodobenzylguanidine (MIBG), may be administered in cases of locally advanced tumors or distant metastases. However, the current therapies are limited in terms of efficacy and implementation. [211At] meta-astatobenzylguanidine (MABG) is an alpha-emitting radionuclide-labeled ligand that has demonstrated remarkable tumor-reducing effects in preclinical studies, and is expected to have a high therapeutic effect on pheochromocytoma cells.MethodsWe are currently conducting an investigator-initiated first-in-human clinical trial to evaluate the pharmacokinetics, safety, and efficacy of [211At] MABG. Patients with locally unresectable or metastatic PPGL refractory to standard therapy and scintigraphically positive [123I] MIBG aggregation are being recruited, and a 3 + 3 dose escalation design was adopted. The initial dose of [211At] MABG is 0.65 MBq/kg, with a dose escalation in a 1:2:4 ratio in each cohort. Dose-limiting toxicity is observed for 6 weeks after a single bolus dose of [211At] MABG, and the patients are observed for 3 months to explore safety and efficacy profiles. The primary endpoint is dose-limiting toxicity to determine both maximum tolerated and recommended doses. The secondary endpoints include radiopharmacokinetics, urinary radioactive excretion rate, urinary catecholamine response rate, objective response rate, progression free survival, [123I] MIBG scintigraphy on reducing tumor accumulation, and quality of life.Trials registrationjRCT2021220012 registered on 17 June 2022.

Trapeziometacarpal osteoarthritis (TMC-OA) reduces the range of motion (ROM) of the thumb. However, the kinematic change achieved through surgical treatment remains unclear. Therefore, to quantify the kinematic change following TMC-OA surgery, we performed a three-dimensional motion analysis of the thumb using an optical motion capture system preoperatively and 1 year postoperatively in 23 patients with TMC-OA scheduled for arthrodesis (AD) or trapeziectomy with suspensionplasty (TS). Eighteen hands of nine healthy volunteers were also included as controls. Both procedures improved postoperative pain and Disability of the Arm, Shoulder and Hand scores, and AD increased pinch strength. The ROM of the base of the thumb was preserved in AD, which was thought to be due to the appearance of compensatory movements of adjacent joints even if the ROM of the TMC joint was lost. TS did not improve ROM. Quantifying thumb kinematic changes following TMC-OA surgery can improve our understanding of TMC-OA treatment and help select surgical procedures and postoperative assessment.

AimTo clarify the efficacy of atezolizumab (ATZ) plus bevacizumab (BEV) as the second-line therapy for patients with unresectable hepatocellular carcinoma (HCC).MethodsThe subjects were 82 patients with HCC receiving ATZ/BEV, including 33 patients with previous therapies with molecular-targeted agents (MTA). Therapeutic efficacy was evaluated using contrast-enhanced CT according to the mRECIST.ResultsThe Child-Pugh scores were 5, 6,7 and 8 in 40, 35, 5 and 2 patients, respectively, and the extents of HCC progression were BCLC stage A, B and C in 3, 31 and 48 patients, respectively. Early therapeutic efficacy was evaluated in 67 patients, and percentages of patients achieving CR/PR/SD/PD until 12 weeks were 3.0%/29.9%/49.3%/17.9%, respectively, indicating ORR of 32.8% and DCR of 82.1%, The ORR was higher in MTA-naïve patients (40.5%) than in those after discontinuation of lenvatinib due to PD (7.7%, P = 0.0410), while the DCR was equivalent between both patients (83.3% vs 80.0%, P = 0.1184), and the multivariate analysis revealed previous MTA therapies with lenvatinib alone as a factor to deteriorate the ORR (HR of 4.846 (P = 0.0619)). The OS rates at 24 and 48 weeks were 86% and 72%, respectively, and the rates did not differ between MTA-naïve and MTA-experienced patients. Multivariate analyses revealed that achievement of CR, PR or SD and peripheral neutrophil/lymphocyte ratio were associated with a favorable outcome (HR of 0.124, PConclusionsATZ/BEV merits consideration even for MTA-experienced patients, since the OS was equivalent to those in MTA-naïve patients despite of an unfavorable early therapeutic efficacy.

The phosphorylation of eukaryotic translational initiation factors has been shown to play a significant role in controlling the synthesis of protein. Viral infection, environmental stress, and growth circumstances cause phosphorylation or dephosphorylation of plant initiation factors. Our findings indicate that casein kinase 2 can phosphorylate recombinant wheat eIFiso4E and eIFiso4G generated from E. coli in vitro. For wheat eIFiso4E, Ser-207 was found to be the in vitro phosphorylation site. eIFiso4E lacks an amino acid that can be phosphorylated at the position corresponding to Ser-209, the phosphorylation site in mammalian eIF4E, yet phosphorylation of eIFiso4E has effects on VPg binding affinity that are similar to those of phosphorylation of mammalian eIF4E. The addition of VPg and phosphorylated eIFiso4F to depleted wheat germ extract (WGE) leads to enhancement of translation of both uncapped and capped viral mRNA. The addition of PABP together with eIFiso4Fp and eIF4B to depleted WGE increases both uncapped and capped mRNA translation. However, it exhibits a translational advantage specifically for uncapped mRNA, implying that the phosphorylation of eIFiso4F hinders cap binding while promoting VPg binding, thereby facilitating uncapped translation. These findings indicate TEV virus mediates VPg-dependent translation by engaging a mechanism entailing phosphorylated eIFiso4Fp and PABP. To elucidate the molecular mechanisms underlying these observed effects, we studied the impact of PABP and/or eIF4B on the binding of VPg with eIFiso4Fp. The inclusion of PABP and eIF4B with eIFiso4Fp resulted in about 2-fold increase in affinity for VPg (Kd = 24 ± 1.7 nM), as compared to the affinity of eIFiso4Fp alone (Kd = 41.0 ± 3.1 nM). The interactions between VPg and eIFiso4Fp were determined to be both enthalpically and entropically favorable, with the enthalpic contribution accounting for 76-97% of the ΔG at 25°C, indicating a substantial role of hydrogen bonding in enhancing the stability of the complex. The binding of PABP to eIFiso4Fp·4B resulted in a conformational alteration, leading to a significant enhancement in the binding affinity to VPg. These observations suggest PABP enhances the affinity between eIFiso4Fp and VPg, leading to an overall conformational change that provides a stable platform for efficient viral translation.

BackgroundIn Japan, preoperative adjuvant chemotherapy followed by surgical resection is the standard treatment for patients with locally advanced esophageal squamous cell carcinoma. However, the risk of recurrence after surgical resection remains high. Although a randomized controlled trial evaluating the efficacy of nivolumab, a fully human monoclonal anti-programmed death 1 antibody, as postoperative adjuvant therapy after neoadjuvant chemoradiotherapy and surgery established its superior efficacy as adjuvant therapy, the efficacy for patients who received preoperative adjuvant chemotherapy has not been demonstrated. This study aims to elucidate the efficacy and safety of nivolumab as postoperative adjuvant therapy for patients with esophageal squamous cell carcinoma after preoperative adjuvant chemotherapy with docetaxel and cisplatin plus 5-fluorouracil followed by surgical resection.MethodsThis study is a multi-institutional, single-arm, Phase II trial. We plan to recruit 130 esophageal squamous cell carcinoma patients, who have undergone preoperative adjuvant chemotherapy with docetaxel and cisplatin plus 5-fluorouracil followed by surgical resection. If the patient did not have a pathological complete response, nivolumab is started as a postoperative adjuvant therapy within 4-16 weeks after surgery. The nivolumab dose is 480 mg/day every four weeks. Nivolumab is administered for up to 12 months. The primary endpoint is disease-free survival; the secondary endpoints are overall survival, distant metastasis-free survival, and incidence of adverse events.DiscussionTo our knowledge this study is the first trial establishing the efficacy of nivolumab as postoperative adjuvant therapy for patients with esophageal squamous cell carcinoma after preoperative adjuvant chemotherapy with docetaxel and cisplatin plus 5-fluorouracil followed by surgical resection. In Japan, preoperative adjuvant chemotherapy followed by surgery is a well-established standard treatment for resectable, locally advanced esophageal squamous cell carcinoma. Therefore, developing an effective postoperative adjuvant therapy has been essential for improving oncological outcomes.

Although sevoflurane is one of the most commonly used inhalational anesthetic agents, the popularity of desflurane is increasing to a level similar to that of sevoflurane. Inhalational anesthesia generally activates and represses the expression of genes related to xenobiotic metabolism and immune response, respectively. However, there has been no comprehensive comparison of the effects of sevoflurane and desflurane on the expression of these genes. Thus, we used a next-generation sequencing method to compare alterations in the global gene expression profiles in the livers of rats subjected to inhalational anesthesia by sevoflurane or desflurane. Our bioinformatics analyses revealed that sevoflurane and, to a greater extent, desflurane significantly activated genes related to xenobiotic metabolism. Our analyses also revealed that both anesthetic agents, especially sevoflurane, downregulated many genes related to immune response.

The Japanese national guidelines recommend significantly lower doses of carvedilol for heart failure with reduced ejection fraction (HFrEF) management than the US guidelines. Using real-world data, we determined whether initial and target doses of carvedilol in Japanese patients (JPNs) differ from those in US patients (USPs), especially in Asian Americans (ASA) and Caucasians (CA), and investigated differences in outcomes. We collected data from the electronic medical records, including demographics, carvedilol dosing, tolerability, cardiac functional indicators like EF, cardiovascular events including all-cause deaths, and laboratory values from the University of California, San Diego Health and Osaka University. JPNs had significantly lower doses (mg/day) of carvedilol initiation (66 USPs composed of 38 CAs and 28 ASAs, 17.1±16.2; 93 JPNs, 4.3±4.2, p

Previous studies have shown that interpregnancy weight fluctuations impact perinatal outcomes. In order to examine this in Japanese women, we analyzed the data of 2,861 women in their first and second pregnancies who delivered singletons between 2000 and 2022. We compared the second pregnancy perinatal outcomes of women whose interpregnancy body mass index (BMI) change was -1 to 1 unit with those of women whose BMI change was < -1 or ≥ 1 unit. An interpregnancy BMI change ≥ 1 unit was associated with an increased risk of developing gestational diabetes mellitus (adjusted odds ratio [aOR], 1.51; 95% confidence interval [CI], 1.18-1.95) and delivering a large for gestational age neonate (aOR, 1.67; 95% CI, 1.15-2.42) but a decreased risk of preterm birth (aOR, 0.66; 95% CI, 0.46-0.95). An interpregnancy BMI change < -1 unit was associated with a decreased risk of developing gestational diabetes mellitus (aOR, 0.51; 95% CI, 0.31-0.85). In a subgroup analysis of three groups divided according to prepregnancy BMI, interpregnancy BMI changes ≥ 1 unit in women with a BMI of < 18.5 kg/m2 before their first pregnancy were associated with a remarkable risk reduction of developing preterm birth (aOR, 0.30; 95% CI, 0.11-0.81). Interpregnancy BMI changes < -1 unit in women with a BMI of ≥ 25 kg/m2 before their first pregnancy were associated with a remarkable risk reduction of developing gestational diabetes mellitus (aOR, 0.33; 95% CI, 0.12-0.88). Weight gain during interpregnancy period was related to an increased risk of gestational diabetes mellitus and delivery of a large-for-gestational-age neonate, whereas weight loss was related to a decreased risk of developing gestational diabetes mellitus. These results indicate the importance of interpregnancy weight control as part of preconception care; therefore, women considering additional pregnancies should be educated on the importance of maintaining a healthy weight.

Bone and soft-tissue sarcomas are rare malignancies with histological diversity and tumor heterogeneity, leading to the lack of a common molecular target. Telomerase is a key enzyme for keeping the telomere length and human telomerase reverse transcriptase (hTERT) expression is often activated in most human cancers, including bone and soft-tissue sarcomas. For targeting of telomerase-positive tumor cells, we developed OBP-301, a telomerase-specific replication-competent oncolytic adenovirus, in which the hTERT promoter regulates adenoviral E1 gene for tumor-specific viral replication. In this study, we present the diagnostic potential of green fluorescent protein (GFP)-expressing oncolytic adenovirus OBP-401 for assessing virotherapy sensitivity using bone and soft-tissue sarcomas. OBP-401-mediated GFP expression was significantly associated with the therapeutic efficacy of OBP-401 in human bone and soft-tissue sarcomas. In the tumor specimens from 68 patients, malignant and intermediate tumors demonstrated significantly higher expression levels of coxsackie and adenovirus receptor (CAR) and hTERT than benign tumors. OBP-401-mediated GFP expression was significantly increased in malignant and intermediate tumors with high expression levels of CAR and hTERT between 24 and 48 h after infection. Our results suggest that the OBP-401-based GFP expression system is a useful tool for predicting the therapeutic efficacy of oncolytic virotherapy on bone and soft-tissue sarcomas.

Reconstruction of the biliary system is indispensable for the regeneration of transplantable liver grafts. Here, we report the establishment of the first continuous three-dimensional biliary system scaffold for bile acid excretion using a novel method. We confirmed the preservation of the liver-derived extracellular matrix distribution in the scaffold. In addition, hepatocyte progenitors decellularized via the bile duct by slow-speed perfusion differentiated into hepatocyte- and cholangiocyte-like cells, mimicking hepatic cords and bile ducts, respectively. Furthermore, qRT-PCR demonstrated increased ALB, BSEP, and AQP8 expression, revealing bile canaliculi- and bile duct-specific genetic patterns. Therefore, we concluded that locally preserved extracellular matrices in the scaffold stimulated hepatic progenitors and provided efficient differentiation, as well as regeneration of a three-dimensional continuous biliary system from hepatic cords through bile ducts. These findings suggest that organ-derived scaffolds can be utilized for the efficient reconstruction of functional biliary systems.

Atlanto-axial instability is a common disease that affects toy-breed dogs. Most cases of atlanto-axial instability are congenital. Furthermore, patients with atlanto-axial instability are predisposed to other concurrent diseases. Therefore, this study aimed to retrospectively determine the presence of concurrent diseases in cases with atlanto-axial instability using imaging data and analyze the relationship between clinical parameters and the incidence of complex malformations. The clinical data and imaging findings of 41 toy-breed dogs diagnosed with atlanto-axial instability were analyzed using their medical records and imaging data. Occipital dysplasia (17/27), atlanto-occipital overlapping (22/34), dens dysplasia (27/41), Chiari-like malformation (8/34), syringomyelia (5/34), lateral ventricular enlargement (20/36), and intracranial arachnoid cyst (5/35) were observed in patients with atlanto-axial instability. The body weight of the patients in the groups with atlanto-occipital overlapping and lateral ventricular enlargement was lower than that of those in the groups without these diseases (1.78 ± 0.71 vs 2.71 ± 1.15 kg, P = 0.0269, 1.60 ± 0.40 vs 2.75 ± 1.08 kg, P = 0.001, respectively). Furthermore, when the correlation between the total number of concurrent diseases and the age at onset and body weight was examined, it became clear that lower body weight was associated with the incidence of a greater number of concurrent diseases. Thus, the findings of this study suggest that toy-breed dogs are more likely to present with complex malformations and should be evaluated carefully with additional examinations and treatment methods.

BackgroundIt has been shown that serum brain-derived neurotrophic factor (BDNF) is associated with skeletal muscle energy metabolism and that BDNF is a predictor of mortality in heart failure patients. However, little is known about the relationship between BDNF and cardiac rehabilitation (CR). Therefore, this study retrospectively investigated the effects of baseline serum BDNF levels on the CR-induced exercise capacity improvement in patients with cardiovascular disease (CVD).MethodsWe assigned 99 CVD patients (mean age 71±12 years, male = 60) to Low, Middle, and High groups based on the tertiles of baseline BDNF levels. Cardiopulmonary exercise testing was done using supervised bicycle ergometer twice before and after 3 weeks of CR. Analysis of covariance (ANCOVA) followed by post-hoc analysis using Tukey's HSD test was conducted to assess the multivariate associations between baseline BDNF levels categorized by BDNF tertiles (as independent variable) and %increases in AT and peak VO2 after 3-week CR (as dependent variables) after adjustment for age and gender (as covariates), as a main statistical analysis of the present study.ResultsThe higher the baseline BDNF levels, the better nutritional status evaluated by the CONUT score (pConclusionsLow baseline BDNF levels were associated with malnutrition in CVD patients. A positive association between baseline BDNF levels and CR-induced increases in peak VO2 was found. It was suggested that CVD patients with low baseline BDNF levels may be poor responders to CR.

This study investigated the effects of animated food consumption on human psychology. We developed a movable, edible robot and evaluated the participants' impressions induced by the visualization of its movements and eating of the robot. Although several types of edible robots have been developed, to the best of our knowledge, the psychological effects associated with the eating of a robot have not been investigated. We developed a pneumatically driven edible robot using gelatin and sugar. We examined its perceived appearance and the participants' impressions when it was eaten. In the robot-eating experiment, we evaluated two conditions: one in which the robot was moved and one in which it was stationary. Our results showed that participants perceived the moving robot differently from the stationary robot, leading to varied perceptions, when consuming it. Additionally, we observed a difference in perceived texture when the robot was bitten and chewed under the two conditions. These findings provide valuable insights into the practical applications of edible robots in various contexts, such as the medical field and culinary entertainment.

The development of diabetes mellitus (DM) after living donor kidney transplantation (KT) is a risk factor for worsening transplant kidney function, cardiac disease, and cerebrovascular disease, which may affect prognosis after KT. At our institution, all patients' glucose tolerance is evaluated perioperatively by oral glucose tolerance tests (OGTTs) at pre-KT, and 3, 6, and 12 month (mo.) after KT. We analyzed the insulinogenic index (ISI) and homeostasis model assessment beta cell (HOMA-β) based on the immunoreactive insulin (IRI) levels to determine how glucose tolerance changed after KT in 214 patients who had not been diagnosed with DM before KT. In addition, we analyzed the body mass index (BMI) which may also influence glucose tolerance after KT. The concentration of tacrolimus (TAC) in blood was also measured as the area under the curve (AUC) to examine its effects at each sampling point. The preoperative-OGTTs showed that DM was newly diagnosed in 22 of 214 patients (10.3%) who had not been given a diagnosis of DM by the pre-KT fasting blood sugar (FBS) tests. The glucose tolerance was improved in 15 of 22 DM patients at 12 mo. after KT. ISI and IRI deteriorated only at 3 mo. after KT but improved over time. There was a trend of an inverse correlation between HOMA-β and TAC-AUC. We also found inverse correlations between IRI and an increase in BMI from 3 to 12 mo. after KT. Early corticosteroid withdrawal or the steroid minimization protocol with tacrolimus to maintain a low level of diabetogenic tacrolimus and BMI decrease after KT used by our hospital individualizes lifestyle interventions for each patient might contribute to an improvement in post-KT glucose tolerance.

BackgroundIt is shown that the postoperative adjuvant chemotherapy for non-small cell lung cancer (NSCLC) was associated with survival benefit in an elderly population. We aimed to analyze the feasibility and efficacy of alternate-day S-1, an oral fluoropyrimidine, for adjuvant chemotherapy in elderly patients with completely resected pathological stage IA (tumor diameter > 2 cm) to IIIA (UICC TNM Classification of Malignant Tumours, 7th edition) NSCLC.MethodsElderly patients were randomly assigned to receive adjuvant chemotherapy for one year consisting of either alternate-day oral administration of S-1 (80 mg/m2/day) for 4 days a week (Arm A) or a daily oral administration of S-1 (80 mg/m2/day) for 14 consecutive days followed by 7-day rest (Arm B). The primary endpoint was feasibility (treatment completion rate), which was defined as the proportion of patients who completed the allocated intervention for 6 months with a relative dose intensity (RDI) of 70% or more.ResultsWe enrolled 101 patients in which 97 patients received S-1 treatment. The treatment completion rate at 6 months was 69.4% in Arm A and 64.6% in Arm B (p = 0.67). Treatment completion rate in Arm B tended to be lower compared to Arm A, as the treatment period becomes longer (at 9 and 12 months). RDI of S-1 at 12 months and completion of S-1 administration without dose reduction or postponement at 12 months was significantly better in Arm A than in Arm B (p = 0.026 and p < 0.001, respectively). Among adverse events, anorexia, skin symptoms and lacrimation of any grade were significantly more frequent in Arm B compared with Arm A (p = 0.0036, 0.023 and 0.031, respectively). The 5-year recurrence-free survival rates were 56.9% and 65.7% for Arm A and B, respectively (p = 0.22). The 5-year overall survival rates were 68.6% and 82.0% for Arm A and B, respectively (p = 0.11).ConclusionAlthough several adverse effects were less frequent in Arm A, both alternate-day and daily oral administrations of S-1 were demonstrated to be feasible in elderly patients with completely resected NSCLC.Trial registrationUnique ID issued by UMIN: UMIN000007819 (Date of registration: Apr 25, 2012) https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000009128. Trial ID issued by jRCT: jRCTs061180089 (Date of registration: Mar 22, 2019, for a shift toward a "specified clinical trial" based on Clinical Trials Act in Japan) https://jrct.niph.go.jp/en-latest-detail/jRCTs061180089.

Colorectal cancer (CRC) cells harboring KRAS or BRAF mutations show a more-malignant phenotype than cells with wild-type KRAS and BRAF. KRAS/BRAF-wild-type CRCs are sensitive to epidermal growth factor receptor (EGFR)-targeting agents, whereas KRAS/BRAF-mutant CRCs are resistant due to constitutive activation of the EGFR-downstream KRAS/BRAF signaling pathway. Novel therapeutic strategies to treat KRAS/BRAF mutant CRC cells are thus needed. We recently demonstrated that the telomerase-specific replication-competent oncolytic adenoviruses OBP-301 and p53-armed OBP-702 exhibit therapeutic potential against KRAS-mutant human pancreatic cancer cells. In this study, we evaluated the therapeutic potential of OBP-301 and OBP-702 against human CRC cells with differing KRAS/BRAF status. Human CRC cells with wild-type KRAS/BRAF (SW48, Colo320DM, CACO-2), mutant KRAS (DLD-1, SW620, HCT116), and mutant BRAF (RKO, HT29, COLO205) were used in this study. The antitumor effect of OBP-301 and OBP-702 against CRC cells was analyzed using the XTT assay. Virus-mediated modulation of apoptosis, autophagy, and the EGFR-MEK-ERK and AKT-mTOR signaling pathways was analyzed by Western blotting. Wild-type and KRAS-mutant CRC cells were sensitive to OBP-301 and OBP-702, whereas BRAF-mutant CRC cells were sensitive to OBP-702 but resistant to OBP-301. Western blot analysis demonstrated that OBP-301 induced autophagy and that OBP-702 induced autophagy and apoptosis in human CRC cells. In BRAF-mutant CRC cells, OBP-301 and OBP-702 suppressed the expression of EGFR, MEK, ERK, and AKT proteins, whereas mTOR expression was suppressed only by OBP-702. Our results suggest that p53-armed oncolytic virotherapy is a viable therapeutic option for treating KRAS/BRAF-mutant CRC cells via induction of autophagy and apoptosis.

Lactate, which is synthesized as an end product by lactate dehydrogenase A (LDHA) from pyruvate during anaerobic glycolysis, has attracted attention for its energy metabolism and oxidant effects. A novel histone modification-mediated gene regulation mechanism termed lactylation by lactate was recently discovered. The present study examined the involvement of histone lactylation in undifferentiated cells that underwent differentiation into osteoblasts. C2C12 cells cultured in medium with a high glucose content (4500 mg/L) showed increases in marker genes (Runx2, Sp7, Tnap) indicating BMP-2-induced osteoblast differentiation and ALP staining activity, as well as histone lactylation as compared to those cultured in medium with a low glucose content (900 mg/L). Furthermore, C2C12 cells stimulated with the LDH inhibitor oxamate had reduced levels of BMP-2-induced osteoblast differentiation and histone lactylation, while addition of lactate to C2C12 cells cultured in low glucose medium resulted in partial restoration of osteoblast differentiation and histone lactylation. These results indicate that lactate synthesized by LDHA during glucose metabolism is important for osteoblast differentiation of C2C12 cells induced by BMP-2. Additionally, silencing of p300, a possible modifier of histone lactylation, also inhibited osteoblast differentiation and reduced histone lactylation. Together, these findings suggest a role of histone lactylation in promotion of undifferentiated cells to undergo differentiation into osteoblasts.

Experimental verification of impairment to cognitive abilities and cognitive dysfunction resulting from inorganic arsenic (iAs) exposure in children and adults is challenging. This study aimed to elucidate the effects of arsenite (iAsIII; 1, 10 and 20 μM) or monomethylarsonous acid (MMAIII; 0.1, 1 and 2 μM) exposure on arsenic metabolism and tight junction (TJ) function in the blood-brain barrier (BBB) using a rat in vitro-BBB model. The results showed that a small percentage (~15%) of iAsIII was oxidized or methylated within the BBB, suggesting the persistence of toxicity as iAsIII. Approximately 65% of MMAIII was converted to low-toxicity monomethylarsonic acid and dimethylarsenic acid via oxidation and methylation. Therefore, it is estimated that MMAIII causes TJ injury to the BBB at approximately 35% of the unconverted level. TJ injury of BBB after iAsIII or MMAIII exposure could be significantly assessed from decreased expression of claudin-5 and decreased transepithelial electrical resistance values. TJ injury in BBB was found to be significantly affected by MMAIII than iAsIII. Relatedly, the penetration rate in the BBB by 24 h of exposure was higher for MMAIII (53.1% ± 2.72%) than for iAsIII (43.3% ± 0.71%) (p < 0.01). Exposure to iAsIII or MMAIII induced an antioxidant stress response, with concentration-dependent increases in the expression of nuclear factor-erythroid 2-related factor 2 in astrocytes and heme oxygenase-1 in a group of vascular endothelial cells and pericytes, respectively. This study found that TJ injury at the BBB is closely related to the chemical form and species of arsenic; we believe that elucidation of methylation in the brain is essential to verify the impairment of cognitive abilities and cognitive dysfunction caused by iAs exposure.

IntroductionIn the current era of the severe acute respiratory syndrome-coronavirus-2 epidemic, the need for respiratory care, including mechanical ventilatory (MV) management, has increased. However, there are no well-developed educational strategies for training medical personnel dealing with respiratory care in MV management.MethodsA novel mixed-methods hands-on seminar for learning MV management was conducted for the residents at Chiba University Hospital in March 2022. The seminar lasted approximately 2 hours. The learning goal for the residents was to develop skills and knowledge in performing basic respiratory care, including MV, during an outbreak of a respiratory infection. The seminar with a flipped classroom consisted of e-learning, including modules on respiratory physiology and MV management, hands-on training with a low-fidelity simulator (a lung simulator), and hands-on training with a high-fidelity simulator (a human patient simulator). The effectiveness of the seminar was evaluated using closed questions (scored on a five-point Likert scale: 1 [minimum] to 5 [maximum]) and multiple-choice questions (maximum score: 6) at the pre- and post-seminar evaluations.ResultsFourteen residents at Chiba University Hospital participated in the program. The questionnaire responses revealed that the participants' motivation for learning about MV was relatively high in the pre-seminar period (seven participants [50%] selected level 5 [very strong]), and it increased in the post-seminar period (all participants selected level 5) (p = 0.016). The responses to the multiple-choice questions revealed that the participants did not have enough knowledge to operate a mechanical ventilator, while the total score significantly improved from the pre- to post-seminar period (pre-seminar: 3.3 ± 1.1, post-seminar: 4.6 ± 1.0, p = 0.003).ConclusionsThe seminar implemented in this study helped increase the residents' motivation to learn about respiratory care and improved knowledge of MV management in a short time. In particular, the flipped classroom may promote the efficiency of education on MV management.

People with communication difficulties encounter several challenges in their daily online interactions, such as a limited right to talk (RoT), insufficient social support (SS), and a low sense of being attended to (SoBA). Computer-mediated technologies are limited in addressing such problems owing to their limited capacity in transferring verbal and nonverbal cues between users. In this study, to address the limited RoT, low SS, and low SoBA challenges, we proposed a robotic video conference system with two teleoperated robot avatars. The proposed system was compared with another robotic video conference system that adopts only one teleoperated robot avatar. In the field experiment, 37 participants took part in two discussion sessions using each system type, where RoT, SS, and SoBA were adopted as the measured indices. The proposed system significantly increased the users' RoT and SS compared with other robotic video conference systems. This study contributes to the literature by demonstrating the effect exerted by the type of robotic video conference adopted on users' feelings about RoT, SS, and SoBA.

Rabbit anti-asialo-GM1 (ASGM1) serum or polyclonal antibodies can eliminate mouse splenic natural killer (NK) cell activity in vitro and in vivo. We developed rabbit monoclonal antibodies (mAbs) against ASGM1 using a single-cell analysis and isolation system. Five mAbs (GA109, GA115, GA116, GA131, and GA134) that were reactive to ASGM1 were isolated from the spleen lymphocytes of rabbits immunized with ASGM1. Enzyme-linked immunosorbent assay and thin-layer chromatography immunostaining results showed that the mAbs strongly reacted with ASGM1. Two mAbs (GA116 and GA134) reacted exclusively with ASGM1, whereas three mAbs (GA109, GA115, and GA131) showed slight or considerable cross-reactivity with GM1. The administration of the mAbs (4-20 μg) to BALB/c mice completely abolished NK cell activity in vivo. The anti-ASGM1 rabbit mAbs obtained in this study may provide a useful and reproducible tool for various future studies, such as depleting NK cell activity to enhance xenograft engraftment in mouse models.

Immune checkpoint inhibitors (ICIs) have been developed for canine tumour treatment, and pilot clinical studies have demonstrated their antitumour efficacy in dogs with oral malignant melanoma (OMM). Although ICIs have been approved for various human malignancies, their clinical benefits in other tumour types remain to be elucidated in dogs. Here, we conducted a clinical study of c4G12, a canine chimeric anti-PD-L1 antibody, to assess its safety and efficacy in dogs with various advanced malignant tumours (n = 12) at the Veterinary Teaching Hospital of Hokkaido University from 2018 to 2023. Dogs with digit or foot pad malignant melanoma (n = 4), osteosarcoma (n = 2), hemangiosarcoma (n = 1), transitional cell carcinoma (n = 1), nasal adenocarcinoma (n = 1), B-cell lymphoma (n = 1), or undifferentiated sarcoma (n = 2) were treated with 2 or 5 mg/kg c4G12 every 2 weeks. Treatment-related adverse events of any grade were observed in eight dogs (66.7%), including elevated aspartate aminotransferase (grade 3) in one dog (8.3%) and thrombocytopenia (grade 4) in another dog (8.3%). Among dogs with target disease at baseline (n = 8), as defined by the response evaluation criteria for solid tumours in dogs (cRECIST), one dog with nasal adenocarcinoma and another with osteosarcoma experienced a partial response (PR), with an objective response rate of 25.0% (2 PR out of 8 dogs; 95% confidence interval: 3.2-65.1%). These results suggest that c4G12 is safe and tolerable and shows antitumor effects in dogs with malignant tumours other than OMM. Further clinical studies are warranted to identify the tumour types that are most likely to benefit from c4G12 treatment.

In this study, a novel rat model of knee joint adhesion was developed, and its formation was analyzed quantitatively over time. Thirty-nine Wistar rats were randomly divided into intact control (n = 3) and experimental (n = 36) groups. The latter was equally divided into three groups according to the experimental intervention: fixed with deep bending of the knee joint (group I), fixed after incision of the capsule (group II), and fixed after exposure of the patellofemoral joint to artificial patellar subluxation (group III). All rats were subdivided according to their joint immobilization period (1, 2, or 4 weeks). Thereafter, the limited range of motion of the knee joint with (limited knee range of motion) and without (limited knee joint intrinsic range of motion) skin and muscles were measured. The lengths of adhesions of the anterior knee joint and posterior capsules were evaluated histologically. The limited intrinsic range of motion of the knee joint was found to be increased in groups II and III compared to that in group I 4 weeks after immobilization. Adhesions were confirmed within 1 week after immobilization in groups II and III. The length of the adhesions in group III was significantly longer than in other groups at 2 weeks and remained longer than in group I at 4 weeks. This model may contribute to the assessment of the adhesion process and development of new therapeutic avenues following trauma or surgical invasion.